Compounds and methods for modulating GPCR signaling

Abstract

The advent of ultra-large libraries of drug-like compounds has significantly broadened the possibilities in structure-based virtual screening, accelerating the discovery and optimization of high-quality lead chemotypes for diverse clinical targets. We explored new chemical spaces using reactions of sulfur(VI) fluorides to create a combinatorial library consisting of several hundred million compounds. We screened this virtual library for Cannabinoid Type II receptor (CB2) antagonists in conjunction with a rationally designed antagonist, AM10257. The top-predicted compounds were then synthesized and tested in vitro for CB2 binding and functional antagonism, achieving an experimentally validated hit rate of 55%. Our findings demonstrate the effectiveness of reliable reactions, such as Sulfur Fluoride Exchange (SuFEx) reactions, for diversifying ultra-large chemical spaces and facilitating the discovery of new lead compounds for important biological targets.

Description

[0001] COMPOUNDS AND METHODS FOR MODULATING GPCR SIGNALING RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No.63 / 570,649, filed March 27, 2024, which is incorporated herein by reference. BACKGROUND OF THE INVENTION Despite recent advancements in science and technology, the success rate for developing a new drug remains a meager 4%, with an estimated cost of transitioning a therapeutic from research to clinical application reaching up to $2.8 billion. While the lion's share of the costs is incurred at the clinical trial phases, one of the significant limitations in the discovery of initial hits is the size and diversity of compound libraries used for screening. Consequently, low-quality initial hits necessitate extensive optimization efforts, consuming years and significant resources, eroding the span of the intellectual property protection and cost recovery. Expanding the available chemical space for screening has the potential to significantly streamline both the discovery of initial hits and their subsequent optimization into lead compounds. Recent innovations in parallel synthesis techniques have led to the development of ultra-large virtual chemical libraries, composed of REadily AvailabLe (REAL) compounds. These libraries now feature tens of billions of compounds that can be rapidly synthesized on-demand with a high success rate of over 80%. Concurrently, the burgeoning availability of structural information—especially the increasing coverage of G protein-coupled receptor (GPCR) structures—facilitates the efficient screening of these expansive libraries. This structure-based screening approach has been rigorously validated through the identification of viable hit and lead compounds across various target classes. By incorporating new methods of organic synthesis into essential building blocks, these libraries can be further diversified. This approach offers a pathway to explore new chemical spaces and significantly aids in the discovery of novel drug-like compounds. Importantly, for this approach to yield a high success rate in synthesis, it should be applied selectively to the most practical and reliable synthetic methods. Recent progress in the chemistry of organic sulfur(VI)fluorides reignited interest this new clickable scaffold due to the high stability and selective reactivity of the –SO2F functional group. Sulfur Fluoride Exchange (SuFEx) reactions are marked by high selectivity and exquisite reactivity profiles, making them very suitable for the rapid synthesis of functional molecules. In 2018, we published a protocol for the regioselective synthesis of fluorosulfonyl 1,2,3-triazoles and isoxazoles from bromosulfonyl fluoride (Br-ESF), generating a synthetic pathway to the previously inaccessible sulfonamide functionalized heterocycles (Org. Lett.2018, 20 (13), 3749). This method is well-suited for the generation of new libraries as it can be performed under mild conditions, has good functional 1 530.044WO1 USC 2024-132-02 group tolerance, and is regiospecific and metal-free. Most importantly, the reaction sequence generates a promising drug-like scaffold that has, to the best of our knowledge, not been enumerated on a large scale to date. There is a need for new therapeutic agents based on the previously inaccessible sulfonamide functionalized heterocycle scaffold. This disclosure provides new families of sulfonamide functionalized heterocyclic therapeutic agents. SUMMARY This disclosure provides new chemotypes of cannabinoid receptors ligands. Using reactions of sulfur(VI) fluorides, a virtual combinatorial library consisting of several hundred million compounds was developed. This virtual library was screened for Cannabinoid Type II receptor (CB2R) antagonists, using the high-resolution CB2R structure bound to an antagonist. Highly active compounds from the screen were then synthesized and tested in vitro for CB2R binding and functional antagonism, resulting in the discovery of a new series of CB2R antagonists with sub- micromolar affinities and potencies. The