Sulfonimide amide compounds and uses thereof

Abstract

Described herein is sulfonimide amide compound, its solvate, its tautomer and the above-mentioned pharmaceutically acceptable salt.Further described herein is the method of using said compound, solvate, tautomer or its pharmaceutically acceptable salt to treat the disorder of the subject who needs treatment, such as NLRP3-mediated disorder.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of China priority application PCT / CN 2021 / 107085, filed on July 19, 2021, and China priority application PCT / CN 2022 / 077518, filed on February 23, 2022, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates to sulfonimide amide compounds as described herein and their use in treating disorders responsive to modulation of cytokines (such as IL-1β and IL-18), modulation of NLRP3, or inhibition of activation of NLRP3 or related components of the inflammatory process. [Background technology]

[0003] The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of inflammatory processes and its aberrant activity is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), as well as complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis.

[0004] NLRP3 is an intracellular receptor protein that senses certain inflammatory signals. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). The NLRP3-ASC complex then polymerizes to form large aggregates known as ASC specks. The polymerized NLRP3-ASC then 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 proinflammatory cytokines IL-1β and IL-18 to yield their active forms, mediating a type of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to trigger apoptotic cell death.

[0005] Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to cause pyroptosis. Through its control of the pyroptosis cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation, allowing IL-1α to be liberated. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathways, can contribute to caspase-1-dependent inflammation.

[0006] NLRP3-dependent ASC specks are released into the extracellular environment where they can activate caspase-1, induce processing of caspase-1 substrates, and propagate inflammation. Thus, NLPR3 inhibitors may affect these downstream inflammatory processes.

[0007] Active cytokines derived from NLRP3 inflammasome activation are key drivers of inflammation and interact with other cytokine pathways to shape immune responses to infection and injury. For example, IL-1β signaling induces secretion of the proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th17 cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also act synergistically to induce IFN-γ production from memory T cells and NK cells that drive Th1 responses.

[0008] Other intracellular pattern recognition receptors (PRRs) can also form inflammasomes. These include other NLR family members such as NLRP1 and NLRC4, as well as non-NLR PRRs such as double-stranded DNA (dsDNA) sensor absent in melanoma 2 (AIM2) and interferon, gamma-inducible protein 16 (IFI16). NLRP3-dependent IL-1β processing can also be activated by an indirect non-canonical pathway downstream of caspase-11.

[0009] The inherited CAPS disorders Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease are caused by gain-of-function mutations in NLRP3, thus defining it as a key component of the inflammatory process. NLRP3 is also involved in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, among others.

[0010] The role of NLRP3 in diseases of the central nervous system is becoming clear, and lung diseases have also been shown to be influenced by NLRP3. In addition, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations were defined using mice with constitutive NLRP3 activation, but insights into the specific activation of NLRP3 in these diseases also exist. In type 2 diabetes, deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0011] There is a need to provide compounds and pharmaceutical compositions that have improved pharmacological and / or physiological and / or physicochemical properties and / or that offer useful alternatives to known compounds and pharmaceutical compositions. Summary of the Invention

[0012] In some embodiments, provided herein is a compound selected from the group consisting of: TIFF2024528656000002.tif237170TIFF2024528656000003.tif250170TIFF2024528656000004.t if240170TIFF2024528656000005.tif209170TIFF2024528656000006.tif239170TIFF20245286560 00007.tif235170TIFF2024528656000008.tif239170TIFF2024528656000009.tif245170TIFF2024528656000010.tif244170TIFF2024528656000011.tif132170 or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0013] [Figure 1]1 is a graph plotting percent human PXR activation vs. IC90 at 10 μM in human whole blood (μM) for two compounds of the present disclosure, compounds 2 and 6, compared to other sulfonimide amide (SIA) compounds. [Diagram 2] 1 is a graph plotting rat bioavailability (%) versus IC90 in human whole blood (μM) for two compounds of the present disclosure, compounds 2 and 6, compared to other sulfonimide amide (SIA) compounds. [Diagram 3] 1 is a graph plotting rat half-life (h) versus IC90 in human whole blood (μM) for two compounds of the present disclosure, compounds 2 and 6, compared to other sulfonimide amide (SIA) compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition The compounds described herein (or solvates or pharma- ceutically acceptable salts thereof) can exist in one or more stereoisomeric forms (e.g., containing one or more asymmetric carbon atoms). Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the subject matter disclosed herein. Similarly, it is understood that a compound or salt can exist in tautomeric forms other than those shown in its formula, which are also included within the scope of the subject matter disclosed herein. It is understood that the subject matter disclosed herein includes combinations and subsets of the specific groups described herein. Unless otherwise specified, the scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. It is understood that the subject matter disclosed herein includes combinations and subsets of the specific groups defined herein.

[0015] Unless otherwise specified, the subject matter disclosed herein also includes isotopically labeled forms of the compounds described herein, e.g., in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein (as well as tautomers and pharma- ceutically acceptable salts of the foregoing) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I can be mentioned.

[0016] As used herein, the terms "including," "containing," and "comprising" are used in their open-ended sense.

[0017] As used in this disclosure, the articles "a" and "an" can refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. For example, "an element" can mean one element or more than one element.

[0018] A "patient" or "subject" can include both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates, such as chimpanzees, monkeys, baboons, or rhesus monkeys, as well as other ape and monkey species; livestock animals, such as cows, horses, sheep, goats, and pigs; companion animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. A "patient" or "subject" can include both humans and animals. In some embodiments, the patient or subject is a human.

[0019] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound (or a tautomer, solvate or pharma- ceutically acceptable salt thereof) or pharmaceutical composition sufficient to produce a desired therapeutic outcome, such as reducing the severity of the duration of a disorder, stabilizing the severity of a disorder, or eliminating one or more signs, symptoms, or causes of a disorder. With respect to therapeutic use, beneficial or desirable results may include, for example, a reduction in one or more (biochemical, histological, and / or behavioral) symptoms caused by a disorder, including complications and intermediate pathological phenotypes that appear during the progression of a disorder, an increase in the quality of life of a subject suffering from a disorder, a reduction in the dose of other medications required to treat the disorder, an enhancing effect of another medication, a delay in the progression of a disorder, and / or an extension of the subject's survival.

[0020] The term "additive" as used herein refers to an inert or inactive substance that may be used in the manufacture of a drug or pharmaceutical composition, such as a tablet containing a compound (or a solvate, tautomer, or pharma- ceutically acceptable salt) described herein as an active ingredient. A variety of substances may be encompassed by the term additive, including, but not limited to, any substance used as a diluent, filler or bulking agent, binder, disintegrant, wetting agent, coating, emulsifier or dispersant, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulator. In some cases, the term "additive" encompasses a pharma- ceutically acceptable carrier.

[0021] "Pharmaceutically acceptable salts" include salts that are generally safe and not biologically or otherwise undesirable, and include those that are acceptable for veterinary and human pharmaceutical use. Such salts can be prepared by any suitable method, such as treating a free acid with an inorganic or organic base (e.g., if the compound or its tautomer is a free acid) or treating a free base with an inorganic or organic acid (e.g., if the compound or its tautomer is a free base). Suitable pharmaceutically acceptable salts can include, for example, those derived from inorganic acids, organic acids, pyranosidyl acids, amino acids, aromatic acids, sulfonic acids, and the like. Suitable pharmaceutically acceptable salts can also include, for example, those derived from organic bases (e.g., amines, e.g., primary, secondary, or tertiary amines), alkali metal hydroxides or alkaline earth metal hydroxides, and the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (such as glycine or arginine); ammonia; primary, secondary and tertiary amines; cyclic amines (such as piperidine, morpholine, piperazine); and inorganic salts.

[0022] As used herein, numerical ranges can include consecutive integers. For example, a range expressed as "from 0 to 5" includes 0, 1, 2, 3, 4, and 5.

[0023] The present disclosure relates to the compounds described herein and their tautomers, solvates and pharmaceutically acceptable salts.The use of the terms "pharmaceutically acceptable salts", "solvates" and "tautomers" is intended to apply equally to the tautomers, solvates, pharmaceutically acceptable salts of the compounds disclosed herein.Thus, for example, the compounds described herein or their solvates, tautomers or pharmaceutically acceptable salts include the pharmaceutically acceptable salts of the solvates of the compounds; and the tautomers of the solvates of the compounds; and the pharmaceutically acceptable salts of the tautomers of the compounds, etc.

[0024] The compounds of the present disclosure may exist as solvates. The term "solvate" may refer to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of the present disclosure, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally called hydrates. Hydrates may include compositions that contain stoichiometric amounts of water and compositions that contain variable amounts of water.

[0025] As used herein, the term "treat" or "treatment" is meant to refer to postponing the onset of one or more disorders; preventing the onset of one or more disorders; and / or reducing the severity of one or more symptoms of a disorder that will or is expected to develop. Thus, these terms can include alleviating one or more existing symptoms of a disorder; preventing one or more further symptoms; alleviating or preventing the underlying cause of one or more symptoms; inhibiting a disorder, e.g., halting the progression of a disorder; alleviating a disorder; inducing relapse of a disorder; alleviating a symptom caused by a disorder; or halting or alleviating a symptom of a disorder.

[0026] As used herein, the term "about," when referring to a value, is meant to encompass variations from the specified amount, for example, in some embodiments, ±20%, in some embodiments, ±10%, in some embodiments, ±5%, in some embodiments, ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1%, such variations being appropriate for practicing the disclosed methods or using the disclosed compositions.

[0027] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of the range, and any other stated or intervening value within that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges, which may be independently included in smaller ranges, are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0028] Issues with sulfonimidamide compounds Compounds with a sulfonimidamide (SIA) core structure are attractive options for inhibition of the NLRP3 pathway. They generally exhibit high potency compared to other NLPR3 inhibitor compound scaffolds and are synthetically available. However, potency, although important, is not the only factor required for an effective and safe therapy for human administration. Biological systems are complex, and real-world patients often have additional health considerations and medications. Thus, important parameters to consider in drug development include the risk of drug-drug interactions (DDIs) and the expected human dose.

[0029] DDI risk may be particularly impactful when developing pharmaceutical compounds to treat chronic conditions, or in certain patient populations, or both. Chronic conditions, by their nature, require long-term administration of therapeutic agents that may overlap with administration of other drugs. Certain patient populations may be more likely to be taking additional drugs, such as to control other symptoms of disease or to treat comorbidities that may occur at a higher rate in the population. Thus, balancing potency with DDI risk may be crucial for patient safety. One way to assess DDI risk is through the effect of the compound on the pregnane xenobiotic receptor (PXR), a receptor that mediates the expression of enzymes, including CYP3A4, the main CYP enzyme that metabolizes drugs in the liver and intestine. Activation of PXR leads to higher expression levels of CYP3A4. Since CYP3A4 is involved in the metabolic clearance of a wide range of current pharmaceutical drugs, increased expression of CYP3A4 may lead to increased metabolic clearance and subsequent reduced efficacy of co-administered medications. As a result, promising drug candidates that exhibit high PXR activation, despite high potency against their intended targets, may be considered too dangerous to be administered long-term or with other medications in humans.

[0030] Projected human dose may also be an important factor. The human dose required to obtain effective plasma levels may be influenced by factors including bioavailability and in vivo half-life (which affect how much of the drug enters the blood system and for how long) and is specific to each compound. Even if a compound exhibits high potency in vitro, low bioavailability, short in vivo half-life, or both, there is a risk of toxicity and poor patient compliance due to the required drug doses being very high and / or very frequent. Bioavailability is the amount of drug that enters the bloodstream after administration, such as oral administration. Drugs with low bioavailability, even if very potent and with low DDI risk, may require high doses to get enough drug in the blood for efficacy. In vivo half-life relates to the time it takes for the drug to leave the bloodstream via mechanisms such as excretion (e.g., via the kidneys) or metabolism (e.g., broken down by liver enzymes). Drugs with short half-lives may need to be administered more frequently to maintain sufficient plasma levels for biological action. Even if highly potent, with low DDI risk and good bioavailability, drugs with short half-lives may require multiple daily dosing to maintain effective plasma levels. Drugs with high doses, or frequent dosing, or both, pose the risk of toxicity and poor patient compliance. These are adverse effects both from a safety standpoint and from a development success standpoint. Compounds with DDI and / or estimated human dose risk may be successfully administered to patients, but finding compounds that minimize these risks while maintaining high potency would be particularly advantageous. However, simply identifying that this combination of properties is desirable does not indicate that finding such a compound is easy, predictable, or even possible.

[0031] Provided herein are two SIA compounds, Compound 2 and Compound 6, that exhibit an unexpected and surprising combination of high potency, low DDI risk as measured by PXR activation, and low estimated human dose as measured by bioavailability and in vivo half-life. TIFF2024528656000012.tif72170

[0032] These properties are supported by experimental data and distinguish these two compounds as unexpectedly advantageous compared to hundreds of similar SIA compounds, including dozens of close structural analogs.

[0033] compound In some embodiments, provided herein is a compound selected from the compounds of Group 1 or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: TIFF2024528656000013.tif237170TIFF2024528656000014.tif252170TIFF2024528656000015.t if249170TIFF2024528656000016.tif219170TIFF2024528656000017.tif162170TIFF20245286560 00018.tif213170TIFF2024528656000019.tif243170TIFF2024528656000020.tif255170TIFF2024528656000021.tif218170TIFF2024528656000022.tif248170 or a solvate, tautomer, or pharma- ceutically acceptable salt thereof.

[0034] Further provided herein is a pharmaceutical composition comprising a compound of Group 1, or a solvate, tautomer, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0035] In some embodiments, the compound is Compound 1: TIFF2024528656000023.tif27170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 1. Further provided is a pharmaceutical composition comprising Compound 1, or a solvate, tautomer or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising Compound 1 and a pharma- ceutically acceptable excipient.

[0036] In some embodiments, the compound is Compound 2: TIFF2024528656000024.tif27170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 2, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 2. Further provided is a pharmaceutical composition comprising Compound 2, or a solvate, tautomer or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising Compound 2, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising Compound 2 and a pharma- ceutically acceptable excipient.

[0037] In some embodiments, the compound is Compound 3: TIFF2024528656000025.tif27170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 3, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 3. Further provided is a pharmaceutical composition comprising Compound 3, or a solvate, tautomer or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising Compound 3, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising Compound 3 and a pharma- ceutically acceptable excipient.

[0038] In some embodiments, the compound is Compound 4: TIFF2024528656000026.tif27170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 4, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 4. Further provided is a pharmaceutical composition comprising compound 4, or a solvate, tautomer or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 4, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 4 and a pharma- ceutically acceptable excipient.

[0039] In some embodiments, the compound is Compound 5: TIFF2024528656000027.tif27170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 5. Further provided is a pharmaceutical composition comprising compound 5, or a solvate, tautomer or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 5, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 5 and a pharma- ceutically acceptable excipient.

[0040] In some embodiments, the compound is Compound 6: TIFF2024528656000028.tif24170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6. Further provided is a pharmaceutical composition comprising compound 6, or a solvate, tautomer or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 6, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 6 and a pharma- ceutically acceptable excipient.

[0041] In some embodiments, the compound is Compound 7: TIFF2024528656000029.tif24170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 7, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 7. Further provided is a pharmaceutical composition comprising compound 7, or a solvate, tautomer or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 7, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 7 and a pharma- ceutically acceptable excipient.

[0042] In some embodiments, the compound is Compound 8: TIFF2024528656000030.tif27170 or a solvate, tautomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 8, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 8. Further provided is a pharmaceutical composition comprising compound 8, or a solvate, tautomer or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 8, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 8 and a pharma- ceutically acceptable excipient.

[0043] In some embodiments, the compound provided herein is Compound 2 or Compound 6: TIFF2024528656000031.tif72170

[0044] Chemical names can be generated based on the compound structures provided herein according to naming conventions known to those skilled in the art, such as those provided by the International Union of Pure and Applied Chemistry (IUPAC). Chemical names can be generated using ChemDraw® software, such as ChemDraw® version 19.1.

[0045] Pharmaceutical Compositions Provided herein is a pharmaceutical composition comprising the compound provided herein, or its solvate, tautomer or pharmaceutically acceptable salt, and pharmaceutically acceptable additive.The conventional procedure for the selection and preparation of suitable pharmaceutical compositions is described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 1988, which is incorporated herein by reference in its entirety.In certain embodiments, the compound is a solvate, and the solvate is a hydrate.

[0046] Further provided is a process for preparing a pharmaceutical composition, comprising combining one or more of the disclosed compounds (e.g., compounds from group 1), or solvates, tautomers, or pharma- ceutically acceptable salts thereof, with one or more pharma- ceutically acceptable additives. In some embodiments, the compound is Compound 1, Compound 2, Compound 3, or Compound 4, or solvates, tautomers, or pharma- ceutically acceptable salts thereof. In some embodiments, the compound is Compound 5, Compound 6, Compound 7, or Compound 8, or solvates, tautomers, or pharma- ceutically acceptable salts thereof. The pharmaceutical composition can be prepared, for example, according to conventional dissolving, mixing, granulating, or coating methods, or combinations thereof. Such pharma-ceutically acceptable excipients may include, for example, one or more of sugars, starches, cellulose and derivatives thereof, tragacanth, malt, gelatin, talc, suppository waxes, oils, glycols, esters, agar, buffers, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants, coloring agents, release agents, coating agents, sweeteners, and flavoring and perfuming agents. Preservatives and antioxidants can also be present in the pharmaceutical compositions, according to the judgment of the formulator.

[0047] Depending on the intended mode of administration, the disclosed pharmaceutical compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained release capsules, and the like, in some cases in unit doses, consistent with conventional pharmaceutical practice. These modes may include systemic or local administration, such as oral, nasal, parenteral (by intravenous (both bolus and drip), intramuscular or subcutaneous injection), transdermal, vaginal, buccal, rectal, or topical (by powder, ointment, or drops) modes of administration. These modes may also include intracisternal, intraperitoneal, as oral or nasal sprays, or as liquid aerosol or dry powder pharmaceutical compositions for inhalation. In some embodiments, the pharmaceutical compositions provided herein include one or more of the disclosed compounds, solvates thereof, tautomers thereof, and / or pharma- ceutically acceptable salts thereof, and are for oral administration. In other embodiments, the pharmaceutical compositions are for intravenous administration.

[0048] Solid dosage forms for oral administration may include capsules (e.g., soft and hard filled gelatin capsules), tablets, pills, powders and granules.Solid dosage forms may in some embodiments be prepared with one or more coatings and / or shells, such as release-controlling coatings, for example enteric coatings.Solid dosage forms may be formulated to release one or more disclosed compounds (or their solvates, tautomers or pharma-ceutically acceptable salts) solely, or primarily, or preferentially, in a particular part of the digestive tract, optionally in a delayed manner.Solid dosage forms may also include, for example, microencapsulated forms.

[0049] In some embodiments, it may be desirable to extend the effect of one or more compounds disclosed herein (e.g., compounds of Group 1) or solvates, tautomers, or pharma- ceutically acceptable salts thereof from administration by subcutaneous or intramuscular injection. In some embodiments, the compound is Compound 1, Compound 2, Compound 3, or Compound 4, or solvates, tautomers, or pharma- ceutically acceptable salts thereof. In some embodiments, the compound is Compound 5, Compound 6, Compound 7, or Compound 8, or solvates, tautomers, or pharma- ceutically acceptable salts thereof. In some embodiments, the compound is Compound 2, or solvates, tautomers, or pharma- ceutically acceptable salts thereof. In some embodiments, the compound is Compound 6, or solvates, tautomers, or pharma- ceutically acceptable salts thereof.

[0050] The pharmaceutical compositions provided herein may be packaged in unit-dose or multi-dose containers, such as sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid additive (e.g., diluent, carrier, e.g., water) for injection immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, or tablets of the type described herein. Unit-dosage formulations include those containing a daily dose or daily unit sub-dose, or an appropriate fraction thereof, of the active ingredient.

[0051] The subject matter further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary additive or carrier for the active ingredient. The veterinary additive or carrier is a substance useful for the purpose of administering the composition and may be a solid, liquid or gaseous substance that is otherwise inert or acceptable in the veterinary arts and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

[0052] How to use One or more of the disclosed Group 1 compounds, or solvates, tautomers, or pharma- ceutically acceptable salts thereof, and compositions comprising them, may be useful as pharmaceuticals, as discussed herein. In some embodiments, the compound is Compound 1, Compound 2, Compound 3, or Compound 4, or solvates, tautomers, or pharma- ceutically acceptable salts thereof. In some embodiments, the compound is Compound 5, Compound 6, Compound 7, or Compound 8, or solvates, tautomers, or pharma- ceutically acceptable salts thereof. In some embodiments, the compound is Compound 2, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 6, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. Without wishing to be bound by any theory, one or more compounds provided herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, may show greater inhibition of NLRP3, greater inhibition of NLRP3 activation, or greater inhibition of NLRP3-dependent inflammasome pathway, or any combination thereof, compared to other known sulfonimide amide compounds.One or more compounds provided herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, may show a lower IC50 or a lower IC90 in one or more assays evaluating inhibition of NLRP3, inhibition of NLRP3 activation, inhibition of NLRP3-dependent inflammasome pathway, or any combination thereof, compared to other sulfonimide amide compounds (e.g., assays using peripheral blood mononuclear cells or whole human blood cells).One or more compounds provided herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, may have a lower predicted human dosage, a lower metabolic clearance rate, or a combination thereof, compared to other known sulfonimide amide compounds. One or more of the compounds provided herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, may have lower PXR activation compared to other known sulfonimide amide compounds.One or more of the compounds provided herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, may possess any combination of such advantageous properties.

[0053] Provided herein is a method of treating a disorder in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of group 1 described herein or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. Further provided is a method of treating a disorder in a subject in need of such treatment, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of group 1 described herein or a solvate, tautomer, or pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the compound is Compound 1 or Compound 2 or Compound 3 or Compound 4, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 5, Compound 6, Compound 7, or Compound 8, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 2 or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 6 or a solvate, tautomer, or pharma- ceutically acceptable salt thereof.

[0054] In certain embodiments, the disorder is responsive to inflammasome inhibition.

[0055] Further provided herein is a compound of group 1 as described herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for use in treating a disorder in a subject in need of such treatment. Also provided herein is a pharmaceutical composition comprising a compound of group 1 as described herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, for use in treating a disorder in a subject in need of such treatment. In certain embodiments, the disorder is responsive to inflammasome inhibition. In some embodiments, the compound is compound 1, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 2, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 3, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 4, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 5, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 7, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 8, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof.

[0056] The present disclosure also provides the use of a compound of group 1 described herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, in the treatment of a disorder in a subject in need of such treatment. Further provided is the use of a pharmaceutical composition comprising a compound described herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in the treatment of a disorder in a subject in need of such treatment. In certain embodiments, the disorder is responsive to inflammasome inhibition. In some embodiments, the compound is compound 1, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 2, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 3, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 4, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 5, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 7, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 8, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof.

[0057] Provided herein is the use of a compound of Group 1 as described herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder in a subject in need of such treatment. Also provided is the use of a pharmaceutical composition as described herein, comprising a compound of Group 1 as described herein, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, for the manufacture of a medicament for the treatment of a disorder in a subject in need of such treatment. In certain embodiments, the disorder is responsive to inflammasome inhibition. In some embodiments, the compound is Compound 1, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 2, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 3, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 4, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is Compound 5, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 7, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 8, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof.

[0058] In certain embodiments of the methods of treatment, the use of the compounds or pharmaceutical compositions, the compounds or pharmaceutical compositions for use, and the use in the manufacture of medicines described herein, the disorder is responsive to the inhibition of the activation of NLRP3 inflammasome.According to some embodiments, one or more compounds of the present disclosure or their solvates, tautomers or pharmacologic acceptable salts, or pharmaceutical compositions are useful as specific inhibitors of NLRP3.

[0059] In some embodiments, the disorder is a disorder of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, respiratory system, central nervous system, is a cancer or other malignancy, and / or is caused by or associated with a pathogen.

[0060] In some embodiments, the disorder is a disorder of the immune system, a disorder of the liver, a disorder of the lungs, a disorder of the skin, a disorder of the cardiovascular system, a disorder of the renal system, a disorder of the gastrointestinal tract, a disorder of the respiratory system, a disorder of the endocrine system, a disorder of the central nervous system (CNS), an inflammatory disorder, an autoimmune disorder, or a cancer, tumor, or other malignancy.

[0061] It will be understood that the general embodiments defined according to broad categories of disorders are not mutually exclusive. In this regard, any particular disorder can be classified according to two or more of the general embodiments disclosed herein. A non-limiting example is type I diabetes, which is an autoimmune disease and a disease of the endocrine system.

[0062] In some embodiments, the disorder is an immune system disorder. In some embodiments, the disorder is an inflammatory disorder or an autoimmune disorder. In some embodiments, the disorder is a liver, lung, skin, or cardiovascular disorder. In some embodiments, the disorder is a liver disorder. In some embodiments, the disorder is a lung disorder. In some embodiments, the disorder is a skin disorder. In some embodiments, the disorder is a cardiovascular disorder.

[0063] In some embodiments, the disorder is cancer, tumor, or other malignant tumor. As used herein, cancer, tumor, and malignant tumor refer to a disorder or a cell or tissue associated with the disorder characterized by ectopic or abnormal cell proliferation, differentiation, and / or migration, often accompanied by an ectopic or abnormal molecular phenotype, including one or more genetic mutations or other genetic changes associated with oncogenes, expression of tumor markers, loss of tumor suppressor expression or activity, and / or ectopic or abnormal cell surface marker expression. In general embodiments, cancer, tumor, and malignant tumors can include, but are not limited to, sarcoma, lymphoma, leukemia, solid tumor, blastoma, glioma, carcinoma, melanoma, and metastatic cancer.

[0064] In some embodiments, the disorder is a disorder of the renal system, gastrointestinal tract, respiratory system, endocrine system, central nervous system, or cardiovascular system. In some embodiments, the disorder is a disorder of the renal system. In some embodiments, the disorder is a disorder of the gastrointestinal tract. In some embodiments, the disorder is a disorder of the respiratory system. In some embodiments, the disorder is a disorder of the endocrine system. In some embodiments, the disorder is a disorder of the central nervous system (CNS). In some embodiments, the disorder is a disorder of the cardiovascular system.

[0065] In some embodiments, the disorder is caused by or associated with a pathogen. The pathogen may be, but is not limited to, a virus, a bacterium, a protozoan, a parasite, or a fungus, or any other organism that can infect a mammal. Non-limiting examples of viruses include, but are not limited to, influenza virus, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus (HIV), alphaviruses such as Chikungunya virus and Ross River virus, flaviviruses such as Dengue virus, Zika virus, and papilloma virus.Non-limiting examples of pathogenic bacteria include Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurea multicida, Shigella dysenteriae, Mycobacterium tuberculosis, and the like. tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella Examples of suitable pathogens include, but are not limited to, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, and Yersinia pestis.Non-limiting examples of protozoa include, but are not limited to, Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, and Trypanosomes. Non-limiting examples of parasites include, but are not limited to, helminths, including Schistosoma, Roundworms, Tapeworms, and Trematodes. Non-limiting examples of fungi include, but are not limited to, Candida and Aspergillus.

[0066] In some embodiments, the disorder is homeostatic inflammation including cryoprenaline-associated periodic syndromes (CAPS): Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID); autoinflammatory diseases: familial Mediterranean fever (FMF), tumor necrotic fibrosis receptor-associated periodic syndromes (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majed syndrome, septic arthritis, pyoderma gangrenosum, and acne (PAPA), haploinsufficiency of A20 (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune deficiency (PLAID), PLCG2-associated autoinflammatory, antibody deficiency, and immune deficiency (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD). ;Sweet's syndrome;Chronic nonbacterial osteomyelitis (CNO);Chronic recurrent multifocal osteomyelitis (CRMO) and synovitis;Acne;Pustulosis;Osteoporosis;Osteitis syndrome (SAPHO);Autoimmune diseases including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjogren's syndrome, and Schnitzler's syndrome;Idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis. respiratory diseases, including; central nervous system diseases, including Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, and brain damage due to pneumococcal meningitis; metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout; eye diseases, including ocular epithelial disease, age-related macular degeneration (AMD), corneal infections, uveitis, and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy, and diabetic nephropathy; liver diseases, including nonalcoholic steatohepatitis and alcoholic liver disease; inflammatory reactions of the skin, including contact hypersensitivity and sunburn; inflammatory reactions of the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and relapsing polychondritis; viral infections, including alphaviruses (chikungunya, Ross River) and flaviviruses (dengue, Zika virus), influenza, and HIV; skin diseases causing pustular hydradenitis (HS) and other cysts;cancer, including lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, and leukemia; polymyositis; stroke; myocardial infarction; graft-versus-host disease; hypertension; colitis; helminth infection; bacterial infection; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis, including Dressler's syndrome; ischemia-reperfusion injury; and any disorder in which the individual is determined to have a germline or somatic non-silent mutation in NLRP3;

[0067] In some embodiments, the disorder is cryopyrin-associated periodic syndromes (CAPS).

[0068] In some embodiments, the disorder is atherosclerosis.

[0069] In one non-limiting example of the described, the disorder to be treated is NASH.NLRP3 inflammasome activation is central to inflammatory recruitment in NASH, and inhibition of NLRP3 can prevent and reverse liver fibrosis.One or more group 1 compounds, or their pharma- ceutically acceptable salts, solvates and tautomers, or pharmaceutical compositions of the present disclosure, can cause histological reduction of liver inflammation, reduction of macrophage and neutrophil recruitment, and suppression of NF-κB activation by interrupting the function of NLRP3 inflammasome in liver tissue.Inhibition of NLRP3 can reduce hepatic expression of pro-IL-1β and normalize hepatic and circulating IL-1β, IL-6 and MCP-1 levels, thereby aiding in the treatment of the disorder.

[0070] In a further non-limiting example of the described, the disorder to be treated is severe steroid-resistant (SSR) asthma. Respiratory infection induces the NLRP3 inflammasome / caspase-I / IL-1β signaling axis in the lungs, which promotes SSR asthma. The NLRP3 inflammasome recruits and activates procaspase-1 to induce IL-1β responses. Thus, although the IL-β response induced by the NLRP3 inflammasome is important in controlling infection, excessive activation leads to abnormal inflammation and is associated with the pathogenesis of SSR asthma and COPD. The administration of one or more compounds of the present disclosure, or a solvate, tautomer, or pharma-ceutically acceptable salt thereof, or a pharmaceutical composition comprising them, that targets a specific disease process is more therapeutically attractive than non-specific inhibition of steroid- or IL-1β-induced inflammatory responses. Thus, targeting the NLRP3 inflammasome / caspase-1 / IL-1β signaling axis of the present disclosure with one or more compounds, or solvates, tautomers or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions providing same, may be useful in the treatment of SSR asthma and other steroid-resistant inflammatory conditions.

[0071] In some embodiments of the methods of treatment, use of a compound or pharmaceutical composition, compound or pharmaceutical composition for use, and use in the manufacture of a medicament described herein, the disorder being treated is selected from, but is not limited to, bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, liver fibrosis, hepatic steatosis, fatty liver disease, gout, lupus, lupus nephritis, Crohn's disease, IBD (inflammatory bowel disease), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[0072] In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH); myelodysplastic syndromes (MDS); myeloproliferative neoplasms (MPN); cryopyrin-associated periodic syndromes (CAPS); idiopathic pulmonary fibrosis (IPF); MI(R / I) (myocardial infarction and reperfusion injury); gout; I / O (immuno-oncology); asthma; inflammatory bowel disease (IBD); renal fibrosis; adult-onset Still's disease; systemic juvenile idiopathic arthritis (SJIA); tumor necrosis factor receptor-associated periodic syndromes (TRAPS); colchicine-resistant familial Mediterranean fever (FMF); hyper-IgD syndrome (HIDS) / mevalonate kinase deficiency (MKD) ); traumatic brain injury; Parkinson's disease; moderate to severe inflammatory acne; acute non-anterior non-infectious uveitis (NIU); Alzheimer's disease; chronic obstructive pulmonary disease (COPD); sepsis; multiple sclerosis (MS); Behcet's disease; Crohn's disease; rheumatoid arthritis (RA); erosive osteoarthritis; type 1 diabetes; type 2 diabetes; obesity; osteoporosis; cystic fibrosis; alcoholic liver disease; aging; hepatocellular carcinoma (HCC); depression; endometriosis; pyoderma gangrenosum (PG); lupus; lupus nephritis; epilepsy; ischemic stroke; hearing loss; sickle cell disease; lupus erythematosus (SLE); and spinal cord injury.

[0073] In some embodiments, the disorder is selected from the group consisting of lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, Crohn's disease, and inflammatory bowel disease (IBD). In some embodiments, the disorder is gout. In some embodiments, the disorder is lupus. In some embodiments, the disorder is lupus nephritis. In some embodiments, the disorder is Crohn's disease. In some embodiments, the disorder is IBD (inflammatory bowel disease). In some embodiments, the disorder is MDS (myelodysplastic syndrome). In some embodiments, the disorder is MPN (myeloproliferative neoplasm).

[0074] For therapeutic uses as referred to herein, the dosage administered will of course vary depending on the compound(s), solvates (e.g., hydrates), tautomers or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions used, the mode of administration, the desired treatment and the disorder indicated. For example, the daily dosage of the compound(s), solvates (e.g., hydrates), tautomers or pharma- ceutically acceptable salts thereof of the present disclosure, when inhaled, may range from about 0.05 micrograms per kilogram of body weight (μg / kg) to about 100 micrograms per kilogram of body weight (μg / kg). Alternatively, the daily dosage of the compound(s), solvates (e.g., hydrates), tautomers or pharma- ceutically acceptable salts thereof of the present disclosure, when administered orally, may range from about 0.01 micrograms per kilogram of body weight (μg / kg) to about 100 milligrams per kilogram of body weight (mg / kg). In some embodiments, the daily dosage is from 10 mg to 1000 mg, or from 10 mg to 500 mg, or from 500 mg to 1000 mg of the compound, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof.

[0075] Combination therapy In some embodiments, one or more compounds, solvates, tautomers or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions described herein may be used alone or together, or may be co-administered, or may be used in combination with known therapeutic agents or pharmaceutical compositions. "Co-administration" or "used in combination" may refer to any mode of administration of two or more different compounds or pharmaceutical compositions, such that a second compound or pharmaceutical composition is administered while the previously administered compound or pharmaceutical composition is still effective in the body. For example, different compounds or pharmaceutical compositions may be administered either simultaneously, sequentially, or by separate administration of individual therapeutic components, either in the same formulation or in separate formulations. In some embodiments, different compounds or pharmaceutical compositions may be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or within 1 week of each other. Thus, an individual undergoing such treatment may benefit from the combined effects of different compounds or pharmaceutical compositions.

[0076] Methods for preparing compounds The compounds disclosed herein can be prepared by methods known in the art of organic synthesis, as partially described by the following synthetic schemes. In the schemes described herein, it is well understood that, according to general principles or chemical reactions, protective groups for sensitive or reactive groups are utilized, if necessary. Protective groups are manipulated according to standard methods of organic synthesis (TW Greene and PG M Huts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis, using methods readily apparent to those skilled in the art. The selected processes, as well as the reaction conditions and the order of their implementation, must be consistent with the preparation of the compounds disclosed herein. The compounds described herein may be prepared from commercially available starting materials or may be synthesized using known organic, inorganic, and / or enzymatic processes.

[0077] By way of example, compounds of the present disclosure (e.g., compounds of Group 1, or solvates, tautomers, or pharma- ceutically acceptable salts thereof) can be synthesized according to the steps outlined in general schemes 1, 2, and 3, which include examples of assembling compounds of the present disclosure. Starting materials are either commercially available or prepared by known procedures reported in the literature or as illustrated. Synthetic methods include, but are not limited to, those described herein.

[0078] General Scheme 1 TIFF2024528656000032.tif58170 In General Scheme 1, PG G1is a protecting group. Sulfonamide (A) is protected to give protected sulfonamide (B). Protected sulfonamide (B) is converted to protected sulfonimidamide (C) by activation (e.g., deoxychlorination or catalysis) and treatment with an ammonia source. Protected sulfonimidamide (C) is reacted with isocyanate (D) to give compound (E). Compound (E) is then deprotected to give compound (F).

[0079] General Scheme 2 TIFF2024528656000033.tif30170 In General Scheme 2, PG G2 is a protecting group, LG 1 is a leaving group (e.g., a halogen that can be activated as a reactive species, e.g., via lithium-halogen exchange). Compound (G) is reacted with compound (H), followed by activation and treatment with an ammonia source to produce protected sulfonimidamide (I). Protected sulfonimidamide (I) is reacted with isocyanate (J) to give compound (K). Compound (K) is then deprotected to give compound (L).

[0080] General Scheme 3 TIFF2024528656000034.tif44170 The sulfonyl chloride (S) is converted to a sulfinic acid methyl ester (T) via reduction, followed by the formation of a sulfinyl chloride, which is then esterified. The sulfinic acid methyl ester (T) is converted to a sulfinamide (U) via reaction with an amine source (such as LiHMDS), which is then hydrolyzed. The sulfinamide (U) is reacted with an isocyanate (V) to give compound (W). Compound (W) is then converted to a sulfonimidamide (X) via oxidative chlorination followed by reaction with an amine or ammonia source.