invention thus provides, in one embodiment, a compound of Formula I: wherein R1is aryl, heteroaryl, heterocycle, or alkyl, preferably aryl or heteroaryl; L is –CH(R11)–, –C(=O)–, or a direct bond, wherein when present, R11is H, aryl, heteroaryl, heterocycle, or alkyl, each optionally substituted with one or more substituents; N-Het is a nitrogen-containing heterocyclic ring, such as triazole or isoxazole, optionally substituted, for example with halo, nitro, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, –N(R12)2, –SR13, or –OR14, wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heteroaryl or heterocycle, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H or alkyl and R3is alkyl, benzyl, or (C3-C8)cycloalkyl, optionally substituted with one or more substituents, which substituents are optionally hydroxy, hydroxyalkyl, phenyl, or heteroaryl, such as imidazole; and wherein each aryl, heteroaryl, heterocycle, or alkyl is optionally substituted with one or more substituents, which substituents are optionally halo, nitro, –N(R12)2, –SR13, or –OR14, alkyl, alkoxy- 2 530.044WO1 USC 2024-132-02 alkyl, cycloalkyl, cycloalkoxy, benzyl, and benzyloxy optionally substituted with one or more halo, wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Also provided are methods of treating or reducing the symptoms of a neurodegenerative disorder, for example, treating or reducing the symptoms of a condition that is responsive to CB2R modulation, comprising administering to a subject in need thereof an effective amount of a compound or composition described herein (e.g., a compound of Formula I), thereby treating or reducing the symptoms of the neurodegenerative disorder, or treating or reducing the symptoms of the condition that is responsive to CB2R modulation. The compound can be a CB2R agonist, antagonist, partial agonist, or inverse agonist. The condition can comprise, for example, inflammation or cancer. The invention thus provides novel compounds of Formulas I-VII (and their sub-formulas), described hereinbelow, intermediates for the synthesis of compounds of Formulas I-VII, as well as methods of preparing compounds of Formulas I-VII. The invention also provides compounds of Formulas I-VII that are useful as intermediates for the synthesis of other useful compounds. The invention provides for the use of compounds of Formulas I-VII for the manufacture of medicaments useful for the treatment of conditions (e.g., diseases or disorders) in a mammal, such as a human. The medicament can include a pharmaceutically acceptable diluent, excipient, or carrier. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention. However, one skilled in the art will understand that portions of the example or aspect may be used in combination with other examples or aspects of the invention. Figure 1. Flowchart of library design procedure. Steps for library generation (see Grotsch et al., ACS Chem. Biol.2024, 19, 866−874 and Supporting Information, incorporated by reference). Figure 2A-C. Receiver Operating Characteristics (ROC). (A) Performance evaluation for CB2 crystal structure and ligand-guided optimized models. Examples of predicted binding poses of selected known high-affinity CB2 ligands in optimized models with agonist (B) and antagonist (C) molecules. Figure 3. Tanimoto distance of lead compounds BRI-13900, BRI-13903, BRI-13901, BRI- 13907, BRI-13912, and BRI-13911. Figure 4. CB2 competition binding of lead compounds. Characterization of the best six CB2 hits. Dose-response curves for the best six compounds at CB2 tested in a radioligand binding assay 3 530.044WO1 USC 2024-132-02 where compound AM10257 was used as a positive control. See Figure 7B for dose-response curves of the top six compounds in functional β-arrestin recruitment Tango assays at the CB2 receptor where SR144528 was used as a positive control. Figure 5. Predicted docking poses of experimentally confirmed hits better than 10 μM for CB2 receptor. Figure 6. Predicted receptor binding pocket – ligand interactions for experimentally confirmed hits better than 10μM for CB2 receptor. Figure 7A-B. Dose-response curves of cannabinoid receptors with the hits. The relative antagonist activity of hits to CB1 (A) and CB2 (B) receptors were determined by β-arrestin recruitment tango assay. The compounds rimonabant (A) and SR144528 (B) were used as positive controls. The assays were carried out in the presence of 100 nM (EC80) of the dual CB1 / CB2 agonist CP55,940. The data were presented as mean ± SEM with three technical replicates and n=3 biological replicates. Figure 8A-D. Primary screening of the V-SYNTHES predicted compounds with β-arrestin recruitment tango assay. All the predicted compounds were tested at 10 µM concentrations. (A-B) Relative agonist activity of CB1 (A) and CB2 (B) receptors. The dual CB1 / CB2 agonist CP55,940 at 1 µM was used as positive control, and DMSO was used as negative control. (C-D) Relative antagonist activity of CB1 (C) and CB2 (D) receptors. 