[0081] Enumeration of embodiments E1. A compound comprising: TIFF2024528656000035.tif25170, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E2.A compound according to E1, TIFF2024528656000036.tif25170, compound. E3. A pharmaceutical composition comprising a compound according to E1, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. E4. A compound comprising: TIFF2024528656000037.tif25170, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E5.A compound according to E4, TIFF2024528656000038.tif25170, compound. E6. A pharmaceutical composition comprising a compound according to E4, or a solvate, tautomer or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. E7. A compound comprising: TIFF2024528656000039.tif25170, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E8.A compound according to E7, TIFF2024528656000040.tif25170, compound. E9. A pharmaceutical composition comprising a compound according to E7, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. E10. A compound comprising: TIFF2024528656000041.tif25170, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E11. A compound according to E10, TIFF2024528656000042.tif25170, compound. E12. A pharmaceutical composition comprising a compound according to E10, or a solvate, tautomer or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. E13. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described in E1, E4, E7 or E10, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E14. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described in E3, E6, E9 or E12. E15. The method of claim E13 or E14, wherein the disorder is responsive to inhibition of activation of the NLRP3 inflammasome. E16. The method of any one of E13-E15, wherein the disorder is an immune system disorder, a liver disorder, a lung disorder, a skin disorder, a cardiovascular system disorder, a renal system disorder, a gastrointestinal tract disorder, a respiratory system disorder, an endocrine system disorder, a central nervous system (CNS) disorder, an inflammatory disorder, an autoimmune disorder, or a cancer, tumor, or other malignancy. E17. The method of any one of E13-E16, wherein the disorder is a bacterial infection, a viral infection, a fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, hepatic fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, Crohn's disease, or inflammatory bowel disease (IBD). E18. A compound according to E1, E4, E7 or E10, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for use in treating a disorder in a subject in need of such treatment. E19. The pharmaceutical composition of E3, E6, E9 or E12 for use in treating a disorder in a subject in need of such treatment. E20. Use of a compound according to E1, E4, E7 or E10, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, in treating a disorder in a subject in need thereof. E21. Use of a pharmaceutical composition described in E3, E6, E9 or E12 in treating a disorder in a subject in need thereof. E22. A compound according to E1, E4, E7 or E10, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof. E23. The pharmaceutical composition of E3, E6, E9 or E12 for use in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof. E24. The compound for use according to E18, the pharmaceutical composition for use according to E19, the use of the compound according to E20, the use of the pharmaceutical composition according to E21, the compound for use in the manufacture of a medicament according to E22, or the pharmaceutical composition for use in the manufacture of a medicament according to E23, wherein the disorder is responsive to inhibition of activation of the NLRP3 inflammasome. E25. A compound for use according to E18 or E24; a pharmaceutical composition for use according to E19 or E24; the use of a compound according to E20 or E24; the use of a pharmaceutical composition according to E21 or E24; a compound for use in the manufacture of a medicament according to E22 or E24; or a pharmaceutical composition for use in the manufacture of a medicament according to E23 or E24, wherein the disorder is a disorder of the immune system, a disorder of the liver, a disorder of the lungs, a disorder of the skin, a disorder of the cardiovascular system, a disorder of the renal system, a disorder of the gastrointestinal tract, a disorder of the respiratory system, a disorder of the endocrine system, a disorder of the central nervous system (CNS), an inflammatory disorder, an autoimmune disorder, or a cancer, tumor or other malignancy. E26. The disorder is bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, hepatic fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, clotting factor receptor deficiency syndrome (CLS), inflammatory bowel disease (IGF ... a compound for use according to E18, E24 or E25; a pharmaceutical composition for use according to E19, E24 or E25; the use of a compound according to E20, E24 or E25; the use of a pharmaceutical composition according to E21, E24 or E25; a compound for use in the manufacture of a medicament according to E22, E24 or E25; or a pharmaceutical composition for use in the manufacture of a medicament according to E23, E24 or E25, wherein the treatment is for Crohn's disease or inflammatory bowel disease (IBD). E27. A compound comprising: TIFF2024528656000043.tif28170, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E28. A compound according to E27, TIFF2024528656000044.tif28170, compound. E29. A pharmaceutical composition comprising a compound according to E27, or a solvate, tautomer or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. E30. A method of treating a disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound according to E27, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E31. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described in E29. E32. The method of claim E30 or E31, wherein the disorder is responsive to inhibition of activation of the NLRP3 inflammasome. E33. The method of any one of E30-E32, wherein the disorder is an immune system disorder, a liver disorder, a lung disorder, a skin disorder, a cardiovascular system disorder, a renal system disorder, a gastrointestinal tract disorder, a respiratory system disorder, an endocrine system disorder, a central nervous system (CNS) disorder, an inflammatory disorder, an autoimmune disorder, or a cancer, tumor, or other malignancy. E34. The method of any one of E30-E33, wherein the disorder is a bacterial infection, a viral infection, a fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, hepatic fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, Crohn's disease, or inflammatory bowel disease (IBD). E35. A compound according to E27, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for use in treating a disorder in a subject in need of such treatment. E36. The pharmaceutical composition of E29 for use in treating a disorder in a subject in need thereof. E37. Use of a compound according to E27, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, in treating a disorder in a subject in need thereof. E38. Use of a pharmaceutical composition as described in E29 in treating a disorder in a subject in need thereof. E39. A compound according to E27, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof. E40. The pharmaceutical composition of E29 for use in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof. E41. The compound for use according to E35, the pharmaceutical composition for use according to E36, the use of the compound according to E37, the use of the pharmaceutical composition according to E38, the compound for use in the manufacture of a medicament according to E39, or the pharmaceutical composition for use in the manufacture of a medicament according to E40, wherein the disorder is responsive to inhibition of activation of the NLRP3 inflammasome. E42. A compound for use according to E35 or E41; a pharmaceutical composition for use according to E36 or E41; a use of a compound according to E37 or E41; a use of a pharmaceutical composition according to E38 or E41; a compound for use in the manufacture of a medicament according to E39 or E41; or a pharmaceutical composition for use in the manufacture of a medicament according to E40 or E41, wherein the disorder is a disorder of the immune system, a disorder of the liver, a disorder of the lungs, a disorder of the skin, a disorder of the cardiovascular system, a disorder of the renal system, a disorder of the gastrointestinal tract, a disorder of the respiratory system, a disorder of the endocrine system, a disorder of the central nervous system (CNS), an inflammatory disorder, an autoimmune disorder, or a cancer, tumor, or other malignancy. E43. The disorder is bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, hepatic fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, clotting factor receptor deficiency syndrome (CLS), inflammatory bowel disease (IGF ... a compound for use according to E35, E41 or E42; a pharmaceutical composition for use according to E36, E41 or E42; the use of a compound for use according to E37, E41 or E42; the use of a pharmaceutical composition for use according to E38, E41 or E42; a compound for use in the manufacture of a medicament for use according to E39, E41 or E42; or a pharmaceutical composition for use in the manufacture of a medicament for use according to E40, E41 or E42, wherein the treatment is for Crohn's disease or inflammatory bowel disease (IBD). E44. A compound selected from the group consisting of: TIFF2024528656000045.tif234170TIFF2024528656000046.tif253170TIFF2024528656000047.t if249170TIFF2024528656000048.tif210170TIFF2024528656000049.tif220170TIFF20245286560 00050.tif235170TIFF2024528656000051.tif238170TIFF2024528656000052.tif245170TIFF2024528656000053.tif224170TIFF2024528656000054.tif190170 or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E45. A pharmaceutical composition comprising a compound according to E44, or a solvate, tautomer or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. E46. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to E44, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof. E47. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described in E45. E48. The method of E46 or E47, wherein the disorder is responsive to inhibition of activation of the NLRP3 inflammasome. E49. The method of any one of E46-E48, wherein the disorder is an immune system disorder, a liver disorder, a lung disorder, a skin disorder, a cardiovascular system disorder, a renal system disorder, a gastrointestinal tract disorder, a respiratory system disorder, an endocrine system disorder, a central nervous system (CNS) disorder, an inflammatory disorder, an autoimmune disorder, or a cancer, tumor, or other malignancy. E50. The method of any one of E46-E49, wherein the disorder is a bacterial infection, a viral infection, a fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, hepatic fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, Crohn's disease, or inflammatory bowel disease (IBD). E51. A compound according to E44, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for use in treating a disorder in a subject in need of such treatment. E52. The pharmaceutical composition of E45 for use in treating a disorder in a subject in need thereof. E53. Use of a compound according to E44, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, in treating a disorder in a subject in need thereof. E54. Use of a pharmaceutical composition according to E45 in treating a disorder in a subject in need thereof. E55. A compound according to E44, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof. E56. A pharmaceutical composition as described in E45 for use in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof. E57. The compound for use according to E51, the pharmaceutical composition for use according to E52, the use of the compound according to E53, the use of the pharmaceutical composition according to E54, the compound for use in the manufacture of a medicament according to E55, or the pharmaceutical composition for use in the manufacture of a medicament according to E56, wherein the disorder is responsive to inhibition of activation of the NLRP3 inflammasome. E58. A compound for use according to E51 or E57; a pharmaceutical composition for use according to E52 or E57; a use of a compound according to E53 or E57; a use of a pharmaceutical composition according to E54 or E57; a compound for use in the manufacture of a medicament according to E55 or E57; or a pharmaceutical composition for use in the manufacture of a medicament according to E56 or E57, wherein the disorder is a disorder of the immune system, a disorder of the liver, a disorder of the lungs, a disorder of the skin, a disorder of the cardiovascular system, a disorder of the renal system, a disorder of the gastrointestinal tract, a disorder of the respiratory system, a disorder of the endocrine system, a disorder of the central nervous system (CNS), an inflammatory disorder, an autoimmune disorder, or a cancer, tumor, or other malignancy. E59. The disorder is bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, hepatic fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, clotting factor receptor deficiency syndrome (CLS), inflammatory bowel disease (IGF ... a compound for use according to E51, E57 or E58; a pharmaceutical composition for use according to E52, E57 or E58; the use of a compound according to E53, E57 or E58; the use of a pharmaceutical composition according to E54, E57 or E58; a compound for use in the manufacture of a medicament according to E55, E57 or E58; or a pharmaceutical composition for use in the manufacture of a medicament according to E56, E57 or E58, wherein the treatment is for Crohn's disease or inflammatory bowel disease (IBD). E60. The invention described herein. EXAMPLES

[0082] Abbreviations used in the examples below may include the following: DAST: Diethylaminosulfur trifluoride DCE: Dichloroethane DCM: dichloromethane DEA: Diethylamine DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide EtOAc: ethyl acetate EtOH: Ethanol HOAc: acetic acid HPLC: High-performance liquid chromatography IPA: Isopropanol LCMS: Liquid Chromatography Mass Spectrometry MeOH: Methanol MsCl: methanesulfonyl chloride MTBE: Methyl tert-butyl ether NBS: N-bromosuccinimide NMR: nuclear magnetic resonance PTSA: p-Toluenesulfonic acid TBAF: Tetra-n-butylammonium fluoride TBSCl: tert-butyldimethylsilyl chloride TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography Preparative TLC: Preparative thin-layer chromatography SFC: Supercritical Fluid Chromatography

[0083] Synthetic Procedures: Compounds in Group 1 are synthesized according to the general procedures described below using fragments synthesized as described in the Examples below.

[0084] General procedure for isocyanate formation: TIFF2024528656000055.tif9170 Triphosgene (0.5 equiv.) can be added to a solution of aniline (1 equiv.) and TEA (2 equiv.) in THF (0.05-0.10 M) at 0 °C. After 1 h, the reaction mixture can be used directly in the next step or the triethylammonium salts can be filtered off by filtering the reaction through a silica plug and the filtrate can be used directly in the next step.

[0085] General procedure for coupling protected sulfonimide amides with isocyanates: TIFF2024528656000056.tif37170 Sodium methoxide (1.5 equiv.) or NaH (2.5 equiv.) can be added to a solution of sulfonimide amide (1 equiv.) in THF (0.05-0.1 M) at 25 °C. After 30 min, isocyanate (1-2 equiv.) can be added to the reaction mixture. After 1-24 h, the reaction can be concentrated under reduced pressure and the crude residue can be purified to deliver the desired product.

[0086] General procedure for TBS deprotection: TIFF2024528656000057.tif43170TBAF (2 equiv.) can be added to a solution of the substrate (1 equiv.) in THF (0.1-0.2 M) at 25 °C. After 30 min, the reaction mixture can be concentrated under reduced pressure and the crude residue can be purified to deliver the desired deprotected product.

[0087] General procedure for Trt deprotection: TIFF2024528656000058.tif37170 Methanesulfonic acid (5-6 equiv.) can be added to a solution of substrate (1 equiv.) in DCM (0.01-0.05 M) at 0 °C. After 0.5 h, the reaction mixture can be adjusted to pH = 8 by adding saturated aqueous NaHCO3. The reaction can be concentrated to dryness under reduced pressure and the crude residue can be purified to deliver the desired deprotected product.

[0088] Example L1: Synthesis of 7-(S-amino-N-trityl-sulfonimidoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole Step 1: Synthesis of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000059.tif17170To a solution of 2,3-dihydropyrazolo[5,1-b]oxazole (2.0 g, 18.2 mmol) in MeCN (40 mL), NBS (3.9 g, 21.8 mmol) was added portionwise at 0° C., and the reaction mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was purified by reverse phase column (MeCN / H2O) to give 3 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole (2.4 g, yield: 71%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ=7.30(s,1H),5.12(t,J=8.0 Hz,2H),4.35(t,J=8.0 Hz,2H).

[0089] Step 2: Synthesis of N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000060.tif23170 To a stirred solution of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole (200 mg, 1.06 mmol) in THF (6 mL) was added dropwise at -78 °C under a N2 atmosphere, n-BuLi (2.5 M in hexanes, 0.51 mL, 1.27 mmol). After 1 h, a solution of TrtNSO (388 mg, 1.27 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at -78 °C for 20 min, at which point the reaction was placed in a 0 °C ice bath where the reaction was stirred for an additional 10 min. tert-Butyl hypochlorite (0.15 mL, 1.33 mmol) was added dropwise at 0 °C. After 20 min, NH3 gas was bubbled through the mixture for 10 min. The reaction was allowed to warm to room temperature and stirred for an additional 16 h. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-2% MeOH in DCM) to give N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (140 mg, 31% yield) as a yellow solid.1 H NMR(400 MHz,DMSO-d6)δ=7.43(d,J=7.6 Hz,6H),7.22-7.13(m,6H),7.13-7.06(m,3H),7.04(s,1H),6.38(s,2H),5.03(t,J=8.0 Hz,2H),4.18-4.07(m,2H).

[0090] Example L2: Synthesis of 2-methyl-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfinamide Step 1: Synthesis of 1-[3-(2-bromo-1-methyl-ethoxy)pyrazol-1-yl]ethanone: TIFF2024528656000061.tif24170 Diisopropyl azodicarboxylate (47.2 mL, 237.9 mmol) was added to a solution of 2-acetyl-1H-pyrazol-5-one (20 g, 158.6 mmol) and triphenylphosphine (62.4 g, 237.9 mmol) in THF (230 mL) at 0 °C. After 1 h, 1-bromo-2-propanol (70 wt%, 24.5 mL, 190.3 mmol) was added. The reaction was allowed to warm to room temperature. After 16 h, the reaction The reaction was concentrated under reduced pressure. The crude residue was dissolved in MTBE (230 mL) and concentrated. The crude residue was then redissolved in MTBE (230 mL) and stirred for 30 min. Triphenylphosphine oxide was filtered off and the filtrate was concentrated. The crude residue was purified by flash column chromatography (silica, 0% to 30% isopropyl acetate-heptane) to give 1-[3-(2-bromo-1-methyl-ethoxy)pyrazol-1-yl]ethanone (15 g, 60.7 mmol, 38% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.06(s, 1H), 5.97(s, 1H), 5.08-4.97(m, 1H), 3.64-3.58(m, 2H), 2.58(s, 3H), 1.51(dd, J=6.3, 3H).

[0091] Step 2: Synthesis of 2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000062.tif11170 Potassium carbonate (16.8 g, 121.4 mmol) was added to a solution of 1-[3-(2-bromo-1-methyl-ethoxy)pyrazol-1-yl]ethanone (15 g, 60.7 mmol) in MeOH (22.7 mL) and MeCN (152 mL). The reaction was sealed with a yellow cap and heated at 80° C. for 16 h. After cooling to room temperature, the reaction was filtered through a pad of Celite® using dichloromethane. The filtrate was carefully concentrated under reduced pressure (200 torr, bath temperature 60° C.). The crude residue was taken to the next step without further purification.

[0092] Step 3: Synthesis of 7-bromo-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000063.tif13170 N-Bromosuccinimide (10.8 g, 60.7 mmol) was added portionwise to a solution of 2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (crude, 7.5 g, 60.7 mmol) in MeCN (243 mL) at 0 °C. After 1 h, the reaction was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate-heptane) to give 7-bromo-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (10.4 g, 51.2 mmol, 84% yield over two steps). 1 H NMR (400 MHz, chloroform-d) δ 7.30 (s, 1H), 5.52-5.40 (m, 1H), 4.42 (dd, J=9.3, 7.9 Hz, 1H), 3.90 (dd, J=9.4, 8.0, 1H), 1.65 (d, J=6.4 Hz, 3H).

[0093] Step 4: Synthesis of 2-methyl-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfinamide: TIFF2024528656000064.tif13170 n-Butyllithium (2.5 M in hexanes, 6.5 mL, 16 mmol) was added to a solution of 7-bromo-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (3.0 g, 15 mmol) in THF (74 mL) at -78 °C. After 20 min, a solution of [diphenyl-(sulfinylamino)methyl]benzene (5.0 g, 16 mmol) in THF (30 mL) was added to the reaction mixture over 5 min. After 20 min, the reaction was allowed to warm to room temperature and stirred for an additional 16 h. The reaction was concentrated under reduced pressure. The crude residue was dissolved in 5% methanol / DCM and the solution was subjected to flash column chromatography (silica, 5% methanol-dichloromethane) to give 2-methyl-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfinamide (3.4 g, 7.9 mmol, 54% yield).

[0094] Step 5: Synthesis of 7-(S-amino-N-trityl-sulfonimidoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000065.tif15170To a solution of 2-methyl-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfinamide (3.0 g, 7.0 mmol) in THF (70 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (1.4 g, 7.0 mmol) at 0° C. After 5 min, the reaction was allowed to warm to room temperature and stirred for an additional 20 min. Ammonia (gas) was then bubbled through the reaction for 10 min. The reaction was then stirred at room temperature for an additional 2 h. The reaction was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 50% isopropyl acetate-heptane) to give 7-(S-amino-N-trityl-sulfonimidoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (2.65 g, 5.96 mmol, 85% yield).

[0095] Example L3: Synthesis of 7-(S-amino-N-trityl-sulfonimidoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole Step 1: Synthesis of 1-[3-(2-bromopropoxy)pyrazol-1-yl]ethanone TIFF2024528656000066.tif13170 Diisopropyl azodicarboxylate (28.3 mL, 142.7 mmol) was added to a solution of 2-acetyl-1H-pyrazol-5-one (12 g, 95.2 mmol) and triphenylphosphine (37.4 g, 142.7 mmol) in THF (136 mL) at 0 °C. After 1 h, 2-bromopropan-1-ol (16.7 g, 114.2 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure. The crude residue was redissolved in MTBE (136 mL) and concentrated. The crude residue was then dissolved in MTBE (136 mL) and stirred for 30 min. Triphenylphosphine oxide was filtered off and the filtrate was concentrated. The crude residue was purified by flash column chromatography (silica, 0% to 30% isopropyl acetate-heptane) to give 1-[3-(2-bromopropyl)pyrazol-1-yl]ethanone (11.5 g, 46.5 mmol, 49% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 3.0 Hz, 1H), 5.99 (d, J = 3.0 Hz, 1H), 4.54-4.31 (m, 3H), 2.58 (s, 3H), 1.83-1.76 (m, 3H).

[0096] Step 2: Synthesis of 3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole TIFF2024528656000067.tif12170 Potassium carbonate (12.9 g, 93.1 mmol) was added to a solution of 1-[3-(2-bromopropoxy)pyrazol-1-yl]ethanone (11.5 g, 46.5 mmol) in MeOH (17.4 mL) and MeCN (116 mL). The reaction was sealed with a yellow cap and heated at 80° C. for 16 h. After cooling to room temperature, the reaction was filtered through a pad of Celite® using dichloromethane. The filtrate was carefully concentrated under reduced pressure (200 torr, bath temperature 60° C.). The crude residue was taken to the next step without further purification.

[0097] Step 3: 7-Bromo-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole TIFF2024528656000068.tif17170 N-Bromosuccinimide (8.29 g, 46.6 mmol) was added portionwise to a solution of 3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (crude, 5.78 g, 46.6 mmol) residue in MeCN (186 mL) at 0 °C. After 1 h, the reaction was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate-heptane) to give 7-bromo-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (8.1 g, 40 mmol, 86% yield over two steps). 1 H NMR (400 MHz, chloroform-d) δ 7.30 (s, 1H), 5.22-5.11 (m, 1H), 4.70-4.58 (m, 2H), 1.56 (d, J=6.0 Hz, 3H).

[0098] Step 4: Synthesis of 7-(S-amino-N-trityl-sulfonimidoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole TIFF2024528656000069.tif22170 n-Butyllithium (2.5M in hexanes, 6.5 mL, 16 mmol) was added to a solution of 7-bromo-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (3.0 g, 15 mmol) in THF (74 mL) at -78 °C. After 20 min, a solution of [diphenyl-(sulfinylamino)methyl]benzene (5.0 g, 16 mmol) in THF (30 mL) was added to the reaction mixture over 5 min. The reaction was stirred at -78 °C for 20 min, at which point the reaction was placed in a 0 °C ice bath and stirred for an additional 10 min. 1,3-Dichloro-5,5-dimethylhydantoin (2.90 g, 15 mmol) was added and the reaction was continued to stir at 0 °C for 30 min. Ammonia (gas) was bubbled through the reaction for 10 minutes, then the reaction was stirred at room temperature for an additional 2 hours. The reaction was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 50% isopropyl acetate-heptane) to give 7-(S-amino-N-trityl-sulfonimidoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (3.4 g, 7.6 mmol, 52% yield).

[0099] Example L4: Synthesis of 2,2-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate: TIFF2024528656000070.tif13170To a solution of 1H-pyrazol-3(2H)-one (20.0 g, 238 mmol) in DCM (300 mL) was added triethylamine (37 mL, 267 mmol) at 0 °C. After 10 min, Boc2O (57.11 g, 262 mmol) in DCM (100 mL) was added dropwise. After the addition, the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and the crude residue was dissolved in water (100 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (2.8 g, 6% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ=10.92(s,1H),7.97(d,J=3.2 Hz,1H),5.89(d,J=2.8 Hz,1H),1.53(s,9H).

[0100] Step 2: Synthesis of tert-butyl 3-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-1-carboxylate: TIFF2024528656000071.tif31170 To a solution of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (2.8 g, 15.2 mmol) in MeCN (56 mL) was added K2CO3 (4.2 g, 30.4 mmol) at room temperature under nitrogen atmosphere. The reaction was heated at 80 °C. After 1 h, ethyl 2-bromo-2-methylpropanoate (3.0 g, 15.2 mmol) was added and the mixture was stirred at 80 °C for another 16 h. After cooling to room temperature, the reaction mixture was filtered and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to give tert-butyl 3-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (3.1 g, yield: 68%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.84(d,J=2.8 Hz,1H),5.87(d,J=3.2 Hz,1H),4.22(q,J=6.8 Hz,2H),1.70(s,6H),1.59(s,9H),1.23(t,J=7.2 Hz,3H).

[0101] Step 3: Synthesis of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropan-1-ol: TIFF2024528656000072.tif26170To a suspension of LiAlH4 (1.2 g, 31.17 mmol) in THF (90 mL) was added a solution of tert-butyl 3-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (3.1 g, 10.39 mmol) in THF (20 mL) dropwise at 0 °C under nitrogen atmosphere. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 min. The reaction was quenched by the addition of saturated aqueous Na2SO4. The resulting mixture was dried over Na2SO4. The solids were removed by filtration and the filtrate was concentrated to give 2-((1H-pyrazol-5-yl)oxy)-2-methylpropan-1-ol (1.5 g, 92% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ=9.45(s,1H),7.39(d,J=2.4 Hz,1H),5.80(d,J=2.4 Hz,1H),4.85(s,1H),3.63(s,2H),1.37(s,6H).

[0102] Step 4: Synthesis of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropyl methanesulfonate: TIFF2024528656000073.tif26170 To a stirred solution of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropan-1-ol (1.1 g, 7.04 mmol) and triethylamine (2.93 mL, 21.13 mmol) in DCM (33 mL) was added MsCl (0.5 mL, 7.04 mmol) under nitrogen atmosphere at 0 °C. After 1 h, water (10 mL) was added. The aqueous layer was extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give 2-((1H-pyrazol-5-yl)oxy)-2-methylpropyl methanesulfonate (600 mg, 14% yield) as a yellow oil. MS: m / z 234.9 (M+H + ).

[0103] Step 5: Synthesis of 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000074.tif21170 To a solution of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropyl methanesulfonate (500 mg, 0.79 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 38 mg, 0.95 mmol) at 0 °C under nitrogen atmosphere. After the addition, the reaction was allowed to warm to room temperature and stirred for an additional 12 h. The reaction was cooled to 0 °C and saturated aqueous NH4Cl (3 mL) was added. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (180 mg, 50% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=7.36(d,J=2.0 Hz,1H),5.30(d,J=1.6 Hz,1H),4.03(s,2H),1.63(s,6H).

[0104] Step 6: Synthesis of 7-bromo-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000075.tif23170 To a solution of 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (150 mg, 1.09 mmol) in MeCN (5 mL) was added NBS (193 mg, 1.09 mmol) at 0 °C. After the addition, the reaction was allowed to warm to room temperature. After 1 h, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-30% EtOAc in petroleum ether) to give 7-bromo-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (120 mg, yield: 51%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ=7.32(s,1H),4.07(s,2H),1.67(s,6H).

[0105] Step 7: Synthesis of 2,2-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000076.tif281707-Bromo-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (120 mg, 0.55 mmol) in THF (5 mL) was added dropwise at -78 °C under nitrogen atmosphere with n-BuLi (2.5 M in hexanes, 0.3 mL, 0.61 mmol). After 30 min, a solution of TrtNSO (186 mg, 0.61 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at -78 °C for 30 min, at which point the reaction was placed in a 0 °C ice bath where the reaction was stirred for an additional 10 min. tert-Butyl hypochlorite (0.1 mL, 0.6 mmol) was added at 0 °C. After 30 min, NH3 gas was bubbled through the mixture for 10 min. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 h. The mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-80% EtOAc in petroleum ether) to give 2,2-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide as a white solid, 120 mg, 50% yield. MS: m / z 481.1 (M+Na + ).

[0106] Example L5: Synthesis of 3,3-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of di-tert-butyl 1-(1-hydroxy-2-methylpropan-2-yl)hydrazine-1,2-dicarboxylate TIFF2024528656000077.tif14170To a stirred mixture of Mn(dmp)3 (872 mg, 1.4 mmol) in 2-propanol (240 mL), 2-methyl-2-propen-1-ol (8 g, 110.94 mmol) and phenylsilane (12 g, 110.9 mmol) were added under N2 atmosphere. Di-tert-butyl azodicarboxylate (38.3 g, 166.4 mmol) was then added portionwise to the reaction mixture at 0°C. The mixture was stirred under N2 atmosphere at 0°C for 1 h and then at 25°C for 15 h. The solvent was evaporated and the residue was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to afford di-tert-butyl 1-(1-hydroxy-2-methylpropan-2-yl)hydrazine-1,2-dicarboxylate (31.7 g, yield: 94%) as a white solid. 1 H NMR (400 MHz, methanol-d4): δ = 3.88 (d, J = 10.8 Hz, 1H), 3.49 (d, J = 11.2 Hz, 1H), 1.48 (s, 9H), 1.45 (s, 9H), 1.33 (s, 3H), 1.29 (s, 3H).

[0107] Step 2: Synthesis of 2-hydrazinyl-2-methylpropan-1-ol hydrochloride TIFF2024528656000078.tif111701,4-A solution of 4M HCl (160 mL, 640 mmol) in dioxane was added to di-tert-butyl 1-(1-hydroxy-2-methylpropan-2-yl)hydrazine-1,2-dicarboxylate (15 mg, 49.28 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 15 h. The mixture was concentrated and MTBE (50 mL×3) was added to the crude product. The resulting solid was filtered and dried to give 2-hydrazino-2-methyl-propan-1-ol hydrochloride (7.6 g, yield: 87%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=3.38(s,2H),3.35(s,1H),1.11(s,6H).

[0108] Step 3: Synthesis of ethyl 5-hydroxy-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxylate TIFF2024528656000079.tif22170 A mixture of 2-hydrazino-2-methyl-propan-1-ol hydrochloride (7.6 g, 42.8 mmol) and K2CO3 (11.8 g, 85.6 mmol) in EtOH (152 mL) was stirred at room temperature for 10 min. Then diethyl ethoxymethylenemalonate (9.3 g, 42.8 mmol) was added. The reaction mixture was heated to 90 °C and stirred under N2 atmosphere for 15 h. After cooling to room temperature, the reaction mixture was concentrated. The crude residue was purified by silica gel column chromatography (10% MeOH in DCM) to give ethyl 5-hydroxy-1-(2-hydroxy-1,1-dimethyl-ethyl)pyrazole-4-carboxylate (4.1 g, yield: 42%) as a brown oil. MS: m / z 229.1 (M+H + ).

[0109] Step 4: Synthesis of ethyl 3,3-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-carboxylate TIFF2024528656000080.tif23170 To a solution of ethyl 5-hydroxy-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxylate (3.8 g, 16.4 mmol) and PPh3 (12.9 g, 49.3 mmol) in THF (120 mL) was added DIAD (9.8 mL, 49.3 mmol) dropwise at 0° C. under N2 atmosphere. The reaction was then stirred at 25° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to afford ethyl 3,3-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-carboxylate (2.6 g, yield: 74%) as a light yellow oil. 1 H NMR (400 MHz, CDCl3): δ=7.74(s,1H),4.84(s,2H),4.32-4.23(m,2H),1.59(s,6H),1.33(t,J=7.2 Hz,3H).

[0110] Step 5: Synthesis of 3,3-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-carboxylic acid TIFF2024528656000081.tif22170To a stirred solution of ethyl 3,3-dimethyl-2H-pyrazolo[5,1-b]oxazole-7-carboxylate (2.6 g, 12.1 mmol) in THF (25 mL) and MeOH (25 mL), LiOH·H2O (2.5 g, 60.7 mmol) in water (25 mL) was added. The mixture was stirred at 25 °C for 15 h. The organic solvents were removed under reduced pressure. The pH of the mixture was adjusted to pH = 4 with 2N HCl. The aqueous layer was extracted with 10% MeOH in DCM (50 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated to give 3,3-dimethyl-2H-pyrazolo[5,1-b]oxazole-7-carboxylic acid (2.2 g, yield: 97%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ=12.08(s,1H),7.61(s,1H),4.92(s,2H),1.47(s,6H).

[0111] Step 6: Synthesis of 7-bromo-3,3-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole TIFF2024528656000082.tif18170 To a stirred solution of 3,3-dimethyl-2H-pyrazolo[5,1-b]oxazole-7-carboxylic acid (2.2 g, 11.8 mmol) in DMF (55 mL) was added NBS (2.1 g, 11.9 mmol) and NaHCO3 (1.5 g, 17.7 mmol). The mixture was stirred at 25 °C under N2 atmosphere for 1 h. The reaction mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (30% EtOAc in petroleum ether) to give 7-bromo-3,3-dimethyl-2H-pyrazolo[5,1-b]oxazole (2.5 g, yield: 98%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ=7.31(s,1H),4.74(s,2H),1.57(s,6H).

[0112] Step 7: Synthesis of 3,3-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000083.tif221707-Bromo-3,3-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (510 mg, 2.4 mmol) in THF (10.2 mL) was added dropwise at −78° C. under nitrogen atmosphere to a stirred solution, and the mixture was stirred at this temperature for 1 h. A solution of TrtNSO (804 mg, 2.6 mmol) in THF (10.2 mL) was added dropwise, and the mixture was stirred at −78° C. for 30 min, then placed in an ice bath and stirred at −0° C. for 1 h. Then tert-butyl hypochlorite (0.3 mL, 2.5 mmol) was added to it at 0° C., and the mixture was stirred at 0° C. for 0.5 h. NH3 (excess) gas was then bubbled through the mixture for 20 min at 0 °C, and the resulting solution was stirred for 16 h at 25 °C. The mixture was concentrated and the crude residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in petroleum ether) to give 3,3-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (530 mg, yield: 52%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.42(d,J=7.6 Hz,6H),7.20-7.15(m,6H),7.13-7.05(m,10H),6.41(s,2H),4.74(s,2H),1.41(s,3H),1.37(s,3H).MS:m / z 481.4(M+Na + ).

[0113] Example L6: Synthesis of 2-(methoxymethyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of 1-(3-((1-chloro-3-methoxypropan-2-yl)oxy)-1H-pyrazol-1-yl)ethanone: TIFF2024528656000084.tif181701-(3-hydroxy-1H-pyrazol-1-yl)ethanone (3.0 g, 23.8 mmol), 1-chloro-3-methoxypropan-2-ol (4.5 g, 35.7 mmol), and PPh3 (12.5 g, 47.6 mmol) in anhydrous THF (40 mL) was slowly added dropwise at 0 °C under nitrogen atmosphere to DIAD (9.4 mL, 47.6 mmol). The reaction was allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 0-10% ethyl acetate in petroleum ether) to give 1-(3-((1-chloro-3-methoxypropan-2-yl)oxy)-1H-pyrazol-1-yl)ethanone (1.84 g, 33%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ=8.07(d,J=3.2 Hz,1H),6.02(d,J=3.2 Hz,1H),5.15-5.03(m,1H),3.95-3.80(m,2H),3.76(d,J=4.8 Hz,2H),3.44(s,3H),2.58(s,3H).

[0114] Step 2: Synthesis of 2-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000085.tif23170A mixture of 1-(3-((1-chloro-3-methoxypropan-2-yl)oxy)-1H-pyrazol-1-yl)ethanone (1.84 g, 7.9 mmol), K2CO3 (3.28 g, 23.7 mmol) and KI (0.26 g, 1.6 mmol) in DMF (20 mL) was stirred at 120 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in petroleum ether) to give 2-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (750 mg, 62%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=7.35(d,J=1.2 Hz,1H),5.45-5.37(m,1H),5.34(d,J=2.0 Hz,1H),4.34(t,J=9.2 Hz,1H),4.16-4.11(m,1H),3.72(d,J=4.8 Hz,2H),3.45(s,3H).MS:m / z 155.1(M+H + ).

[0115] Step 3: Synthesis of 7-bromo-2-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000086.tif25170To a stirred solution of 2-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (750 mg, 4.87 mmol) in MeCN (10 mL) was added NBS (952 mg, 5.35 mmol) portionwise at 0 °C. After 1 h, the reaction was quenched with water (30 mL). The aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 0-20% EtOAc in petroleum ether) to give 7-bromo-2-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (820 mg, 72%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ=7.29(s,1H),5.50-5.42(m,1H),4.36(t,J=9.2 Hz,1H),4.26-4.16(m,1H),3.79-3.71(m,2H),3.45(s,3H).

[0116] Step 4: Synthesis of 2-(methoxymethyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000087.tif28170 To a solution of 7-bromo-2-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (400 mg, 1.72 mmol) in THF (10 mL) was added 2.5 M n-BuLi (2.5 M in hexane, 0.77 mL, 1.92 mmol) under N2 atmosphere at -78 °C. After 1 h, a solution of TrtNSO (587 mg, 1.92 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78 °C for 30 min and then placed in an ice bath at 0 °C. After stirring at 0 °C for an additional 1 h, tert-butyl hypochlorite (0.21 mL, 1.87 mmol) was added to the solution at 0 °C. After 30 min, NH3 gas was bubbled through the mixture for 20 min. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 h. The mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 0-3% methanol in DCM) to give 2-(methoxymethyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (720 mg, yield: 88%) as a brown solid.

[0117] Example L7: Synthesis of 3-(methoxymethyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of 1-benzyloxy-3-chloro-propan-2-ol and 3-benzyloxy-2-chloro-propan-1-ol: TIFF2024528656000088.tif11170To a stirred solution of 3-benzyloxypropane-1,2-diol (21.0 g, 115 mmol) and triphenylphosphine (39.3 g, 150 mmol) in toluene (750 mL) was added DIAD (35.0 g, 173 mmol) dropwise at 0 °C. After 30 min, TMSCl (3.1 g, 28.5 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 16 h. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and petroleum ether (1:10; 200 mL) were added to the crude residue and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, 15% EtOAc in petroleum ether) to give both 1-benzyloxy-3-chloro-propan-2-ol (4.2 g, yield: 18%) and 3-benzyloxy-2-chloro-propan-1-ol (8.1 g, yield: 35%) as colorless oils. :1 H NMR (400 MHz, CDCl3): δ = 7.28-7.05 (m, 5H), 4.50-4.38 (m, 2H), 3.86 (t, J = 5.6 Hz, 1H), 3.54-3.42 (m, 4H). 3-Benzyloxy-2-chloro-propan-1-ol: 1 H NMR (400 MHz, CDCl3): δ=7.25-7.11(m,5H),4.43(s,2H),4.00(s,1H),3.77-2.77(m2H),3.59(d,J=6.0 Hz,2H).

[0118] Step 2: Synthesis of 1-(3-(3-(benzyloxy)-2-chloropropoxy)-1H-pyrazol-1-yl)ethan-1-one: TIFF2024528656000089.tif17170To a solution of 2-acetyl-1H-pyrazol-5-one (5.5 g, 43.6 mmol), 3-benzyloxy-2-chloro-propan-1-ol (8.75 g, 43.6 mmol) and PPh3 (17.2 g, 65.4 mmol) in THF (120 mL) was slowly added DIAD (8.8 g, 43.6 mmol) under nitrogen atmosphere at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (0-10% ethyl acetate in petroleum ether) to give 1-(3-(3-(benzyloxy)-2-chloropropoxy)-1H-pyrazol-1-yl)ethanone (silica, 8.9 g, yield: 66%) as a colorless oil. 1 H NMR(400 MHz, CDCl3): δ 8.07(d,J=2.8 Hz,1H),7.38-7.28(m,5 H),5.99(d,J=2.8 Hz,1H),4.61(s,2H),4.60-4.54(m,1H),4.52-4.46(m,1H),4.39-4.36(m,1H),3.85-3.75(m,2H),2.58(s,3H).

[0119] Step 3: Synthesis of 3-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole: A mixture of 1-(3-(3-(benzyloxy)-2-chloropropoxy)-1H-pyrazol-1-yl)ethanone (9.7 g, 31.4 mmol), K2CO3 (13.0 g, 94.3 mmol) and KI (1.0 g, 6.3 mmol) in DMF (130 mL) was stirred at 120 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 10% to 30% ethyl acetate in petroleum ether) to give 3-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (3.7 g, yield: 51%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=7.36-7.27(m,4H),7.26-7.21(m,2H),5.31(d,J=2.0 Hz,1H),5.12-5.03(m,1H),4.97-4.93(m,1H),4.69-4.57(m,1H),4.48(s,2H),3.86-3.83(m,1H),3.77-3.71(m,1H).MS:m / z 231.0(M+H + ).

[0120] Step 4: Synthesis of (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanol: TIFF2024528656000091.tif171703-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (3.7 g, 16.1 mmol) and 10% Pd (1.7 g, 1.6 mmol) in ethanol on carbon (300 mL) were stirred under H2 atmosphere (15 psi) at 25° C. for 72 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to give (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanol (1.7 g crude, yield: 76%) as a white solid. 1 H NMR(400 MHz,DMSO-d6):δ 7.25(d,J=2.0 Hz,1H),5.32(d,J=2.0 Hz,1H),5.12(t,J=8.8 Hz,1H),4.95-4.91(m,1H),4.57-4.51(m,1H),3.75-3.61(m,2H).

[0121] Step 5: Synthesis of 3-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000092.tif22170 To a solution of (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanol (1.58 g, 11.3 mmol) in anhydrous DMF (40 mL) was added NaH (60% in mineral oil, 0.54 g, 13.5 mmol) at 0 °C under N2 atmosphere. After 0.5 h, CHI (1.4 mL, 22.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction was quenched with water (30 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 0-60% ethyl acetate in petroleum ether) to afford 3-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (1.5 g, yield: 86%) as a yellow oil. 1 H NMR (CDCl3,400 MHz): δ=7.34(d,J=1.6 Hz,1H),5.30(d,J=2.0 Hz,1H),5.08(t,J=8.8 Hz,1H),4.98-4.90(m,1H),4.65-4.55(m,1H),3.81-3.63(m,2H),3.33(s,3H).

[0122] Step 6: Synthesis of 7-bromo-3-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000093.tif17170 To a stirred solution of 3-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (1.5 g, 9.73 mmol) in MeCN (30 mL) under nitrogen atmosphere at 0 °C, NBS (1.9 g, 10.7 mmol) was added portionwise. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (silica, 0-40% EtOAc in ether in petroleum) to give 7-bromo-3-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (1.72 g, yield: 76%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.31(s,1H)5.18-5.09(m,1H),5.04-4.97(m,1H),4.71-4.64(m,1H),3.76-3.69(m,2H),3.38(s,3H).

[0123] Step 7: Synthesis of 3-(methoxymethyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000094.tif191707-Bromo-3-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (1.7 g, 7.3 mmol) in THF (30 mL) was added n-BuLi (2.5 M, 3.3 mL, 8.2 mmol) at -78 °C, and the mixture was stirred at this temperature for 1 h under nitrogen atmosphere. A solution of TrtNSO (2.7 g, 8.8 mmol) in THF (10 mL) was added dropwise, and the mixture was stirred at -78 °C for 30 min, then placed in an ice bath and stirred under nitrogen atmosphere for 1 h. tert-Butyl hypochlorite (0.9 mL, 7.7 mmol) was then added to the solution at 0 °C, and the resulting mixture was stirred at 0 °C. NH3 gas was then bubbled through the mixture at 0 °C for 20 min, and the resulting solution was stirred at 25 °C for 16 h. The mixture was concentrated and the crude residue was purified by flash column chromatography (silica, 0-3% methanol in dichloromethane) to give 3-(methoxymethyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (850 mg, 28%) as a brown solid. MS: m / z 497.1 (M+Na + ).

[0124] Example L8: Synthesis of 2-(methoxymethyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate: TIFF2024528656000095.tif25170 To a stirred solution of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (9.0 g, 48.8 mmol) in MeCN (180 mL) was added K2CO3 (13.5 g, 97.7 mmol) and diethyl 2-bromo-2-methylmalonate (12.4 g, 48.8 mmol). The mixture was stirred at 80 °C. After 16 h, the reaction mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 10% EtOAc in petroleum ether) to give diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate (16 g, yield: 92%) as a colorless oil. MS: m / z 256.9 (M-Boc+H + ).

[0125] Step 2: Synthesis of 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol: TIFF2024528656000096.tif21170 A solution of LiAlH4 (4.26 g, 112.2 mmol) in THF (125 mL) was added dropwise to a stirred solution of diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate (10 g, 28.0 mmol) in THF (200 mL) at 0° C. After 2 h, the reaction was quenched with water (4.3 mL), 15% NaOH (4.3 ml) and water (8.6 mL) at 0° C. The mixture was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol (1.0 g, yield: 21%) as a colorless oil, which was used in the next step without further purification. MS: m / z 173.2 (M+H + ).

[0126] Step 3: Synthesis of tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate: TIFF2024528656000097.tif23170To a suspension of 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol (4.5 g, 26.1 mmol), DMAP (318 mg, 2.6 mmol) and TEA (5.52 ml, 39.0 mmol) in DCM (60 mL) was added (Boc)2O (4.5 g, 26.1 mmol) in DCM (10 ml) dropwise at 0° C. The reaction was allowed to warm to room temperature. After 2 h the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography (silica, 50% EtOAc in petroleum ether) to give tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (1.8 g, yield: 25%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=7.86(d,J=2.4 Hz,1H),5.87(d,J=2.8 Hz,1H),4.24-4.00(m,2H),3.90-3.64(m,4H),1.59(s,9H),1.43-1.32(m,3H).

[0127] Step 4: Synthesis of (2-methyl-2,3-dihydropyrazolo[5,1-b]oxazol-2-yl)methanol: TIFF2024528656000098.tif24170To a solution of compound tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (370.0 g, 75.4% assay, 1.02 mol, 1.0 eq.) in pyridine (3.7 L), SOCl2 (243.8 g, 2.05 mol, 2.0 eq.) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. MTBE was added and then the pyridine HCl salt was removed by filtration. The filtrate was concentrated. The residue was dissolved in MTBE (2 L) and washed with 6N. HCl (500 mL), saturated NaHCO3 (500 mL) and water (500 mL). The organic layer was dried over Na2SO4 and concentrated to give compound tert-butyl 3-((5-methyl-2-oxide-1,3,2-dioxathian-5-yl)oxy)-1H-pyrazole-1-carboxylate (421.0 g, purity 64.8%), which was used directly in the next step.

[0128] To a solution of compound tert-butyl 3-((5-methyl-2-oxido-1,3,2-dioxathiane-5-yl)oxy)-1H-pyrazole-1-carboxylate (420.0 g, crude, 1.32 mol, 1.00 equiv.) in DMF (4.2 L) was added K2CO3 (546.9 g, 3.96 mol, 3.0 equiv.). The mixture was heated to 120° C. and stirred for 16 h. The mixture was cooled to 25° C., filtered, and concentrated. The residue was purified on a silica gel column (eluted with DCM:MeOH=10:1) to give compound (2-methyl-2,3-dihydropyrazolo[5,1-b]oxazol-2-yl)methanol (240.0 g, 50% assay, purity 80.1%, yield 76.0% for two steps). LCMS: 155.2 ([M+H] + ).

[0129] Step 5: Synthesis of (7-bromo-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazol-2-yl)methanol: TIFF2024528656000099.tif24170To a solution of compound (2-methyl-2,3-dihydropyrazolo[5,1-b]oxazol-2-yl)methanol (240.0 g, 50% assay, 0.78 mol, 1.0 equiv.) in MeCN (2.4 L) was added NBS (138.6 g, 0.778 mol, 1.0 equiv.) at 0° C. The mixture was stirred at 25° C. for 2 h. After concentration, the residue was dissolved in DCM (2.4 L), washed with brine (2.4 L) and dried over anhydrous Na2SO4. After concentration, the residue was purified by silica gel column (eluted with heptane:EtOAc=5:1) to give the compound (7-bromo-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazol-2-yl)methanol (140.0 g, purity 95.2%, 77% assay, yield 59.4%) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6):δ 7.33(s,1H),4.27(d,J=9.4 Hz,1H),4.05(d,J=9.4 Hz,1H),3.58(dd,J=32.6,12.2 Hz,2H),1.50(s,3H).