10 µM of Rimonabant (C) or SR144528 (D) was used as positive control, and DMSO was used as negative control. The assays were carried out in the presence of 100 nM (EC80) of CP55,940. All the data were presented as mean ± SEM (n=4) and normalized the relative positive controls, respectively. DETAILED DESCRIPTION The advent of ultra-large libraries of drug-like compounds has significantly broadened the possibilities in structure-based virtual screening, accelerating the discovery and optimization of high-quality lead chemotypes for diverse clinical targets. Compared to traditional high- throughput screening (HTS), which is constrained to libraries of approximately one million compounds, the ultra-large virtual screening approach offers substantial advantages in both cost and time efficiency. By expanding the chemical space with compounds synthesized from easily accessible and reproducible reactions, and utilizing a large, diverse set of building blocks, we can enhance both the diversity and quality of the discovered lead chemotypes. In this disclosure, we describe the exploration of new chemical spaces using reactions of sulfur(VI) fluorides to create a combinatorial library consisting of several hundred million compounds. We screened this virtual library for Cannabinoid Type II receptor (CB2) antagonists, using a high-resolution structure in conjunction with a rationally designed antagonist, AM10257. The top-predicted compounds were then synthesized and tested in vitro 4 530.044WO1 USC 2024-132-02 for CB2 binding and functional antagonism, achieving an experimentally validated hit rate of 55%. Our findings demonstrate the effectiveness of reliable reactions, such as SuFEx, in diversifying ultra-large chemical spaces and facilitates the discovery of new lead compounds for important biological targets. Definitions. The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley’s Condensed Chemical Dictionary 14thEdition, by R.J. Lewis, John Wiley & Sons, New York, N.Y., 2001. References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described. The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and / or the recitation of claim elements or use of "negative" limitations. The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrases "one or more" and "at least one" are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit. For example, one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is disubstituted. As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." 5 530.044WO1 USC 2024-132-02 These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value without the modifier "about" also forms a further aspect. The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms "about" and "approximately" are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a recited range as discussed above in this paragraph. As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub- ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed, individually, and as part of a range. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as “number1” to “number2”, implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, 1 to 10 means 1, 2, 3, 4, 5, … 9, 10. It also means 1.0, 1.1, 1.2. 6 530.044WO1 USC 2024-132-02 1.3, …, 9.8, 9.9, 10.0, and also means 1.01, 1.02, 1.03, and so on. If the variable disclosed is a number less than “number10”, it implies a continuous range that includes whole numbers and fractional numbers less than number10, as discussed above. Similarly, if the variable disclosed is a number greater than “number10”, it implies a continuous range that includes whole numbers and fractional numbers greater than number10. These ranges can be modified by the term “about”, whose meaning has been described above. The recitation of a), b), c), …or i), ii), iii), or the like in a list of components or steps do not confer any particular order unless explicitly stated. One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation. The term "contacting" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo. An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect. Alternatively, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate 7 530.044WO1 USC 2024-132-02 "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment). The terms "treating", "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and / or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate. As used herein, "subject" or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy. A patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, the patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic 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. In one embodiment of the methods provided herein, the mammal is a human. As used herein, the terms “providing”, “administering,” “introducing,” are used interchangeably herein and refer to the placement of a compound of the disclosure into a subject by a method or route that results in at least partial localization of the compound to a desired site. The compound can be administered by any appropriate route that results in delivery to a desired location in the subject. The compound and compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs. 8 530.044WO1 USC 2024-132-02 The terms "inhibit", "inhibiting", and "inhibition" refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting. The term “substantially” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For example, the term could refer to a numerical value that may not be 100% the full numerical value. The full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%. Wherever the term “comprising” is used herein, options are contemplated wherein the terms “consisting of” or “consisting essentially of” are used instead. As used herein, “comprising” is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the aspect element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the aspect. In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms. The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. This disclosure provides methods of making the compounds and compositions of the invention. The compounds and compositions can be prepared by any of the applicable techniques described herein, optionally in combination with standard techniques of organic synthesis. Many techniques such as etherification and esterification are well known in the art. However, many of these techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol.1, Ian T. Harrison and Shuyen Harrison, 1971; Vol.2, Ian T. Harrison and Shuyen Harrison, 1974; Vol.3, Louis S. Hegedus and Leroy Wade, 1977; Vol.4, Leroy G. Wade, Jr., 1980; Vol.5, Leroy G. Wade, Jr., 1984; and Vol.6; as well as standard organic reference texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., by M. B. Smith and J. March (John Wiley & Sons, New York, 2001); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing); Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Cary and Sundberg (1983); for heterocyclic synthesis see Hermanson, Greg T., Bioconjugate Techniques, Third Edition, Academic Press, 2013. The formulas and compounds described herein can be modified using protecting groups. Suitable amino and carboxy protecting groups are known to those skilled in the art (see for example, Protecting Groups in Organic Synthesis, Second Edition, Greene, T. W., and Wuts, P. G. M., John 9 530.044WO1 USC 2024-132-02 Wiley & Sons, New York, and references cited therein; Philip J. Kocienski; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), and references cited therein); and Comprehensive Organic Transformations, Larock, R. C., Second Edition, John Wiley & Sons, New York (1999), and referenced cited therein. The term "halo" or "halide" refers to fluoro, chloro, bromo, or iodo. Similarly, the term "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "alkyl" refers to a branched or unbranched hydrocarbon having, for example, from 1-20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms; or for example, a range between 1-20 carbon atoms, such as 2-6, 3-6, 2-8, or 3-8 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (iso-propyl), 1-butyl, 2-methyl-1-propyl (isobutyl), 2-butyl (sec- butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. The alkyl can be unsubstituted or substituted, for example, with a substituent described below or otherwise described herein. The alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can include an alkenyl group or an alkynyl group. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene). An alkylene is an alkyl group having two free valences at a carbon atom or two different carbon atoms of a carbon chain. Similarly, alkenylene and alkynylene are respectively an alkene and an alkyne having two free valences at two different carbon atoms, or an alkenylene can have the two free valences on the same carbon. The term "cycloalkyl" refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted. The cycloalkyl group can be monovalent or divalent and can be optionally substituted as described for alkyl groups. The cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like. The term “heteroatom” refers to any atom in the periodic table that is not carbon or hydrogen. Typically, a heteroatom is O, S, N, P. The heteroatom may also be a halogen, metal or metalloid. The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, 10 530.044WO1 USC 2024-132-02 sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3- to 10-membered, more preferably 4- to 7-membered. Examples of suitable heterocycloalkyl substituents include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-diazapanyl, 1,4-diazapanyl, 1,4-oxazepanyl, and 1,4- oxathiapanyl. The group may be a terminal group or a bridging group (e.g., the variable L). The term "aryl" refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system. The radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system. The aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms. The aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aryl can be unsubstituted or optionally substituted with a substituent described below. For example, a phenyl moiety or group may be substituted with one or more substituents RXwhere RXis at the ortho-, meta-, or para-position, and X is an integer variable of 1 to 5. The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. The heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of "substituted". Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms, wherein the ring skeleton comprises a 5-membered ring, a 6-membered ring, two 5- membered rings, two 6-membered rings, or a 5-membered ring fused to a 6-membered ring. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H- quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl, and xanthenyl. In one embodiment the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (C1-C6)alkylaryl. In some embodiments, heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benzo-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. 11 530.044WO1 USC 2024-132-02 As used herein, the term "substituted" or “substituent” is intended to indicate that one or more (for example, in various embodiments, 1-10; in other embodiments, 1-6; in some embodiments 1, 2, 3, 4, or 5; in certain embodiments, 1, 2, or 3; and in other embodiments, 1 or 2) hydrogens on the group indicated in the expression using “substituted” (or “substituent”) is replaced with a selection from the indicated group(s), or with a suitable group known to those of skill in the art, provided that the indicated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Suitable indicated groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, carboxyalkyl, alkylthio, alkylsulfinyl, and alkylsulfonyl. Substituents of the indicated groups can be those recited in a specific list of substituents described herein, or as one of skill in the art would recognize, can be one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, and cyano. Suitable substituents of indicated groups can be bonded to a substituted carbon atom include F, Cl, Br, I, OR', OC(O)N(R')2, CN, CF3, OCF3, R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R')2, SR', SOR', SO2R', SO2N(R')2, SO3R', C(O)R', C(O)C(O)R', C(O)CH2C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R')2, OC(O)N(R')2, C(S)N(R')2, (CH2)0-2NHC(O)R', N(R')N(R')C(O)R', N(R')N(R')C(O)OR', N(R')N(R')CON(R')2, N(R')SO2R', N(R')SO2N(R')2, N(R')C(O)OR', N(R')C(O)R', N(R')C(S)R', N(R')C(O)N(R')2, N(R')C(S)N(R')2, N(COR')COR', N(OR')R', C(=NH)N(R')2, C(O)N(OR')R', or C(=NOR')R' wherein R’ can be hydrogen or a carbon-based moiety (e.g., (C1-C6)alkyl), and wherein the carbon-based moiety can itself be further substituted. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. When a substituent is divalent, such as O, it is bonded to the atom it is substituting by a double bond; for example, a carbon atom substituted with O forms a carbonyl group, C=O. Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, which form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane- polarized light. In describing an optically active compound, the prefixes D and L, or R and S. are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or 12 530.044WO1 USC 2024-132-02 (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate (defined below), which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The term “IC50” is generally defined as the concentration required to inhibit a specific biological or biochemical function by half, or to kill 50% of the cells in a designated time period, typically 24 hours. Abbreviations used herein include VLS: virtual ligand screening; PDB: protein data bank; ICM: internal coordinates mechanics; CB1 and CB2: cannabinoid receptors 1 and 2; GPCR: G protein-coupled receptor. Embodiments of the Technology. This technology provides various sulfonamide functionalized heterocycles that can be Cannabinoid Type II receptor (CB2R) agonists, antagonists, partial agonists, or inverse agonists. In various embodiments, the invention can be defined by the following Statements of the Invention, formulas, and description below. Statement 1. A sulfonamide functionalized heterocycle of Formula I: wherein R1is aryl or heteroaryl; L is –CH(R11)– or a direct bond, wherein when present, R11is H, aryl, heteroaryl, heterocycle, or alkyl, each optionally substituted with one or more substituents; N-Het is triazole or isoxazole, optionally substituted, for example with halo, nitro, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, –N(R12)2, –SR13, or –OR14, wherein eachR12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heteroaryl or heterocycle, each optionally substituted with one or more substituents, which substituents are optionally pyrimidine, halo-substituted pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H or alkyl and R3is alkyl, benzyl, or (C3-C8)cycloalkyl, optionally substituted with one or more substituents, which substituents are optionally hydroxy, hydroxyalkyl, phenyl, or heteroaryl, such as imidazole; and 13 530.044WO1 USC 2024-132-02 wherein each aryl, heteroaryl, heterocycle, or alkyl is optionally substituted with one or more substituents, which substituents are optionally halo, nitro, –N(R12)2, –SR13, or –OR14, alkyl, alkoxy- alkyl, cycloalkyl, cycloalkoxy, benzyl, and benzyloxy, optionally substituted with one or more halo (e.g., to provide CH2F, CHF2, or CF3, and the like), wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; or a pharmaceutically acceptable salt thereof. In some embodiments, heteroaryl comprises a pyrimidine, halo-substituted pyrimidine, imidazole, or –C(=O)-imidazole. In various embodiments, heterocycle comprises pyrrolidine, piperidine, or piperazine. 