[0130] Step 6: Synthesis of 7-bromo-2-(methoxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000100.tif27170 Compound (7-bromo-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazol-2-yl)methanol (104.0 g, 77% assay, 343 mmol, 1.0 equiv.) in DMF (800 mL) was added NaH (15.1 g, 60%, 377 mmol, 1.1 equiv.) under N2 at 0°C. The mixture was stirred at 0°C for 15 min, then MeI (97.5 g, 687 mmol, 2.0 equiv.) was added dropwise. The mixture was stirred at 25°C for 1 h. After concentration, the residue was dissolved in DCM (30 V), washed with brine (30 V) and dried over anhydrous Na2SO4. After concentration, the residue was purified by silica gel column (eluted with heptane:EtOAc=5:1) to give 7-bromo-2-(methoxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (53.0 g, 95.8% assay, 95.5% purity, 59.8% yield). 1 H NMR (400 MHz, CDCl3): δ 7.29(s,1H),4.36(d,J=9.2 Hz,1H),3.95(d,J=9.6 Hz,1H),3.60(d,J=10.4 Hz,2H),3.52(d,J=10.0 Hz,2H),3.42(s,3H),1.63(s,3H).LCMS:247.0,249.0([M+H] + ).

[0131] Step 7: Synthesis of 2-(methoxymethyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000101.tif281707-Bromo-2-(methoxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (500 mg, 2.0 mmol) in THF (10 mL) was added dropwise at -78 °C under N2 atmosphere to a solution of n-BuLi (2.5 M in hexanes, 0.97 mL, 2.4 mmol). After 1 h, a solution of TrtNSO (1.2 g, 2.0 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at -78 °C for 20 min and then placed in an ice bath at 0 °C. After stirring for an additional 10 min, tert-butyl hypochlorite (958 mg, 2.4 mmol) was added. The reaction was stirred for 20 min and then NH3 gas was bubbled through the mixture for 5 min. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 h. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography (silica, 50% EtOAc in petroleum ether) to give 2-(methoxymethyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (600 mg, yield: 61%) as a white solid. MS: m / z 511.0 (M+Na + ).

[0132] Example L9: Synthesis of 3-((dimethylamino)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of 3-((tert-butoxycarbonyl)amino)propane-1,2-diyl dimethanesulfonate: TIFF2024528656000102.tif23170 To a solution of tert-butyl 2,3-dihydroxypropylcarbamate (5.0 g, 26.2 mmol) and TEA (18.1 mL, 130.7 mmol) in DCM (54 mL) was added MsCl (5.3 mL, 68.2 mmol) at 0 °C. The reaction was allowed to warm to room temperature. After 16 h, the reaction was quenched with water (50 mL). The aqueous layer was extracted with DCM (150 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 3-((tert-butoxycarbonyl)amino)propane-1,2-diyldimethanesulfonate (8.5 g, yield: 94%) as a yellow solid, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ=5.09-4.91(m,2H),4.50-4.44(m,1H),4.39-4.33(m,1H),3.59-3.40(m,2H),3.13(s,3H),3.09(s,3H),1.46(s,9H).

[0133] Step 2: Synthesis of tert-butyl ((2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methyl)carbamate: TIFF2024528656000103.tif14170 To a solution of 1,2-dihydropyrazol-3-one (2.0 g, 23.8 mmol) and K2CO3 (11.5 g, 83.3 mmol) in DMF (80 mL) was added 3-((tert-butoxycarbonyl)amino)propane-1,2-diyldimethanesulfonate (8.5 g, 24.5 mmol). The reaction was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction was quenched with water (100 mL). The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (silica, 30% EtOAc in petroleum ether) to afford tert-butyl ((2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methyl)carbamate (1.5 g, yield: 26%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.16(d,J=1.6 Hz,1H),5.24(d,J=1.6 Hz,1H),4.99(t,J=8.8 Hz,1H),4.72-4.70(m,1H),4.55-4.45(m,1H),3.66-3.54(m,1H),3.47-3.45(m,1H),1.34(s,9H).

[0134] Step 3: Synthesis of (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanamine: TIFF2024528656000104.tif17170 To a stirred solution of tert-butyl ((2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methyl)carbamate (2.9 g, 12.1 mmol) in EtOAc (15 mL) was added 4N HCl / EtOAc (15 mL) at room temperature. After 2 h, the mixture was concentrated under reduced pressure to give (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanamine (1.7 g of HCl salt) as a white solid, which was used directly in the next step without further purification.

[0135] Step 4: Synthesis of 1-(2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)-N,N-dimethylmethanamine: TIFF2024528656000105.tif18170 To a solution of (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanamine (1.7 g, 12.2 mmol) in MeOH (120 mL) was added formaldehyde (1 mL, 36.7 mmol) and AcOH (1.8 mL, 30.5 mmol) at 0 °C. After 5 min, NaBH3CN (3.1 g, 48.9 mmol) was added and the mixture was stirred at 25 °C for 16 h. The reaction was quenched with NaHCO3 (adjusted to pH = 8). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (silica, 2% MeOH in DCM) to give 1-(2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)-N,N-dimethylmethanamine (1.6 g, yield: 78%) as a white solid. MS: m / z 168.1 (M+H + ). 1 H NMR (400 MHz, CDCl3): δ=7.35(d,J=1.6 Hz,1H),5.32(d,J=1.6 Hz,1H),5.14-5.07(m,1H),4.95-4.87(m,1H),4.60-4.51(m,1H),2.90-2.84(m,1H),2.66-2.57(m,1H),2.28(s,6H).

[0136] Step 5: Synthesis of 1-(2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)-N,N-dimethylmethanamine: TIFF2024528656000106.tif141701-To a stirred solution of (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)-N,N-dimethylmethanamine (1.0 g, 5.98 mmol) in MeCN (30 mL) was added NBS (1.1 g, 5.98 mmol) at room temperature. After 30 min, the reaction was quenched with saturated aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted with EtOAc (50 ml). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (silica, 2% MeOH in DCM) to give 1-(7-bromo-2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)-N,N-dimethylmethanamine (1.3 g, yield: 88%) as a yellow solid. 1 H NMR(400 MHz, CDCl3):δ=7.30(s,1H),5.22-5.10(m,1H),5.02-4.92(m,1H)4.67-4.54(m,1H),2.88-2.80(m,1H),2.67-2.57(m,1H),2.28(s,6H).

[0137] Step 6: Synthesis of 3-((dimethylamino)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000107.tif281To a solution of 1-(7-bromo-2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)-N,N-dimethylmethanamine (1.3 g, 5.3 mmol) in THF (30 mL) at 70-78 °C was added n-BuLi (2.5 M in hexanes, 2.5 mL, 6.34 mmol) dropwise under nitrogen atmosphere. After 1 h, a solution of TrtNSO (1.9 g, 6.33 mmol) in THF (10 mL) was added dropwise. The reaction was stirred at -78 °C for 20 min and then placed in an ice bath at 0 °C. After stirring for an additional 10 min, tert-butyl hypochlorite (632 mg, 5.8 mmol) was added. The reaction was stirred for 20 min and then NH3 gas was bubbled through the mixture for 5 min. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 h. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography (silica, 3% MeOH in DCM) to give 3-((dimethylamino)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (600 mg, yield: 23%) as a white solid. MS: m / z 510.1 (M+Na + ).

[0138] Example L10: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of 1-benzyloxy-3-chloro-propan-2-ol and 3-benzyloxy-2-chloro-propan-1-ol: TIFF2024528656000108.tif11170To a stirred solution of 3-benzyloxypropane-1,2-diol (21.0 g, 115 mmol) and triphenylphosphine (39.3 g, 150 mmol) in toluene (750 mL) was added DIAD (35.0 g, 173 mmol) dropwise at 0 °C. After 30 min, TMSCl (3.1 g, 28.5 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 16 h. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and petroleum ether (1:10; 200 mL) were added to the crude residue and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, 15% EtOAc in petroleum ether) to give both 1-benzyloxy-3-chloro-propan-2-ol (4.2 g, yield: 18%) and 3-benzyloxy-2-chloro-propan-1-ol (8.1 g, yield: 35%) as colorless oils. :1 H NMR (400 MHz, CDCl3): δ = 7.28-7.05 (m, 5H), 4.50-4.38 (m, 2H), 3.86 (t, J = 5.6 Hz, 1H), 3.54-3.42 (m, 4H). 3-Benzyloxy-2-chloro-propan-1-ol: 1 H NMR (400 MHz, CDCl3): δ=7.25-7.11(m,5H),4.43(s,2H),4.00(s,1H),3.77-2.77(m2H),3.59(d,J=6.0 Hz,2H).

[0139] Step 2: Synthesis of 1-(3-((1-(benzyloxy)-3-chloropropan-2-yl)oxy)-1H-pyrazol-1-yl)ethanone: TIFF2024528656000109.tif13170To a solution of 2-acetyl-1H-pyrazol-5-one (2.7 g, 21.0 mmol), 1-benzyloxy-3-chloro-propan-2-ol (4.2 g, 20.9 mmol) and triphenylphosphine (8.3 g, 31.5 mmol) in THF (100 mL), DIAD (4.3 g, 21.0 mmol) was added slowly at 0° C. under N2 atmosphere. The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica, 10% EtOAc in petroleum ether) to give 1-(3-((1-(benzyloxy)-3-chloropropan-2-yl)oxy)-1H-pyrazol-1-yl)ethanone (2.2 g, yield: 33%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=8.08(d,J=3.2 Hz,1H),7.41-7.31(m,5H),6.03(d,J=3.2 Hz,1H),5.16-5.12(m,1H),4.70-4.58(m,2H),4.02-3.95(m,1H),3.93-3.83(m,3H),2.57(s,3H).

[0140] Step 3: Synthesis of 2-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000110.tif23170A mixture of 1-(3-((1-(benzyloxy)-3-chloropropan-2-yl)oxy)-1H-pyrazol-1-yl)ethanone (400 mg, 1.4 mmol), K2CO3 (565 mg, 4.1 mmol) and KI (45 mg, 0.27 mmol) in DMF (6 mL) was stirred at 120 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 30% EtOAc in petroleum ether) to give 2-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (240 mg, yield: 77%) as a colorless oil. MS: m / z 231.0 (M+H + )

[0141] Step 4: Synthesis of 2,3-dihydropyrazolo[5,1-b]oxazol-2-ylmethanol: TIFF2024528656000111.tif21170 A mixture of 2-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole on carbon (420 mg, 1.8 mmol) and Pd (190 mg, 0.18 mmol) in EtOH (40 mL) was stirred under H2 atmosphere at 25 °C for 72 h. The reaction mixture was filtered through a short pad of Celite. The filtrate was concentrated to give 2,3-dihydropyrazolo[5,1-b]oxazol-2-ylmethanol (210 mg, yield: 82%) as a white solid. MS: m / z 140.8 (M+H) 1.0 (H ... + ).

[0142] Step 5: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000112.tif21170To a solution of 2,3-dihydropyrazolo[5,1-b]oxazol-2-ylmethanol (440 mg, 3.14 mmol) and imidazole (860 mg, 12.6 mmol) in DCM (50 mL) was added TBSCl (1.4 g, 9.42 mmol) at 25 °C. After 16 h, the reaction was quenched with water (20 mL). The aqueous layer was extracted with DCM (60 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 20% EtOAc in petroleum ether) to afford 2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (650 mg, yield: 81%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=7.33(d,J=2.0 Hz,1H),5.36-5.26(m,2H),4.34-4.27(m,1H),4.23-4.17(m,1H),3.94-3.90(m,2H),0.85(s,9H),0.09(s,3H),0.05(s,3H).

[0143] Step 6: Synthesis of 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000113.tif24170 To a stirred solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (650 mg, 2.6 mmol) in MeCN (20 mL) was added NBS (0.5 g, 2.8 mmol). The resulting solution was stirred at 0 °C for 1 h. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography (silica, 0-20% EtOAc in petroleum ether) to give 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (750 mg, yield: 88%) as a white solid. 1 H NMR(400 MHz, CDCl3): δ=7.28(s,1H),5.45-5.30(m,1H),4.40-4.27(m,2H),4.04-3.97(m,1H),3.93-3.86(m,1H),0.85(s,9H),0.10(s,3H),0.07(s,3H).

[0144] Step 7: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000114.tif27170 To a solution of (7-bromo-2,3-dihydropyrazolo[5,1-b]oxazol-2-yl)methoxy-tert-butyl-dimethyl-silane (750 mg, 2.3 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 1.0 mL, 2.5 mmol) dropwise under N2 atmosphere at -78 °C. The mixture was stirred at -78 °C for 1 h, then a solution of TrtNSO (756 mg, 2.5 mmol) in THF (6 mL) was added dropwise and the mixture was stirred at -78 °C for 20 min. After stirring at 0 °C for 10 min, t-BuOCl (0.3 mL, 2.7 mmol) was added. The reaction mixture was stirred at 0 °C for 20 min, then NH3 gas was bubbled through the mixture for 5 min. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 h. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography (10-30% EtOAc in petroleum ether) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (730 mg, 49% yield) as a yellow oil. MS: m / z 597.1 (M+Na + ).

[0145] Example L11: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of 1-benzyloxy-3-chloro-propan-2-ol and 3-benzyloxy-2-chloro-propan-1-ol: TIFF2024528656000115.tif11170To a stirred solution of 3-benzyloxypropane-1,2-diol (21.0 g, 115 mmol) and triphenylphosphine (39.3 g, 150 mmol) in toluene (750 mL) was added DIAD (35.0 g, 173 mmol) dropwise at 0 °C. After 30 min, TMSCl (3.1 g, 28.5 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 16 h. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and petroleum ether (1:10; 200 mL) were added to the crude residue and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, 15% EtOAc in petroleum ether) to give both 1-benzyloxy-3-chloro-propan-2-ol (4.2 g, yield: 18%) and 3-benzyloxy-2-chloro-propan-1-ol (8.1 g, yield: 35%) as colorless oils. :1 H NMR (400 MHz, CDCl3): δ = 7.28-7.05 (m, 5H), 4.50-4.38 (m, 2H), 3.86 (t, J = 5.6 Hz, 1H), 3.54-3.42 (m, 4H). 3-Benzyloxy-2-chloro-propan-1-ol: 1 H NMR (400 MHz, CDCl3): δ=7.25-7.11(m,5H),4.43(s,2H),4.00(s,1H),3.77-2.77(m2H),3.59(d,J=6.0 Hz,2H).

[0146] Step 2: Synthesis of 1-(3-(3-(benzyloxy)-2-chloropropoxy)-1H-pyrazol-1-yl)ethan-1-one: TIFF2024528656000116.tif19170To a solution of 2-acetyl-1H-pyrazol-5-one (5.5 g, 43.6 mmol), 3-benzyloxy-2-chloro-propan-1-ol (8.75 g, 43.6 mmol) and PPh3 (17.2 g, 65.4 mmol) in THF (120 mL) was slowly added DIAD (8.8 g, 43.6 mmol) under nitrogen atmosphere at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (0-10% ethyl acetate in petroleum ether) to give 1-(3-(3-(benzyloxy)-2-chloropropoxy)-1H-pyrazol-1-yl)ethanone (silica, 8.9 g, yield: 66%) as a colorless oil. 1 H NMR(400 MHz, CDCl3): δ 8.07(d,J=2.8 Hz,1H),7.38-7.28(m,5 H),5.99(d,J=2.8 Hz,1H),4.61(s,2H),4.60-4.54(m,1H),4.52-4.46(m,1H),4.39-4.36(m,1H),3.85-3.75(m,2H),2.58(s,3H).

[0147] Step 3: Synthesis of 3-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole: A mixture of 1-(3-(3-(benzyloxy)-2-chloropropoxy)-1H-pyrazol-1-yl)ethanone (9.7 g, 31.4 mmol), K2CO3 (13.0 g, 94.3 mmol) and KI (1.0 g, 6.3 mmol) in DMF (130 mL) was stirred at 120 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 10% to 30% ethyl acetate in petroleum ether) to give 3-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (3.7 g, yield: 51%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=7.36-7.27(m,4H),7.26-7.21(m,2H),5.31(d,J=2.0 Hz,1H),5.12-5.03(m,1H),4.97-4.93(m,1H),4.69-4.57(m,1H),4.48(s,2H),3.86-3.83(m,1H),3.77-3.71(m,1H).MS:m / z 231.0(M+H + ).

[0148] Step 4: Synthesis of (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanol: A mixture of 3-((benzyloxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (3.7 g, 16.1 mmol) and 10% wt Pd (1.7 g, 1.6 mmol) in ethanol on carbon (300 mL) was stirred under H2 atmosphere (15 psi) at 25° C. for 72 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to give (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanol (1.7 g crude, yield: 76%) as a white solid. 1 H NMR(400 MHz,DMSO-d6):δ 7.25(d,J=2.0 Hz,1H),5.32(d,J=2.0 Hz,1H),5.12(t,J=8.8 Hz,1H),4.95-4.91(m,1H),4.57-4.51(m,1H),3.75-3.61(m,2H).

[0149] Step 5: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000119.tif18170 To a solution of (2,3-dihydropyrazolo[5,1-b]oxazol-3-yl)methanol (1.5 g, 10.7 mmol) and imidazole (2.9 g, 42.8 mmol) in DCM (150 mL) was added TBSCl (4.8 g, 32.1 mmol) at 25 °C. The resulting mixture was stirred at 25 °C under N2 atmosphere for 16 h. The reaction was quenched with H2O (20 mL) and extracted with DCM (60 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (silica, 10-20% EtOAc in petroleum ether) to give 3-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (2.1 g, yield: 77%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=7.32(d,J=1.6 Hz,1H),5.28(d,J=1.6 Hz,1H),5.11-4.98(m,2H),4.60-4.51(m,1H),3.96-3.91(m,2H),0.83(s,9H),0.04(s,3H),-0.04(s,3H).

[0150] Step 6: Synthesis of 7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000120.tif18170 To a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (2.0 g, 7.8 mmol) in acetonitrile (40 mL) was added 1-bromo-2,5-pyrrolidinedione (1.5 g, 8.6 mmol) in portions at 0 °C, which was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography (silica, 0-20% EtOAc in petroleum ether) to give 7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (1.8 g, yield: 69%) as a white solid. 1 H NMR(400 MHz, CDCl3):δ=7.29(s,1H),5.16-5.04(m,2H),4.65-4.58(m,1H),4.01-3.94(m,1 H),3.91-3.85(m,1H),1.50-1.49(m,1H),0.83(s,9H),0.04(s,3H),-0.04(s,3H).

[0151] Step 7: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide TIFF2024528656000121.tif22170 To a solution of 7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole (500 mg, 1.5 mmol) in THF (4 mL) was added n-BuLi (2.5 M in hexanes, 0.8 mL, 1.9 mmol) dropwise at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 0.5 h, then a solution of TrtNSO (504 mg, 1.6 mmol) in THF (10 mL) was added dropwise and the mixture was stirred at −78° C. for 20 min and at 0° C. for 10 min. t-BuOCl (0.2 mL, 1.9 mmol) was then added and the mixture was stirred for 20 min. NH3 gas was then bubbled through the mixture at 0° C. for 5 min. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 h. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography (silica, 10-30% EtOAc in petroleum ether) to give 3-(((tert-butyldimethylsilyl)oxy)methyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (320 mg, 37% yield) as a yellow oil. MS: m / z 597.1 (M+Na + ).

[0152] Example L12: Step 8-Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide Step 1: Synthesis of diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate: TIFF2024528656000122.tif28170 To a stirred solution of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (9.0 g, 48.8 mmol) in MeCN (180 mL) was added K2CO3 (13.5 g, 97.7 mmol) and diethyl 2-bromo-2-methylmalonate (12.4 g, 48.8 mmol). The mixture was stirred at 80 °C. After 16 h, the reaction mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 10% EtOAc in petroleum ether) to give diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate (16 g, yield: 92%) as a colorless oil. MS: m / z 256.9 (M-Boc+H + ).

[0153] Step 2: Synthesis of 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol: TIFF2024528656000123.tif21170 A solution of LiAlH4 (4.26 g, 112.2 mmol) in THF (125 mL) was added dropwise to a stirred solution of diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate (10 g, 28.0 mmol) in THF (200 mL) at 0° C. After 2 h, the reaction was quenched with water (4.3 mL), 15% NaOH (4.3 ml) and water (8.6 mL) at 0° C. The mixture was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol (1.0 g, yield: 21%) as a colorless oil, which was used in the next step without further purification. MS: m / z 173.2 (M+H + ).

[0154] Step 3: Synthesis of tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate: TIFF2024528656000124.tif23170To a suspension of 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol (4.5 g, 26.1 mmol), DMAP (318 mg, 2.6 mmol) and TEA (5.52 ml, 39.0 mmol) in DCM (60 mL) was added (Boc)2O (4.5 g, 26.1 mmol) in DCM (10 ml) dropwise at 0° C. The reaction was allowed to warm to room temperature. After 2 h the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography (silica, 50% EtOAc in petroleum ether) to give tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (1.8 g, yield: 25%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=7.86(d,J=2.4 Hz,1H),5.87(d,J=2.8 Hz,1H),4.24-4.00(m,2H),3.90-3.64(m,4H),1.59(s,9H),1.43-1.32(m,3H).

[0155] Step 4: Synthesis of tert-butyl 3-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate: TIFF2024528656000125.tif24170 To a solution of tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (2.0 g, 7.34 mmol) and imidazole (1.5 g, 22.0 mmol) in DCM (50 mL) was added TBSCl (1.1 g, 7.34 mmol) in DCM (5 mL) dropwise at 0° C. After 2 h, the mixture was concentrated and the crude residue was purified by flash column chromatography (silica, 5% EtOAc in petroleum ether) to give tert-butyl 3-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (1.5 g, yield: 53%) as a colorless oil. MS: m / z 409.1 (M+Na + ).

[0156] Step 5: Synthesis of tert-butyl 3-[1-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-2-methylsulfonyloxy-ethoxy]pyrazole-1-carboxylate: To a mixture of TIFF2024528656000126.tif25170TEA (1.35 mL, 9.31 mmol) and tert-butyl 3-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (1.8 g, 4.66 mmol) in DCM (36 mL) was added MsCl (0.43 mL, 5.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h and at 25° C. for 0.5 h. The reaction mixture was diluted with DCM (20 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-[1-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-2-methylsulfonyloxy-ethoxy]pyrazole-1-carboxylate (2.1 g, yield: 97%) as a colorless oil, which was used in the next step without further purification. MS: m / z 487.1 (M+Na + ).

[0157] Step 6: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000127.tif21170 A mixture of tert-butyl 3-[1-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-2-methylsulfonyloxy-ethoxy]pyrazole-1-carboxylate (2.1 g, 4.52 mmol) and K2CO3 (1.87 g, 13.56 mmol) in DMF (50 mL) was stirred at 120 °C. After 16 h, the reaction was cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 10% EtOAc in petroleum ether) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (800 mg, yield: 66%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=7.33(d,J=2.0 Hz,1H),5.27(s,1H),4.32(d,J=9.2 Hz,1H),3.91(d,J=9.2 Hz,1H),3.83-3.74(m,1H),3.70-3.61(m,1H),1.58(s,3H),0.84(s,9H),0.05(d,J=14.4 Hz,6H).

[0158] Step 7: Synthesis of 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000128.tif22170 To a stirred solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (600 mg, 2.2 mmol) in MeCN (20 mL) was added NBS (358 mg, 2.0 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction was filtered and concentrated. The crude residue was purified by flash column chromatography (silica, 30% EtOAc in petroleum ether) to give 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (650 mg, yield: 91%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ=7.28(s,1H),4.41(d,J=9.2 Hz,1H),3.97(d,J=9.2 Hz,1H),3.82(d,J=10.8 Hz,1H),3.67(d,J=10.8 Hz,1H),1.60(s,3H),0.82(s,9H),0.07(s,3H),0.03(s,3H).

[0159] Step 8: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000129.tif251707-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (350 mg, 1.0 mmol) in THF (10 mL) was added dropwise at −78° C. under a N2 atmosphere to a solution of n-BuLi (2.5 M in hexanes, 0.48 mL, 1.2 mmol). After 1 h, a solution of TrtNSO (615 mg, 2.0 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at −78° C. for 20 min and then placed in an ice bath at 0° C. After stirring for an additional 10 min, tert-butyl hypochlorite (131 mg, 1.2 mmol) was added. The reaction was stirred for 20 min and then NH3 gas was bubbled through the mixture for 5 min. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 h. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography (silica, 50% EtOAc in petroleum ether) to afford 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (240 mg, 40% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ=7.55(d,J=7.6 Hz,6H),7.26-7.18(m,9H),7.18-7.13(m,3H),4.35(d,J=9.2 Hz,1H),3.92-3.78(m,2H),3.70-3.60(m,1H),1.62(s,3H),0.79(d,J=2.4 Hz,9H),0.06(s,3H),0.03(s,3H).

[0160] Example R1: Tricyclo[6.2.0.0 3,6 Synthesis of ]deca-1,3(6),7-trien-2-amine Step 1: Synthesis of 1,4-bis(2-bromoethyl)benzene: TIFF2024528656000130.tif24170 A mixture of 2,2'-(1,4-phenylene)diethanol (3 g, 18.1 mmol) in HBr (30 mL) was stirred at 100 °C. After 20 h, the mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1,4-bis(2-bromoethyl)benzene (4.8 g, yield: 91%) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ=7.18(s,4H),3.57(t,J=7.6 Hz,4H),3.16(t,J=7.6 Hz,4H).

[0161] Step 2: Synthesis of 1,4-dibromo-2,5-bis(2-bromoethyl)benzene: TIFF2024528656000131.tif23170To a mixture of 1,4-bis(2-bromoethyl)benzene (4 g, 13.7 mmol) in CHCl3 (40 mL), I2 (104 mg, 0.4 mmol), Fe (77 mg, 1.4 mmol) and Br2 (1.75 mL, 34.3 mmol) were added at room temperature. After 16 h, the mixture was diluted with water (200 mL). The aqueous layer was extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 1,4-dibromo-2,5-bis(2-bromoethyl)benzene (5.6 g, yield: 91%) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ=7.47(s,2H),3.58(t,J=7.6 Hz,4H),3.25(t,J=7.6 Hz,4H).

[0162] Step 3: Tricyclo[6.2.0.0 3,6 Synthesis of ]deca-1,3(6),7-triene: TIFF2024528656000132.tif14170-100 °C, to a mixture of 1,4-dibromo-2,5-bis(2-bromoethyl)benzene (10 g, 22.3 mmol) in THF (100 mL) was added n-BuLi (17.8 mL, 44.5 mmol). After 30 min, the reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from EtOH (10 mL) to give tricyclo[6.2.0.0]. 3,6 ]Deca-1,3(6),7-triene (1.5 g, yield: 46%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3): δ=6.80(s,2H),3.13(s,8H).

[0163] Step 4: 2-Iodotricyclo[6.2.0.0 3,6 Synthesis of ]deca-1,3(6),7-triene: TIFF2024528656000133.tif19170 Tricyclo[6.2.0.0 in HOAc (10 mL) 3,6 A mixture of ]deca-1,3(6),7-triene (500 mg, 3.8 mmol) and NBS (1.3 g, 5.8 mmol) was stirred at 70 °C. After 3 h, the mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 100% petroleum ether) to give 2-iodotricyclo[6.2.0.0]. 3,6 ]Deca-1,3(6),7-triene (300 mg, yield: 31%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3): δ=6.74(s,1H),3.01(s,8H).

[0164] Step 5: tert-Butyltricyclo[6.2.0.0 3,6 Synthesis of Deca-1,3(6),7-trien-2-ylcarbamate: TIFF2024528656000134.tif18170A mixture of BocNH2 (131 mg, 1.2 mmol), Pd2(dba)3 (36 mg, 0.04 mmol), Xphos (37 mg, 0.08 mmol), t-BuOK (137 mg, 1.2 mmol) and 2-iodotricyclo[6.2.0.0]dibromo[3.2.0.1]propanediol (1.0 mg, 0.02 mmol) in toluene (3 mL). 3,6 A mixture of tert-butyltricyclo[6.2.0.0]deca-1,3(6),7-triene (100 mg, 0.4 mmol) was stirred at 100 °C under a N2 atmosphere. After 12 h, the reaction was cooled to 25 °C and the reaction mixture was filtered and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 100% petroleum ether) to give tert-butyltricyclo[6.2.0.0]deca-1,3(6),7-triene (100 mg, 0.4 mmol). 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamate (60 mg, yield: 63%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3): δ=6.55(s,1H),6.18(s,1H),3.16(d,J=4.0 Hz,4H),3.05(d,J=4.0 Hz,4H),1.52(s,9H).

[0165] Step 6: Tricyclo[6.2.0.0 3,6 Synthesis of Deca-1,3(6),7-trien-2-amine: TIFF2024528656000135.tif17170 tert-Butyltricyclo[6.2.0.0 in DCM (6 mL) 3,6 To a mixture of 1,3(6),7-deca-1,3(6),7-trien-2-ylcarbamate (500 mg, 2.0 mmol) was added TFA (2 mL) at room temperature. After 2 h, the mixture was diluted with water (50 mL) and the solution was adjusted to pH = 8 by adding saturated aqueous NaHCO3 solution. The mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 20% EtOAc in petroleum ether) to give tricyclo[6.2.0.0]. 3,6 ]Deca-1,3(6),7-trien-2-amine (220 mg, yield: 74%) was obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ=6.33(s,1H),3.46(s,2H),3.09-2.97(m,8H).

[0166] Example R2: 7-Bromotricyclo[6.2.0.0 3,6 Synthesis of ]deca-1,3(6),7-trien-2-amine TIFF2024528656000136.tif20170 Tricyclo[6.2.0.0 3,6 To a solution of ]deca-1,3(6),7-trien-2-amine (100 mg, 0.7 mmol) in acetonitrile (5 mL) under nitrogen atmosphere at 0 °C was added NBS (123 mg, 0.7 mmol). After 1 h, the mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 0–7% EtOAc in petroleum ether) to give 7-bromotricyclo[6.2.0.0]. 3,6 ]Deca-1,3(6),7-trien-2-amine (140 mg, yield: 91%) was obtained as a light yellow solid. 1 H NMR(400 MHz,CDCl3):δ=3.46(s,2H),3.04-2.98(m,4H),2.97-2.90(m,4H).MS:m / z 224.0(M+H + ).

[0167] Example R3: 7-fluorotricyclo[6.2.0.0 3,6 Synthesis of ]deca-1,3(6),7-trien-2-amine Step 1: 2-Bromo-7-fluorotricyclo[6.2.0.0 3,6 Synthesis of ]deca-1,3(6),7-triene: TIFF2024528656000137.tif171707-Bromotricyclo[6.2.0.0 3,6To a stirred solution of ]deca-1,3(6),7-trien-2-amine (140 mg, 0.6 mmol) in HF / pyridine (2.5 mL, 0.6 mmol) under nitrogen at 0° C. was added isopentyl nitrite (0.2 mL, 0.9 mmol). The reaction was then heated to 60° C. for 2 h. After cooling to room temperature, the reaction was diluted with EtOAc (50 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (silica, 100% petroleum ether) to give 2-bromo-7-fluorotricyclo[6.2.0.0]. 3,6 ]Deca-1,3(6),7-triene (110 mg, yield: 78%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3): δ=3.12-3.04(m,8H).

[0168] Step 2: N-(diphenylmethylene)-7-fluorotricyclo[6.2.0.0 3,6 Synthesis of Deca-1,3(6),7-trien-2-amine: TIFF2024528656000138.tif171702-Bromo-7-fluorotricyclo[6.2.0.0 3,6 A mixture of ]deca-1,3(6),7-triene (110 mg, 0.5 mmol), benzophenone imine (176 mg, 1.0 mmol), Ruphos Pd G3 (41 mg, 0.05 mmol) and t-BuONa (140 mg, 1.5 mmol) in toluene (4 mL) was stirred at 100 °C for 15 h under nitrogen atmosphere. After cooling to room temperature, water (10 mL) was added. The aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give N-(diphenylmethylene)-7-fluorotricyclo[6.2.0.0]. 3,6 ]Deca-1,3(6),7-trien-2-amine (155 mg crude) was obtained as a brown oil, which was used directly in the next step without further purification. MS: m / z 328.1 (M+H + ).

[0169] Step 3: 7-Fluorotricyclo[6.2.0.0 3,6 Synthesis of Deca-1,3(6),7-trien-2-amine: TIFF2024528656000139.tif18170N-(diphenylmethylene)-7-fluorotricyclo[6.2.0.0 3,6 To a solution of ]deca-1,3(6),7-trien-2-amine (155 mg crude) in THF (3 mL) was added 2M HCl (3 mL, 6 mmol) at room temperature. After 2 h, the reaction mixture was poured into saturated aqueous NaHCO3 solution (15 mL). The aqueous layer was extracted with 10% methanol in dichloromethane (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (silica, 10% EtOAc in petroleum ether) to give 7-fluorotricyclo[6.2.0.0]. 3,6 ]Deca-1,3(6),7-trien-2-amine (70 mg, yield: 91%) was obtained as a yellow solid. 1 H NMR(400 MHz,CDCl3):δ=3.38(s,2H),3.10-3.05(m,4H),3.00-2.95(m,4H).MS:m / z 164.1(M+H + ).

[0170] Example R4: Synthesis of 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine Step 1: Synthesis of 5-bromo-2,3-dihydro-1H-inden-4-ol TIFF2024528656000140.tif17170To a solution of 2,3-dihydro-1H-inden-4-ol (10 g, 74 mmol) and i-Pr2NH (1.05 mL, 7 mmol) in DCM (80 mL) was added NBS (13.3 g, 75 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL). The aqueous layer was extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (100% petroleum ether) to give 5-bromo-2,3-dihydro-1H-inden-4-ol (12 g, yield: 76%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ=7.23(d,J=8.0 Hz,1H),6.70(d,J=8.0 Hz,1H),5.55(s,1H),2.96-2.85(m,4H),2.15-2.07(m,2H).

[0171] Step 2: Synthesis of 4-(benzyloxy)-5-bromo-2,3-dihydro-1H-indene TIFF2024528656000141.tif17170 To a mixture of 5-bromo-2,3-dihydro-1H-inden-4-ol (12 g, 52.32 mmol) and K2CO3 (15.57 g, 112.64 mol) in MeCN (100 mL) was added BnBr (7.4 mL, 62 mmol). The reaction mixture was stirred at 80 °C for 3 h. The mixture was quenched with water (80 mL). The aqueous layer was extracted with EtOAc (60 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (100% petroleum ether) to give 4-(benzyloxy)-5-bromo-2,3-dihydro-1H-indene (11 g, yield: 64%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ=7.55-7.50(m,2H),7.44-7.32(m,4H),6.88(d,J=8.0 Hz,1H),5.01(s,2H),2.97-2.83(m,4H),2.14-1.97(m,2H).

[0172] Step 3: Synthesis of 7-(benzyloxy)-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-1-one TIFF2024528656000142.tif18170 To a stirred solution of 4-benzyloxy-5-bromo-indane (4.0 g, 13.2 mmol) in THF (60 mL) was added NaNH2 (2.1 g, 52.7 mmol) and 1,1-diethoxyethylene (3.1 g, 26.4 mmol). The reaction mixture was stirred at 70 °C under nitrogen atmosphere for 2 h. After cooling to room temperature, the reaction mixture was poured into ice water and the pH was adjusted to pH = 2 by adding 4N HCl. The aqueous layer was extracted with EtOAc (60 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (5% EtOAc in petroleum ether) to give 7-(benzyloxy)-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-1-one (1 g, yield: 28%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ=7.48-7.45(m,2H),7.40-7.31(m,3H),6.93(s,1H),5.52(s,2H),3.80(s,2H),2.96(t,J=7.6 Hz,2H),2.87(t,J=7.6 Hz,2H),2.16-2.07(m,2H).

[0173] Step 4: Synthesis of 7-(benzyloxy)-1-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-1-ol TIFF2024528656000143.tif21170To a stirred solution of 7-(benzyloxy)-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-1-one (1.2 g, 4.5 mmol) in THF (24 mL) was added MeMgBr (1.8 mL, 5.5 mmol) dropwise at -78 °C under nitrogen atmosphere. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 20 min. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL). The aqueous layer was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to give 7-(benzyloxy)-1-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-1-ol (1.1 g, yield: 86%) as a white solid. 1 H NMR(400 MHz, CDCl3):δ=7.49-7.44(m,2H),7.41-7.37(m,2H),7.35-7.30(m,1H),6.70(s,1H),5.50-5.39(m,1H),5.35-5. 23(m,1H),3.34-3.23(m,1H),3.20-3.06(m,1H),2.97-2.76(m,4H),2.34(s,1H),2.09-2.02(m,2H),1.77(s,3H).

[0174] Step 5: Synthesis of 7-(benzyloxy)-1-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene TIFF2024528656000144.tif18170To a stirred solution of 7-(benzyloxy)-1-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (1.1 g, 3.9 mmol) and Et3SiH (0.75 mL, 4.7 mmol) in DCM (44 mL), BF3·Et2O (0.6 mL, 4.7 mmol) was added dropwise at -78 °C. After addition, the reaction mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with DCM (50 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to afford 7-(benzyloxy)-1-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (740 mg, yield: 71%) as a yellow oil. 1 H NMR(400 MHz, CDCl3):δ=7.46-7.36(m,4H),7.34-7.30(m,1H),6.65(s,1H),5.29-5.20(m,1H),5.19-5.13(m,1H),3. 65-3.50(m,1H),3.32-3.27(m,1H),2.92-2.86(m,4H),2.63-2.59(m,1H),2.08-1.99(m,2H),1.52(d,J=6.8 Hz,3H).

[0175] Step 6: Synthesis of 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ol TIFF2024528656000145.tif17170A mixture of 7-(benzyloxy)-1-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (740 mg, 2.8 mmol) and 10% Pd (296 mg, 0.3 mmol) on carbon in MeOH (74 mL) was stirred at room temperature under H2 atmosphere for 1 h. The suspension was filtered through a pad of Celite® and the pad was washed with MeOH (20 mL x 3). The combined filtrate was concentrated and the crude residue was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to give 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ol (450 mg, yield: 92%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ=6.62(s,1H),4.45(s,1H),3.60-3.46(m,1H),3.28-3.23(m,1H),2.91(t,J=7.6 Hz,2H),2.81(t,J=7.2 Hz,2H),2.58-2.55(m,1H),2.11-2.03(m,2H),1.44(d,J=6.8 Hz,3H).

[0176] Step 7: Synthesis of 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl trifluoromethanesulfonate TIFF2024528656000146.tif19170To a stirred solution of 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ol (450 mg, 2.6 mmol) and pyridine (1.04 mL, 12.9 mmol) in DCM (38 mL), Tf2O (0.52 mL, 3.1 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 h. The reaction was quenched with water (50 mL). The aqueous layer was extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to afford 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl trifluoromethanesulfonate (0.7 g, yield: 88.5%) as a colorless oil. 1 H NMR(400 MHz, CDCl3):δ=6.96(s,1H),3.67-3.64(m,1H),3.34-3.29(m,1H),2.97-2.88(m,4H),2.64-2.60(m,1H),2.21-2.06(m,2H),1.43(d,J=6.8 Hz,3H).

[0177] Step 8: Synthesis of N-(diphenylmethylene)-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine A mixture of 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl trifluoromethanesulfonate (700 mg, 2.3 mmol), diphenylmethanimine (497 mg, 2.8 mmol), BINAP (214 mg, 0.4 mmol), Pd(OAc)2 (90 mg, 0.4 mmol) and Cs2CO3 (1.5 g, 4.6 mmol) in 1,4-dioxane (23 mL) was stirred at 100 °C for 4 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of NH4Cl (20 mL). The aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (10 mL), saturated brine (10 mL) and evaporated under reduced pressure to give N-(diphenylmethylene)-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (1 g crude) as a yellow oil, which was used directly in the next step. MS: m / z 338.4 (M+H + ).

[0178] Step 9: Synthesis of 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine TIFF2024528656000148.tif18170 To a solution of N-(diphenylmethylene)-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (1 g, 2.9 mmol) in THF (25 mL) was added 2NHCl (25 mL). The mixture was stirred at room temperature for 15 min. The reaction mixture was then poured into saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with DCM (20 mLx2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to give 2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (340 mg, yield: 66%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.50(s,1H),3.55-3.40(m,3H),3.25-3.21(m,1H),2.89(t,J=7.2 Hz,2H),2.69(t,J=7.2 Hz,2H),2.56-2.53(m,1H),2.13-2.01(m,2H),1.41(d,J=6.8 Hz,3H).

[0179] Example R5: Synthesis of 7-bromo-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine: TIFF2024528656000149.tif191702,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (600 mg, 3.8 mmol) in acetonitrile (28 mL) was added 1-bromo-2,5-pyrrolidinedione (704 mg, 4.0 mmol) at 0 °C. After 1 h, the mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 7% EtOAc in petroleum ether) to give 7-bromo-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (810 mg, yield: 90%) as a brown solid. MS: m / z 240.0 (M+2+H + ).

[0180] Example R6: Synthesis of 3-fluoro-7-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene Step 1: Synthesis of 3-bromo-7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene: TIFF2024528656000150.tif17170 To a stirred solution of 7-bromo-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (810 mg, 3.4 mmol) in HF / Py (14 mL, 3.4 mmol) was added isopentyl nitrite (0.7 mL, 5.1 mmol) at 0° C. The mixture was heated at 60° C. for 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL) and water (50 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 100% petroleum ether) to afford 3-bromo-7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (640 mg, yield: 78%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ=3.11-3.04(m,4H),3.00(t,J=7.6 Hz,2H),2.92(t,J=7.6 Hz,2H),2.15-2.05(m,2H).