2. The compound of Statement 1 wherein the compound is a compound of Formula II: wherein R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; N-Het is triazole or isoxazole, optionally substituted with halo; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered ring, wherein the ring system formed is a pyrrolidine, octahydro-1H- indole, or piperazine, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H and R3is (C3-C8)cycloalkyl optionally substituted with one or more substituents, which substituents optionally include -OH; and wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo; or a pharmaceutically acceptable salt thereof. 3. The compound of Statement 1 or 2 wherein the compound is a compound of Formula IIA: wherein R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; N-Het is triazole or isoxazole, optionally substituted with halo; and R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered ring, wherein the ring system formed is a pyrrolidine, octahydro-1H- 14 530.044WO1 USC 2024-132-02 indole, or piperazine, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo; or a pharmaceutically acceptable salt thereof. 4. The compound of Statement 1 or 2 wherein the compound is a compound of Formula IIB: wherein R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; N-Het is triazole or isoxazole, optionally substituted with halo; and R2is H and R3is (C3-C8)cycloalkyl optionally substituted with one or more substituents, which substituents optionally include -OH; wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo; or a pharmaceutically acceptable salt thereof. 5. The compound of Statement 1 wherein the compound is a compound of Formula III: wherein R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered ring, wherein the ring system formed is a pyrrolidine, octahydro-1H- indole, or piperazine, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H and R3is (C3-C8)cycloalkyl optionally substituted with one or more substituents, which substituents optionally include -OH; and wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo; or a pharmaceutically acceptable salt thereof. 15 530.044WO1 USC 2024-132-02 6. The compound of Statement 1 wherein the compound is a compound of Formula IV: wherein R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered ring, wherein the ring system formed is a pyrrolidine, octahydro-1H- indole, or piperazine, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H and R3is (C3-C8)cycloalkyl optionally substituted with one or more substituents, which substituents optionally include -OH; and R4is H, halo, nitro, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, –N(R12)2, –SR13, or –OR14, wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo (e.g., to provide CH2F, CHF2, or CF3); or a pharmaceutically acceptable salt thereof. 7. The compound of Statement 1 or 5, as represented by Formula IIIA: wherein Raand Rbtaken together with the nitrogen atom and carbon atom, respectively, to which they are attached form a pyrrolidine ring; and Rcis H, alkyl, or pyrimidine; or Rais H; and Rband Rctaken together with the carbon atom to which they are attached form a cycloalkyl ring; or Rais H; Rbis phenyl or pyrazole; and Rcis H, alkyl, or pyrimidine; Rdis H, alkyl, or phenyl; Reis amino alkyl, amino phenyl, benzyl, halo, or phenyl; and Rfis H or halo; wherein each alkyl, amino alkyl, amino phenyl, benzyl, cycloalkyl, phenyl, pyrazole, pyrimidine, and pyrrolidine ring is independently either substituted or unsubstituted; or a pharmaceutically acceptable salt thereof. 16 530.044WO1 USC 2024-132-02 8. The compound of Statement 7, wherein Raand Rbare taken together with the nitrogen atom to which they are attached to form a substituted pyrrolidine ring, and Rcis pyrimidine, wherein the substituted pyrrolidine ring is: . 9. The compound of Statement 7, wherein Raand Rbare taken together with the nitrogen atom to which they are attached to form a substituted pyrrolidine ring, and Rctaken together with Rbforms a cycloalkyl ring, wherein the substituted pyrrolidine ring is: . 10. The compound of Statement 7, wherein Rbis a substituted phenyl (e.g., PhCH2OH); or Rcis a substituted alkyl and Rcis CH2OH. 11. The compound of any one of Statements 7-10, wherein Reis CH2Ph, N(Et2), NPhMe, or Ph. 12. The compound of any one of Statements 1, 6, or 7, as represented by Formula IV: wherein R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered ring, wherein the ring system formed is a pyrrolidine, octahydro-1H- indole, or piperazine, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H and R3is (C3-C8)cycloalkyl optionally substituted with one or five substituents, which substituents optionally include -OH; and R4is H, halo, nitro, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, –N(R12)2, –SR13, or –OR14, wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo; or a pharmaceutically acceptable salt thereof. 