[0181] Step 2: Synthesis of N-(diphenylmethylene)-7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine: TIFF2024528656000151.tif171703-Bromo-7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (640 mg, 2.65 mmol), benzophenone imine (722 mg, 4.0 mmol), Ruphos Pd G3 (222 mg, 0.3 mmol) and tBuONa (765 mg, 8.0 mmol) in toluene (20 mL) were stirred at 100 °C for 15 h under nitrogen atmosphere. After cooling to room temperature, water (20 mL) was added. The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude N-(diphenylmethylene)-7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (1.5 g) as a brown oil, which was used directly in the next step without further purification. MS: m / z 342.1 (M+H + ).

[0182] Step 3: Synthesis of 7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine: TIFF2024528656000152.tif18170 To a solution of N-(diphenylmethylene)-7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (1.5 g crude) in THF (19.3 mL) was added 2M HCl (19.3 mL, 38.6 mmol) at room temperature. After 2 h, the reaction mixture was poured into saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with 10% MeOH in DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 25% EtOAc in petroleum ether) to give 7-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (410 mg, yield: 87% over two steps) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ=3.35(s,2H),3.10-3.03(m,2H),3.01-2.95(m,2H),2.91(t,J=7.6 Hz,2H),2.71(t,J=7.2 Hz,2H),2.17-2.06(m,2H).MS:m / z 178.1(M+H + ).

[0183] Step 4: Synthesis of 3-fluoro-7-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene: To a solution of TIFF2024528656000153.tif181707-Fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (230 mg, 1.3 mmol) and TEA (0.4 mL, 2.6 mmol) in anhydrous THF (12 mL) was added triphosgene (193 mg, 0.6 mmol) under nitrogen atmosphere at 0° C. After 1 h, the reaction was filtered and the filtrate was used directly in the next step.

[0184] Example R - Synthesis of 8-isocyanato-1-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene: Step 1: Synthesis of 1-(methoxymethylene)-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (E / Z mixture) TIFF2024528656000154.tif15170 Methoxymethyl(triphenyl)phosphonium chloride (11.1 g, 32.2 mmol) was dried under reduced pressure at 50° C. for 3.5 hours, then suspended in THF (100 mL) and cooled to −78° C. Then n-BuLi (2.5 mol / L in hexanes, 13.0 mL, 32.5 mmol) was added and the mixture was stirred at −78° C. for 45 minutes (the mixture became orange), then stirred at room temperature for another 15 minutes, then cooled again to −78° C. 8-Nitro-3,5,6,7-tetrahydro-2H-s-indacen-1-one (5.0 g, 23 mmol) in 50 mL of THF was added and the mixture was allowed to warm to room temperature overnight. The mixture became dark. After approximately 23 hours, the reaction was quenched (water 10 mL) and diluted with hexanes (100 mL), then filtered and concentrated. The residue was dissolved in EtOAc (approximately 200 mL) and washed with water and brine (approximately 100 mL each). The organic phase was then dried (Na2SO4), filtered and concentrated. Purification by column chromatography (0-10% EtOAc / hexanes) afforded 1.73 g (7.05 mmol, 31%; E / Z mixture) of the desired product as an orange oil that solidified upon cooling. MS: m / z 246.000 (M+H + ) and 246.100(M+H + ), E / Z isomer.

[0185] Step 2: Synthesis of 3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine TIFF2024528656000155.tif151701-(Methoxymethylene)-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (E / Z mixture, 705 mg, 2.87 mmol) was dissolved in ethanol (29 mL) in a 100 mL round bottom flask. Pd(OH)2 on carbon (20 wt % loading (dry basis), containing ≦50% water, 404 mg) was added. The flask was carefully evacuated and filled with nitrogen three times. The flask was then evacuated and filled with hydrogen. The mixture was stirred at room temperature for 2 h, then filtered and concentrated to give 3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (614 mg, 2.83 mmol, 98%; yellow oil), which was used in the next step without further purification. MS: m / z 218.050 (M+H + ).

[0186] Step 3: Synthesis of 8-isocyanato-1-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene: TIFF2024528656000156.tif18170 In a screw-cap vial, bis(trichloromethyl)carbonate (280 mg, 0.944 mmol) was carefully added to a solution of 3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (614 mg, 2.83 mmol) and triethylamine (0.95 mL, 0.69 g, 6.8 mmol) in THF (9.4 mL) and the mixture was stirred for 1 h 10 min at 70° C. The THF was then removed under reduced pressure and the crude product was suspended in heptane and filtered to remove Et3NHCl. The filtrate was concentrated to give 8-isocyanato-1-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene (602 mg, 2.47 mmol, 88%; yellowish solid), which was used in the next step without further purification.

[0187] Example 1: Synthesis of (S,2S)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6]Deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide; (R,2S)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide; (S,2R)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide; and (R,2R)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide TIFF2024528656000157.tif179170

[0188] Step 1: Synthesis of tert-butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate: TIFF2024528656000158.tif13170To a solution of 1H-pyrazol-3(2H)-one (110 g, 1.31 mol) in DCM (1.4 L) was added TEA (199.48 mL, 1.44 mol) at 0 °C. Then, di-tert-butyl dicarbonate (285.5 g, 1.31 mol) in DCM (500 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (0-5% MeOH in DCM) to give the crude product, which was triturated with petroleum ether (400 mL) to give tert-butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate (110 g, yield: 51%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.82(d,J=2.8 Hz,1H),5.91(d,J=2.8 Hz,1H),1.63(s,9H).

[0189] Step 2: Synthesis of diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate: TIFF2024528656000159.tif23170 To a stirred solution of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (9.0 g, 48.8 mmol) in MeCN (180 mL) was added K2CO3 (13.5 g, 97.7 mmol) and diethyl 2-bromo-2-methylmalonate (12.4 g, 48.8 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (10% EtOAc in petroleum ether) to give diethyl 2-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)oxy)-2-methylmalonate (16 g, yield: 92%) as a colorless oil. 1 H NMR(400 MHz, CDCl3)δ=7.84(d,J=2.8 Hz,1H),6.00(d,J=2.8 Hz,1H),4.35-4.21(m,4H),1.97(s,3H),1.58(s,9H),1.29-1.25(m,6H).

[0190] Step 3: Synthesis of 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol: TIFF2024528656000160.tif21170 To a stirred solution of diethyl 2-(1-tert-butoxycarbonylpyrazol-3-yl)oxy-2-methyl-propanedioate (25.0 g, 70.15 mmol) and CaCl2 (11.68 g, 105 mmol) in EtOH (300 mL) and water (20 mL) was added NaBH4 (7.5 g, 198 mmol) in portions at 0° C. The mixture was stirred at room temperature for 16 h. After cooling to 0° C., water (10 mL) was slowly added to the reaction mixture, followed by 4N HCl solution until pH=4. The resulting mixture was filtered and the filtrate was concentrated to give 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol (10 g crude) as a colorless oil. 1 H NMR(400 MHz,CD3OD)δ=7.45(d,J=2.4 Hz,1H),5.82(d,J=2.4 Hz,1H),3.72-3.62(m,4H),1.22(s,3H).MS:m / z 173.2(M+H + ).

[0191] Step 4: Synthesis of tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate: To a mixture of 2-((1H-pyrazol-3-yl)oxy)-2-methylpropane-1,3-diol (20 g crude, 116.16 mmol), DMAP (1.42 g, 11.62 mmol) and TEA (32.65 mL, 232.32 mmol) in DCM (1000 mL) was added (Boc)2O (25.35 g, 116.16 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (50% EtOAc in petroleum ether) to give tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (9 g, yield: 28%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=7.88(d,J=2.8 Hz,1H),5.89(d,J=2.8 Hz,1H),4.24-4.00(m,2H),3.90-3.64(m,4H),1.61(s,9H),1.36(s,3H).

[0192] Step 5: Synthesis of tert-butyl 3-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate: TIFF2024528656000162.tif21170 To a solution of tert-butyl 3-((1,3-dihydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (24.2 g, 88.87 mmol) and imidazole (18.15 g, 266.62 mmol) in DCM (500 mL) was added TBSCl (13.39 g, 88.87 mmol) slowly at 0° C. The resulting mixture was stirred at 0° C. for 2 h and then at room temperature for 16 h. The mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel (5% EtOAc in petroleum ether) to give tert-butyl 3-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (11.1 g, yield: 32%) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ=7.87(d,J=2.8 Hz,1H),5.86(d,J=2.8 MS:m / z 409.1(M+Na + ).

[0193] Step 6: Synthesis of tert-butyl 3-[1-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-2-methylsulfonyloxy-ethoxy]pyrazole-1-carboxylate: TIFF2024528656000163.tif23170 To a solution of tert-butyl 3-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpropan-2-yl)oxy)-1H-pyrazole-1-carboxylate (17.8 g, 46.05 mmol) and TEA (13.31 mL, 92.09 mmol) in DCM (200 mL) was added MsCl (4.66 mL, 60.15 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 h and then at room temperature for 2 h. The reaction mixture was quenched with H2O (100 mL) and extracted with DCM (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl 3-[1-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-2-methylsulfonyloxy-ethoxy]pyrazole-1-carboxylate (21 g, yield: 98%) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ=7.85(d,J=2.8 Hz,1H),5.88(d,J=3.2 Hz,1H),4.69(d,J=10.4 Hz,1H),4.49(d,J=10.4 Hz,1H),4.03(d,J=10.0 Hz,1H),3.76(d,J=10.0 Hz,1H),3.02(s,3H),1.61(s,9H),1.51(s,3H),0.90-0.88(m,9H),0.06(d,J=4.4 Hz,6H).MS:m / z 487.1(M+Na + ).

[0194] Step 7: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000164.tif21170 To a solution of tert-butyl 3-[1-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-2-methylsulfonyloxy-ethoxy]pyrazole-1-carboxylate (21.0 g, 45.2 mmol) in DMF (300 mL) was added K2CO3 (18.74 g, 135.59 mmol). The resulting mixture was stirred at 120 °C under nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (20% EtOAc in petroleum ether) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (8.4 g, yield: 69%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ=7.33(d,J=2.0 Hz,1H),5.28(d,J=2.0 Hz,1H),4.32(d,J=9.2 Hz,1H),3.91(d,J=9.2 Hz,1H),3.78(d,J=10.8 Hz,1H),3.66(d,J=10.8 Hz,1H),1.58(s,3H),0.84(s,9H),0.07(s,3H),0.03(s,3H).

[0195] Step 8: Synthesis of 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole: TIFF2024528656000165.tif23170 To a stirred solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (10 g, 37.2 mmol) in MeCN (200 mL) was added NBS (6.63 g, 37.2 mmol) in portions. The resulting solution was stirred at 0° C. for 1 h. The reaction was concentrated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel to give 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (8 g, yield: 62%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ=7.27(s,1H),4.40(d,J=9.2 Hz,1H),3.96(d,J=9.2 Hz,1H),3.82(d,J=10.8 Hz,1H),3.67(d,J=10.8 Hz,1H),1.60(s,3H),0.86-0.79(m,9H),0.07(s,3H),0.03(s,3H).

[0196] Step 9: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000166.tif261707-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole (4.3 g, 12.4 mmol) in THF (100 mL) was added dropwise at −78° C. under nitrogen atmosphere to a solution of n-BuLi (2.5 M in hexanes, 5.9 mL, 14.8 mmol). After 1 h, a solution of TrtNSO (7.56 g, 24.8 mmol) in THF (20 mL) was added dropwise. The reaction was stirred at −78° C. for 20 min and then placed in a 0° C. ice bath. After stirring for an additional 10 min, tert-butyl hypochlorite (1.58 g, 14.6 mmol) was added. The reaction was stirred for 20 min, then NH3 gas was bubbled through the mixture for 5 min. The resulting solution was warmed to room temperature and stirred for an additional 16 h. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography on silica gel (30% EtOAc in petroleum ether) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (4 g, yield: 47%) as a yellow solid. MS: m / z 611.1 (M+Na + ).

[0197] Step 10: 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N-(tricyclo[6.2.0.0 3,6 Synthesis of ]deca-1,3(6),7-trien-2-ylcarbamoyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000167.tif28170 Tricyclo[6.2.0.0 3,6To a stirred solution of ]deca-1,3(6),7-trien-2-amine (600 mg, 4.1 mmol) and TEA (0.8 g, 8.3 mmol) in THF (30 mL) was added triphosgene (612 mg, 2.1 mmol) in one portion at 0° C. The mixture was then stirred at 0° C. for 1 h under a nitrogen atmosphere. The reaction mixture was filtered over a silica gel plug to remove triethylamine hydrochloride. The filtrate was used directly in the next step.

[0198] To a stirred solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (1.9 g, 4.1 mmol) in THF (50 mL) was added MeONa (600 mg, 11.1 mmol) at 0° C. After stirring at 0° C. for 0.5 h, a solution of 2-isocyanatricyclo[6.2.0.03,6]deca-1,3(6),7-triene (crude mixture, 4.1 mmol) in THF (30 mL) was added at 0° C. The reaction mixture was then stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography on silica gel (20% EtOAc in petroleum ether) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (2.4 g, yield: 76%) was obtained as a white solid. MS: m / z 782.4 (M+Na + ).

[0199] Step 11: Synthesis of: (S,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (S,2R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (R,2R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000168.tif25170

[0200] 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N-(tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (2.4 g, 3.2 mmol) was purified using a chiral SFC (Daicel Chiralpak AD 250 mm × 50 mm, 10 μm; supercritical CO2 / IPA + 0.1%). Separation by NH4OH=60 / 40; 200 mL / min gave peak 1 (460 mg, 4.944 min, yield: 19%), peak 2 (430 mg, 5.469 min, yield: 18%), peak 3 (430 mg, 6.133 min, yield: 18%) and peak 4 (430 mg, 7.376, yield: 18%). Stereochemistry was arbitrarily assigned to each stereoisomer.

[0201] Step 12: Synthesis of: (S,2S)-2-(hydroxymethyl)-2-methyl-N-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2S)-2-Hydroxy-2-(hydroxymethyl)-N'-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (S,2R)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, and (R,2R)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-N-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000169.tif28170

[0202] To a solution of peak 1 (460 mg, 0.6 mmol) from step 11 above in THF (5 mL) was added TBAF (1.2 mL, 1.2 mmol). The mixture was stirred at 25° C. for 3 h and then concentrated. The crude residue was purified by flash column chromatography on silica gel (2% MeOH in DCM) to give compound 12a (320 mg, yield: 82%) as a white solid.

[0203] Material from peak 2 from step 11 above was deprotected and isolated similarly to give 12b (250 mg, yield: 64%).

[0204] Material from peak 3 from step 11 above was deprotected and isolated similarly to give 12c (260 mg, yield: 67%).

[0205] Material from peak 4 from step 11 above was deprotected and isolated similarly to give 12d (300 mg, yield: 80%).

[0206] Stereochemistry was arbitrarily assigned to each stereoisomer.

[0207] Step 13: Synthesis of: (S,2S)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2S)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (S,2R)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, and (R,2R)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide TIFF2024528656000170.tif28170

[0208] To a solution of material 12a (320 mg, 0.5 mmol) from step 12 above in DCM (5 mL) was added MeSO3H (143 mg, 1.5 mmol) at 0° C. After stirring for 30 min at 0° C., the reaction mixture was adjusted to pH=8 with saturated aqueous NaHCO3 solution and then concentrated. The residue was purified by flash column chromatography (3% MeOH in DCM) to give one stereoisomer of the final product. Materials 12b, 12c and 12d from step 12 above were deprotected and isolated in the same manner to give the remaining three stereoisomers. Each of the four final products was characterized by chiral SFC according to the following method: Method A: Column: ChiralCel OD-3 150×4.6mm ID, 3um Mobile phase: A: CO2 B: Methanol (0.05% DEA) Isocratic: 5% to 40% B in 5.5 min, hold at 40% for 3 min, then hold at 5% B for 1.5 min Flow rate: 2.5mL / min Column temperature: 40℃ ABPR: 100 psi

[0209] Compound A: Method A, 5.174 min, peak 4, 118.61 mg, yield: 59%. 1 H NMR(400 MHz,DMSO-d6):δ=8.64(s,1H),7.57(s,1H),7.38(s,2H),6.46(s,1H),5.31(s,1H),4.27(d,J=9.6 Hz,1H),4.09(d,J=9.6 Hz,1H),3.70-3.51(m,2H),3.02(s,4H),2.88(s,4H),1.52(s,3H).MS:m / z 426.3(M+Na + ), 404.1(M+H).

[0210] Compound B: Method A, 4.831 min, peak 2, 101.13 mg, yield: 65%. 1H NMR(400 MHz,DMSO-d6):δ=8.64(s,1H),7.56(s,1H),7.37(s,2H),6.46(s,1H),5.34(s,1H),4.27(d,J=9.6 Hz,1H),4.08(d,J=9.6 Hz,1H),3.66-3.49(m,2H),3.03(d,J=2.0 Hz,4H),2.88(s,4H),1.53(s,3H).MS:m / z 404.0(M+H + ).

[0211] Compound C: Method A, 4.997 min, peak 3, 124.93 mg, yield: 77%. 1 H NMR(400 MHz,DMSO-d6):δ=8.65(s,1H),7.56(s,1H),7.37(s,2H),6.46(s,1H),5.33(s,1H),4.27(d,J=9.6 Hz,1H),4.08(d,J=10.0 Hz,1H),3.67-3.50(m,2H),3.02(s,4H),2.88(s,4H),1.53(s,3H).MS:m / z 404.0(M+H + ).

[0212] Compound D: Method A, 4.740 min, peak 1, 82.21 mg, yield: 44%. 1 H NMR(400 MHz,DMSO-d6):δ=8.64(s,1H),7.57(s,1H),7.37(s,2H),6.46(s,1H),5.31(s,1H),4.27(d,J=9.6 Hz,1H),4.09(d,J=9.6 Hz,1H),3.69-3.50(m,2H),3.02(s,4H),2.88(s,4H),1.52(s,3H).MS:m / z 404.0(M+H + ).

[0213] Example 2: Determination of the stereochemistry of compound A X-ray quality crystals of compound A were grown from a saturated 1,2-dichloroethane / ethanol / methanol solution followed by deposition of diffracting crystals by vapor diffusion through diethyl ether, and the structure was unambiguously determined using X-ray crystallography. The structure of compound A is: TIFF2024528656000171.tif30170(R,2R)-2-(hydroxymethyl)-2-methyl-N'-(tricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide

[0214] Example 3: Synthesis of (S,2S)-N'-((7-fluorotricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide; (R,2S)-N'-((7-fluorotricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide; (S,2R)-N'-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide; and (R,2R)-N'-((7-fluorotricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide TIFF2024528656000172.tif112170

[0215] Step 1: (R,2R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0 3,6Synthesis of ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000173.tif281707-Fluorotricyclo[6.2.0.0 3,6 To a stirred solution of ]deca-1,3(6),7-trien-2-amine (500 mg, 3.06 mmol) and TEA (0.85 mL, 6.13 mmol) in THF (20 mL) was added triphosgene (450 mg, 1.53 mmol) in one portion at 0° C. The mixture was then stirred at 0° C. for 1 h under a nitrogen atmosphere. The reaction mixture was filtered over a silica gel plug to remove triethylamine hydrochloride. The filtrate was used directly in the next step.

[0216] To a stirred solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (1.5 g, 2.55 mmol) in THF (15 mL) was added MeONa (413 mg, 7.64 mmol) at 0° C. After stirring at 0° C. for 0.5 h, 2-fluoro-7-isocyanato-tricyclo[6.2.0.0]oxazole-7-sulfonimidamide was added in THF (20 mL). 3,6 A solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0]-2,3-dimethylsilyl)-1,3(6),7-triene (crude mixture, 3.06 mmol) was added at 0° C. The reaction mixture was then stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction was concentrated to dryness and the crude residue was purified by flash column chromatography on silica gel (90% EtOAc in petroleum ether) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0]-2,3-dimethylsilyl)-1,3(6),7-triene (crude mixture, 3.06 mmol)). 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (1.7 g, yield: 86%) was obtained as a white solid. MS: m / z 800.3 (M+Na + ).

[0217] Step 2: Synthesis of: (S,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (S,2R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000174.tif23170

[0218] 2-(((tert-Butyldimethylsilyl)oxy)methyl)-N-((7-fluorotricyclo[6.2.0.0 3,6]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (2.0 g, 2.57 mmol) was separated by chiral SFC (Phenomenex Cellulose-2 (250 mm x 50 mm, 10 um; supercritical CO2 / MeOH+0.1% NH4OH=45 / 55; 200 mL / min) to give peak 1 (440 mg, 2.569 min, yield: 22%), peak 2 (400 mg, 3.132 min, yield: 20%), peak 3 (370 mg, 3.933 min, yield: 19%) and peak 4 (400 mg, 5.720 min, yield: 20%). Stereochemistry was arbitrarily assigned to each stereoisomer.