13. The compound of Statement 1 or 12, as represented by Formula IVA: 17 530.044WO1 USC 2024-132-02 wherein Raand Rbtaken together with the nitrogen atom and carbon atom, respectively, to which they are attached form a pyrrolidine ring; and Rcis H, alkyl, or pyrimidine; or Rais H; and Rband Rctaken together with the carbon atom to which they are attached form a cycloalkyl ring; or Rais H; Rbis phenyl or pyrazole; and Rcis H, alkyl, or pyrimidine; Rfis independently H or halo; each Rgand Rhare independently H, alkoxy, cycloalkyloxy, or benzyloxy; or Rgand Rhform a 5-membered heterocycle; and Riis H; or Rhand Riform a benzo ring; wherein each alkyl, alkoxy, cycloalkyl ring, cycloalkyloxy, benzyloxy, cycloalkyl, 5-membered heterocycle, piperazine ring, phenyl, pyrazole, and pyrrolidine ring is independently either substituted or unsubstituted; or a pharmaceutically acceptable salt thereof. 14. The compound of any one of Statements 1, 12, or 13, wherein Raand Rbare taken together with the nitrogen atom to which they are attached to form a substituted piperazine ring, wherein the substituted piperazine ring is: . 15. The compound of any one of Statements 1, 12, or 13, wherein Raand Rbare taken together with the nitrogen atom to which they are attached to form a substituted pyrrolidine ring, and Rcis pyrimidine, wherein the substituted pyrrolidine ring is: . 16. The compound of any one of Statements 1, 12, or 13, wherein Rais CH3 or CH2OH; or Rbis tolyl. 18 530.044WO1 USC 2024-132-02 17. The compound of any one of Statements 1, 12, or 13, wherein Rctaken together with Rbforms a substituted cycloalkyl ring, wherein the substituted cycloalkyl ring is: . 18. The compound of any one of Statements 1 and 7-17, wherein Rgand Rhare independently H, methoxy or cyclopentyloxy, or dichlorobenzyloxy. 19. The compound of any one of Statements 1 and 7-17, wherein Rgand Rhform a 5-membered heterocycle, wherein the substituted 5-membered heterocycle is: . 20. The compound of any one of Statements 1-19 wherein the molecular weight of the compound is less than 505 Da, or less than 502 Da. In other embodiments of the Statement, the compound has a molecular weight of less than 500 Da, less than 495 Da, less than 490 Da, less than 480 Da, less than 470 Da, less than 465 Da, less than 455 Da, less than 450 Da, less than 430 Da, less than 415 Da, less than 410 Da, or less than 400 Da, and similarly, the compound can have a molecular weight of greater than 350 Da, greater than 360 Da, greater than 385 Da, greater than 400 Da, greater than 430 Da, greater than 440 Da, greater than 445 Da, greater than 450 Da, greater than 460 Da, greater than 470 Da, greater than 480 Da, or greater than 490 Da, wherein any of the aforementioned molecular weights can be + / - 1%, 2%, 3%, 5%, 10%, or 15%. 21. The compound of any one of Statements 1-20 wherein the compound has a logP of less than about 5. In other embodiments of the Statement, the compound has a logP of less than 5, less than about 4.9, less than about 4.8, less than about 4.7, less than about 4.6, or less than about 4.5, and / or greater than about 2, greater than about 3, or greater than about 4. 22. The compound of any one of Statements 1-21 wherein the compound is a Cannabinoid Type II receptor (CB2R) antagonist. In other embodiments of the Statement, the compound is a CB2R agonist, partial agonist, or inverse agonist. 23. The compound of any one of Statements 1-22 wherein the compound is: 19 530.044WO1 USC 2024-132-02 or a pharmaceutically acceptable salt thereof. 24. The compound of any one of Statements 1-22 wherein the compound is: 530.044WO1 USC 2024-132-02 or a pharmaceutically acceptable salt thereof. 25. The compound of any one of Statements 1-22 wherein the compound is ISOX-x2 or ISOX-x5: or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Accordingly, specific compounds of the invention include the sulfonamide functionalized heterocycles BRI-13900, BRI-13901, BRI-13902, BRI-13903, BRI-13904, BRI-13905, BRI-13906, and BRI-13907, as well as BRI-13911, BRI-13912, ISOX-x1, ISOX-x2, ISOX-x3, ISOX-x4, and ISOX-x5, or a salt thereof. 26. A pharmaceutical composition comprising the compound of any one of Statements 1-25 and a pharmaceutically acceptable diluent, carrier, or excipient. 27. A method for treating or reducing the symptoms of a neurodegenerative disorder comprising administering to a subject in need thereof an effective amount of a compound or composition of any one of Statements 1-26, thereby treating or reducing the symptoms of the neurodegenerative disorder. 28. A method for treating or reducing the symptoms of a condition that is responsive to CB2R modulation comprising administering to a subject in need thereof an effective amount of a compound or composition of any one of Statements 1-26, thereby treating or reducing the symptoms of the condition that is responsive to CB2R modulation. 