[0219] Step 3: Synthesis of: (S,2S)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2S)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (S,2R)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2R)-N-((7-fluorotricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000175.tif25170

[0220] To a solution of peak 1 (440 mg, 0.57 mmol) from step 2 above in THF (10 mL) was added TBAF (1.13 mL, 1.13 mmol). The mixture was stirred at 25° C. for 2 h and then concentrated. The crude residue was purified by flash column chromatography on silica gel (80% 80% EtOAc in petroleum ether) to give compound 3a (240 mg, yield: 64%).

[0221] Material from peak 2 from step 2 above was deprotected and isolated similarly to give 3b (200 mg, yield: 59%).

[0222] Material from peak 3 from step 2 above was deprotected and isolated similarly to give 3c (190 mg, yield: 60%).

[0223] Material from peak 4 from step 2 above was deprotected and isolated similarly to give 3d (190 mg, yield: 56%).

[0224] Stereochemistry was arbitrarily assigned to each stereoisomer.

[0225] Step 4: Synthesis of: (S,2S)-N'-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2S)-N'-((7-fluorotricyclo[6.2.0.0 3,6 ]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (S,2R)-N'-((7-fluorotricyclo[6.2.0.0 3,6]deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide, (R,2R)-N'-((7-fluorotricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide: TIFF2024528656000176.tif25170

[0226] To a solution of material 3a (240 mg, 0.36 mmol) from step 3 above in DCM (20 mL) was added MeSO3H (0.12 mL, 1.81 mmol) at 0° C. After stirring for 30 min at 0° C., the reaction mixture was adjusted to pH=8 with saturated aqueous NaHCO3 solution and then concentrated. The residue was purified by flash column chromatography on silica gel (0-8% MeOH in DCM) to give compound E (Method B, 6.215 min, peak 4, 110 mg, yield: 72%). Compound E: 1 H NMR(400 MHz,DMSO-d6):δ=8.72(s,1H),7.55(s,1H),7.37(s,2H),5.34(t,J=5.2 Hz,1H),4.26(d,J=9.6 Hz,1H),4.08(d,J=9.6 Hz,1H),3.63-3.59(m,1H),3.56-3.51(m,1H),3.05(s,4H),2.94(s,4H),1.53(s,3H).MS:m / z 444.0(M+Na + ).

[0227] Material 3b from step 3 above was deprotected and isolated similarly to give compound F (Method B, 5.743 min, peak 2, 100 mg, yield: 79%). Compound F: 1H NMR(400 MHz,DMSO-d6):δ=8.72(s,1H),7.55(s,1H),7.37(s,2H),5.35(t,J=5.2 Hz,1H),4.26(d,J=9.6 Hz,1H),4.08(d,J=9.6 Hz,1H),3.63-3.58(m,1H),3.56-3.51(m,1H),3.04(s,4H),2.93(s,4H),1.53(s,3H).MS:m / z 444.0(M+Na + ).

[0228] Material 3c from step 3 above was deprotected and isolated similarly to give compound G (Method B, 5.989 min, peak 3, 104 mg, yield: 86%). Compound G: 1 H NMR(400 MHz,DMSO-d6):δ=8.73(s,1H),7.57(s,1H),7.38(s,2H),5.32(t,J=5.2 Hz,1H),4.27(d,J=9.6 Hz,1H),4.10(d,J=9.6 Hz,1H),3.69-3.62(m,1H),3.58-3.53(m,1H),3.05(s,4H),2.94(s,4H),1.53(s,3H).MS:m / z 444.0(M+Na + ).

[0229] Material 3d from step 3 above was deprotected and isolated similarly to give compound H (Method B, 5.581 min, peak 1, 98 mg, yield: 81%). Compound H: 1 H NMR(400 MHz,DMSO-d6):δ=8.69(s,1H),7.55(s,1H),7.28(s,2H),5.31(s,1H),4.26(d,J=9.6 Hz,1H),4.08(d,J=9.6 Hz,1H),3.68-3.61(m,1H),3.58-3.51(m,1H),3.04(s,4H),2.93(s,4H),1.52(s,3H).MS:m / z 444.0(M+Na + ).

[0230] Stereochemistry was arbitrarily assigned to each stereoisomer. Method B: Column: ChiralPak AD-3 150×4.6mm ID, 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5% to 40% B in 5.5 min, hold 40% for 3 min, then hold 5% B for 1.5 min Flow rate: 2.5mL / min Column temperature: 40℃ Back pressure: 100 bar

[0231] Based on the structural similarity to Compound A above, the structure of the most potent stereoisomer of this group (Compound G) is believed to be: TIFF2024528656000177.tif34170(R,2R)-N'-((7-Fluorotricyclo[6.2.0.0 3,6 ]Deca-1,3(6),7-trien-2-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide

[0232] Example B1: PMBC IL-1β HTRF Assay The compounds provided herein can be evaluated in the following manner.

[0233] Cell culture and NLRP3 inflammasome activation assay: Human frozen peripheral blood mononuclear cells (PBMCs) are purchased from StemCells Technologies. Cells are rapidly thawed in a 37°C water bath and resuspended in fresh assay medium consisting of RPMI 1640 medium containing 1% sodium pyruvate, 10 mM HEPES, 2.5 g / L glucose and 55 μM 2-mercaptoethanol. The cell density is adjusted to 8.1 × 105 cells / mL. Cells were primed by adding lipopolysaccharide (Invivogen Ultrapure lipopolysaccharide from E. coli, tlrl-3pelps) to a final concentration of 100 ng / mL in the cell suspension. 37 μL of cell suspension containing LPS is seeded per well of a 384-well plate and incubated at 37°C and 5% CO2 for 3 h. After priming, PBMCs are pre-incubated with serially diluted test compounds, starting at 40 μM, followed by 2-fold dilutions for a 20-point curve, or vehicle (DMSO) in assay medium for 30 minutes at 37° C. and 5% CO2. Cells are then stimulated with 10 μM nigericin (Invivogen, tlrl-nig-5) for 90 minutes at 37° C. and 5% CO2 to activate the NLRP3-dependent inflammasome pathway and IL-1β release in cell culture supernatants. Cells are centrifuged at 1200 RPM for 1 minute, and 40 μL of the supernatant is transferred to a new plate and stored at -80° C. until IL-1β analysis.

[0234] IL-1β HTRF assay: Add 16 μL of supernatant to a white 384-well homogeneous time-resolved fluorescence (HTRF) plate, then add 4 μL of HTRF cocktail to each well. The plate is quickly centrifuged, sealed, and incubated overnight at room temperature. The next day, the HTRF signal is read on a Pherastar, and the 665 / 620 ratio is calculated based on the manufacturer's protocol to obtain the concentration of IL-1β in the cell culture supernatant.

[0235] Example B2: THP-1 ASC-GFP speck assay The compounds provided herein can be evaluated in the following manner.

[0236] Cell culture: The THP-1 ASC-GFP cell line is purchased from Invivogen, San Diego for inflammasome activation assays. THP-1 ASC-GFP cells stably express a 37.6 kDa ASC::GFP fusion protein that allows monitoring of speck formation by microscopy following activation of the NLRP3-dependent inflammasome pathway. Cells are maintained at a density of 600,000 cells / mL at 37 °C and 5% CO2 in growth medium consisting of RPMI 1640, 2 mM L-glutamine, 25 mM HEPES and 10% heat-inactivated fetal bovine serum. Cells are passaged every 3-4 days and used for assays for up to 20 passages.

[0237] NLRP3 inflammasome activation assay: Harvest THP-1 ASC-GFP cells by centrifuging the cells at 800 RPM for 5 minutes. Remove cell culture supernatant and resuspend cells in fresh medium at a density of 1 x 106 cells / mL in assay medium consisting of RPMI 1640, 2 mM L-glutamine, 25 mM HEPES and 10% heat-inactivated fetal bovine serum. Add phorbol 12-myristate 13 acetate (PMA) (Invivogen, tlrl-pma) to a final concentration of 500 ng / ml to the cell suspension and mix thoroughly. Add 40,000 cells per well of a 384-well plate and differentiate into macrophages overnight at 37 °C and 5% CO2. Cells are primed with 1 μg / mL lipopolysaccharide (Invivogen Ultrapure lipopolysaccharide from E. coli, tlrl-3pelps) in assay medium for 3 hours at 37° C. and 5% CO2. After priming, medium is removed and THP-1 ASCGFP cells are pre-incubated with serially diluted test compounds, starting at 40 μM, followed by 2-fold dilutions for a 20-point curve, or vehicle (DMSO) in assay medium for 30 minutes at 37° C. and 5% CO2. Cells are then stimulated with 10 μM nigericin (Invivogen, tlrl-nig-5) for 90 minutes at 37° C. and 5% CO2 to activate the NLRP3-dependent inflammasome pathway and speck formation. After stimulation, cells are fixed with 4.8% paraformaldehyde (Electron Microscopy Sciences #15710-S) and incubated at room temperature for 15 minutes. Next, cells are washed three times with 100 μL phosphate-buffered saline and permeabilized in the presence of permeabilization / blocking buffer for 20 min at room temperature. Cells are then washed three times with 100 μL phosphate-buffered saline and incubated in the presence of Hoechst for 1 h at room temperature. After staining with Hoechst, cells are washed three times with 100 μL phosphate-buffered saline and imaged for ASC speck formation.

[0238] Imaging of ASC-GFP specks: THP-1 ASC-GFP cells are imaged in the 488 and Hoechst channels. The Hoechst channel is used for cell count and the 488 channel is used to identify the number of GFP ASC specks in the imaged field of view. The percentage of cells with specks is calculated by dividing the number of GFP positive spots by the total number of cells.

[0239] Example B3: In vitro analysis of compounds A, B, C and D Compounds A, B, C and D from Example 1 were evaluated according to the THP-1 ASC-GFP speck assay described above in Example B2. IC50 values ​​are shown in Table 1. Table 1: TIFF2024528656000178.tif37170

[0240] Example B4: In vitro analysis of compounds E, F, G and H Compounds E, F, G and H from Example 3 were evaluated according to the THP-1 ASC-GFP speck assay described above in Example B2. IC50 values ​​are shown in Table 2. Table 2: TIFF2024528656000179.tif37170

[0241] Example B5: Human whole blood assay The ability of selected compounds to inhibit IL-1β production in human blood was evaluated in a human whole blood assay using lipopolysaccharide.

[0242] Fresh human whole blood (HWB) was obtained from healthy donors. HWB was diluted in a ratio of 1 HWB:0.6 RPMI-1640 medium and lipopolysaccharide (Invivogen Ultrapure lipopolysaccharide from E. coli, tlrl-3pelps) was added to a final concentration of 200ng / mL. 140μL of diluted blood+LPS was seeded per well of a 96-well plate and incubated for 2.25 hours at 37℃ and 5% CO2. After priming, the diluted HWB is pre-incubated with serially diluted test compounds, starting at concentrations of 20μM, followed by 3-fold dilutions for a 10-point curve, or vehicle (DMSO) for 45 minutes at 37℃ and 5% CO2. HWB was then stimulated with ATP at a final concentration of 1.75mM for 1 hour at 37℃ and 5% CO2 to activate the NLRP3 inflammasome pathway and release IL-1β. At the end of stimulation, plates were centrifuged for 2 min × 3000 rpm and the supernatants were transferred to new plates and stored at −80°C until IL-1β analysis. IL-1b levels were measured using an electrochemiluminescence immunoassay with anti-IL-1b antibody as the primary detection agent.

[0243] Example B6: PXR activation assay Hepatoma cells expressing endogenous human AhR or transfected with the hPXR nuclear receptor and corresponding response element were seeded into 96-well plates. 24 hours after seeding, cells were treated with six different concentrations of test compound in duplicate wells, and then the cells were returned to the incubator for an additional 24 hours. At the end of this incubation period, the number of viable cells / well was determined using Promega's Cell Titer Fluor cytotoxicity assay. Following this assay, Promega's ONE-Glo was added to the same wells to assess reporter gene activity.

[0244] Data processed using MS-Excel were presented as the average (n=2) fold receptor activation relative to vehicle-treated cells at each of the six different doses. All activation data was normalized to the number of live cells / well. Results were also expressed as a percentage of the response given by the appropriate positive control (rifampicin) at the 10 μM dose. EC 50 and E max Values ​​were derived for the positive control using non-linear regression of log dose-response curves.

[0245] Example B7: Rat Pharmacokinetic (PK) Study The study was conducted at WuXi AppTech Co.,Ltd (Shanghai, PRChina). Food and water were available ad libitum, except for animals that received oral doses in the pharmacokinetic (PK) study, which were fasted overnight before receiving the test compound. Six male Sprague-Dawley rats, aged 6-9 weeks and weighing 200-300 g, were obtained from Vital River Laboratory Animal Technology Co.,Ltd.,Beijing, PRChina, and randomly assigned into two dose groups (three rats were used for the IV group and three rats were used for the PO group). Animals in group 1 were given a single IV bolus cassette dose of 0.5 mg / kg of test compound in a dose volume of 1 mL / kg, formulated in DMSO / PEG400 / water (10 / 60 / 30). Group 2 animals received a 1 mg / kg PO cassette dose of test compound formulated as a suspension in 0.5% methylcellulose / 0.2% Tween 80 (MCT) in a dose volume of 1 mL / kg. Blood samples were collected via a catheter in the femoral artery into tubes containing K2EDTA as an anticoagulant. Both groups had blood sampled at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. All samples were stored at -80°C until analysis. The concentration of test compound in each blood or plasma sample was determined by LC-MS / MS analysis.

[0246] PK parameters were calculated by non-compartmental methods as described by Gibaldi and Perrier (1982) using Phoenix™ WinNonlin (Certara, Princeton, NJ) version 8.3.4.295. Parameters are presented as mean ± SD. Bioavailability (F) was determined by dividing the dose-normalized area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) for each orally dosed animal by the dose-normalized mean AUCinf determined from intravenously dosed animals.

[0247] Example B8: Comparison of Compounds 2 and 6 with other known sulfonimide amide compounds Compounds 2 and 6 (compound A from Example 1 and compound G from Example 3, respectively) were compared to dozens of other SIA compounds, including several close structural analogs, across a variety of properties including potency measured in human whole blood (HWB); PXR activation; rat bioavailability; and rat half-life. Results are shown as scatter plots in Figures 1-3. Compounds for comparison, including unlabeled data points, are previously synthesized and characterized SIA compounds, including many from PCT / US2019 / 042711 and PCT / US2021 / 014133. Data for compound 2, compound 6, and compounds XA-XP are summarized in Table 3 below. Table 3. Potency as measured in human whole blood (HWB); PXR activation; rat bioavailability; and rat half-life of Compound 2, Compound 6, and comparison compounds XA-XP. ND = not determined. TIFF2024528656000180.tif232170TIFF2024528656000181.tif224170TIFF2024528656000182.tif238170

[0248] *Comparative compounds XA-XP have at least one chiral center, and many have two. These compounds were synthesized, each stereoisomer separated by chiral SFC, and the most potent stereoisomer, as determined by the THP1 ASC spec assay described above, was selected for further evaluation. The actual stereochemistry of each chiral center in the listed compounds was not determined unless listed (e.g., XG, where the stereochemistry of the methyl group is known by the identity of the starting material in the synthetic route). Based on the structure determination of compound 2 by X-ray crystallography, it is believed that the S atoms of the above comparators may have the same chirality. Compounds XO and XP, while not considered close analogs, have demonstrated high potency and are therefore included in the table for convenient reference.

[0249] Compounds with SIA scaffolds generally struggle with induction of PXR, which is associated with hepatocyte induction and risk of clinical drug-drug interactions as mentioned above. Avoidance of hepatocyte induction is important for therapeutic compounds used in chronic conditions or in patient populations where they may be co-administered with other drugs. Many NLRP3-associated disorders such as metabolic syndrome, diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus, atherosclerosis, Crohn's disease, inflammatory bowel disease (IBD), Alzheimer's disease and Parkinson's disease fit this chronic and / or comorbidity criterion. Therefore, to minimize DDI risk, it is desirable for PXR activation to remain below 20% at 10 μM compared to the positive control. As shown in Figure 1, compound 2 and compound 6 are the only two compounds that exhibit both PXR < 20% and HWB IC90 < 100 nM (HWB IC90 axes in Figures 1-3 are in μM). All other compounds tested had higher PXR activation (and therefore higher DDI risk) or were less potent. In particular, the close structural analog compound XA-XN showed PXR activation of over 70%, or HWB IC90>150nM, or both. Furthermore, XA-XN are not all clustered around compounds 2 and 6, but are instead distributed across a wide range of PXR activation and HWB IC90 values. This indicates the unpredictability of meeting such high thresholds, and indicates the particularly advantageous and surprising properties of compounds 2 and 6.

[0250] Another common problem with SIA compounds is poor bioavailability. Compounds with poor bioavailability can be problematic because they often result in higher human doses required for adequate target coverage (e.g., plasma concentrations), resulting in higher toxicity risks and poor patient compliance risks. Bioavailability was evaluated in rats according to the procedure of Example B7 for selected compounds, including many from the first group assayed in Figure 1. As shown in Figure 2, compounds 2 and 6 are the only compounds with both rat bioavailability greater than 30% and HWB IC90 less than 100 nM. The next closest compound, XO, has a structurally different left side. Again, the adjacent structural analogs XA, XB, XE, XF, XG, XH, XI, and XN are distributed across the range of IC90 and bioavailability. This loose association between structure, potency, and bioavailability demonstrates the unpredictability of structure-activity relationships in the SIA series. In general, it is highly attractive to use data from previously synthesized molecules to reliably predict which new compounds will achieve both adequate bioavailability and high potency.

[0251] Finally, another factor used to model human dose is the in vivo half-life of the compound evaluated in rats. A longer half-life will result in a lower predicted human dose, while a shorter half-life may result in more frequent and / or higher human doses to achieve adequate target coverage. Many SIA compounds have short half-lives due to low volume distribution (representing total drug rather than unbound drug; concentrations in plasma or blood are higher than in tissues), high clearance (rate at which the compound is removed from the blood), or both. NLRP3 inhibitors can completely suppress inflammatory signaling pathways. min It is desirable to achieve exposure at C max / C min A half-life longer than 10-12 hours is desirable to minimize the ratio, allowing administration of smaller amounts of drug. minThis allows for maintaining high target engagement in rats. In general, compounds that exhibit rat half-lives of more than 2 hours are more commonly observed to have human half-lives of more than 10 hours in subsequent human studies, making them more attractive candidates for once-daily dosing (Sarver et al., Environ. Health Perspect., Nov 1997;105:11, pg 1204-1209). Only compound 2 meets this criterion, while having an HWB IC90 of less than 100 nM. Compound 6 has a half-life of more than 1.5 hours, but not quite 2 hours. The next most potent compound, XO, has a half-life of less than 1 hour and a structurally distinct left side. The remaining structural analogs, XA, XB, XE, XF, XG, XH, XI, and XN, evaluated in rats, have low bioavailability, low potency, or both. Again, these analogs are distributed across a range of possible half-lives and IC90s, demonstrating the unpredictability of these properties in SIA compounds.

Claims

The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, which is according to claim 2.

3. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. A pharmaceutical composition comprising the compound according to claim 2, and a pharmaceutically acceptable additive.

5. A method for treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. A method for treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound according to claim 2.

7. The method according to claim 5 or 6, wherein the disorder is a disorder of the immune system, a disorder of the liver, a disorder of the lung, a disorder of the skin, a disorder of the cardiovascular system, a disorder of the renal system, a disorder of the gastrointestinal tract, a disorder of the respiratory system, a disorder of the endocrine system, a disorder of the central nervous system (CNS), an inflammatory disorder, an autoimmune disorder, or cancer, tumor, or other malignant neoplasm.

8. The method according to claim 5 or 6, wherein the disorder is a bacterial infection, a viral infection, a fungal infection, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndrome (CAPS), myelodysplastic syndrome (MDS), gout, myeloproliferative neoplasm (MPN), atherosclerosis, Crohn's disease, or inflammatory bowel disease (IBD). The method according to claim 5 or 6, wherein the subject is human. The compound according to claim 10, or a pharmaceutically acceptable salt thereof. The compound according to claim 10, which is according to claim 11.

12. A pharmaceutical composition comprising the compound according to claim 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. A pharmaceutical composition comprising the compound according to claim 11, and a pharmaceutically acceptable additive.

14. A method for treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound according to claim 10, or a pharmaceutically acceptable salt thereof.

15. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to claim 11.

16. The method according to claim 14 or 15, wherein the disorder is a disorder of the immune system, a disorder of the liver, a disorder of the lung, a disorder of the skin, a disorder of the cardiovascular system, a disorder of the renal system, a disorder of the gastrointestinal tract, a disorder of the respiratory system, a disorder of the endocrine system, a disorder of the central nervous system (CNS), an inflammatory disorder, an autoimmune disorder, or cancer, a tumor, or other malignancy.

17. The method according to claim 14 or 15, wherein the disorder is a bacterial infection, a viral infection, a fungal infection, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus, lupus nephritis, cryopyrin-associated periodic syndrome (CAPS), myelodysplastic syndrome (MDS), gout, myeloproliferative neoplasm (MPN), atherosclerosis, Crohn's disease or inflammatory bowel disease (IBD).

18. The method according to claim 14 or 15, wherein the subject is a human.

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