29. The method of Statement 28 wherein the compound is a CB2R agonist, antagonist, partial agonist, or inverse agonist. In some embodiments, the compound of this method is a CB2R agonist that is effective for the treatment of an autoimmune disorder, a metabolic disorder, arthritis, or chronic pain. In other embodiments, the compound is an CB2R antagonist that is effective for the treatment of fibrosis, multiple sclerosis, neuroinflammation, or cancer. In various embodiments, the cancer is a solid tumor, for example, solid tumors of bladder cancer, brain cancer, breast cancer, including triple negative breast cancer (TNBC), carcinomas, colon cancer, cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), small cell lung cancer (SCLC), non– small cell lung cancer (NSCLC), lymphoma, melanoma, ovarian cancer, pancreatic cancer, or renal cell carcinoma (RCC). The cancer therapy can be monotherapy, or it can be combination therapy, for example, with known anticancer agents such as one or more of Dabrafenib Mesylate, Jemperli (Dostarlimab-gxly), Entrectinib, Ipilimumab, Keytruda (Pembrolizumab), Larotrectinib Sulfate, Mekinist (Trametinib Dimethyl Sulfoxide), Nivolumab, Pembrolizumab, Retevmo (Selpercatinib), Rozlytrek (Entrectinib), Selpercatinib, Tafinlar (Dabrafenib Mesylate), Temozolomide, Trametinib Dimethyl Sulfoxide, and Vitrakvi (Larotrectinib Sulfate). 21 530.044WO1 USC 2024-132-02 30. The method of Statement 28 or 29 wherein the condition comprises an autoimmune disorder, a metabolic disorder, arthritis, chronic pain, fibrosis, multiple sclerosis, neuroinflammation, or cancer. 31. The method of Statements 30, wherein the condition comprises an autoimmune disorder, a metabolic disorder, arthritis, chronic pain, fibrosis, multiple sclerosis, neuroinflammation, or cancer. 32. The method of any one of Statements 27-31, wherein the compound is: or a pharmaceutically acceptable salt thereof. In some embodiments outlined by the Statements above, alkyl is (C1-C6)alkyl, methyl, ethyl, or propyl. In some embodiments, amino alkyl is amino methyl, amino ethyl, or amino propyl. In some embodiments, amino phenyl comprises an ortho, meta, or para substituent on the phenyl moiety such as halo, hydroxy, hydroxy methyl, methyl, methoxy, or amino. In some embodiments, benzyl comprises an ortho, meta, or para substituent on the phenyl moiety such as halo, hydroxy, hydroxy methyl, methyl, methoxy, or amino. In some embodiments, phenyl comprises an ortho, meta, or para substituent on the phenyl moiety such as halo, hydroxy, hydroxy methyl, methyl, methoxy, or amino. In some embodiments, cyclohexyl is saturated or unsaturated. In some embodiments outlined by the Statements above, R1-L- is dibenzothiophene, such as a dibenzo[b,d]thiophen-4-yl moiety, wherein the benzo ring furthest from the moiety’s point of attachment is substituted with one, two, or three substituents, such as R12, R13, R14, –N(R12)2, –SR13, or –OR14, as defined above, or a moiety selected from hydrogen bond donors such as Me, OMe, halo, CF3, phenoxy, hydroxy, -NH-alkyl, amides such as -NHAc, -O(C2-C8)alkyl, and -CO2(C2-C8)alkyl, wherein any methyl moiety can be substituted with one, two, or three halo groups (such as F or Cl), wherein a substituent can be ortho, meta, or para to the carbon attached to the sulfur atom of the dibenzothiophene. In some preferred embodiments, a substituent is located at the meta and / or para position. In various embodiments, the benzo ring closest to the moiety’s point of attachment is substituted with one, two, or three substituents described in the paragraph, wherein a substituent can 22 530.044WO1 USC 2024-132-02 be meta or para to the carbon attached to the sulfur atom of the dibenzothiophene. In additional embodiments, the 5- or 6-membered heteroaryl or heterocycle formed by R2and R3taken together can be substituted with one, two, or three substituents described in the paragraph. In various embodiments, Formula I can be or can be replaced by any one of Formulas V, VI, or VII: wherein R1, L, R2, and R3are as defined for Formula I, R4is as defined for Formula IV, and A, B, and C are each independently C (e.g., C, CH, or CH2), N, NH, or O, wherein at least one of A, B, and C is N or NH (e.g., to form a pyrazole ring system); or a salt, solvate, or prodrug thereof; wherein R1, L, R2, and R3are as defined for Formula I, and R4is as defined for Formula IV; or a salt, solvate, or prodrug thereof; wherein R1, L, R2, and R3are as defined for Formula I, and R4is as defined for Formula IV; or a salt, solvate, or prodrug thereof. In another embodiment, Formula I can be replaced with Formulas VA: wherein R1and R4are any alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, optionally substituted, provided that R1–, R1–L–, and R4– are each not a moiety of Table B – Table G2 of Example 3 below; L, R2, and R3are as defined for Formula I, and A, B, and C are as defined for Formula V; or a salt, solvate, or prodrug thereof. The exclusionary moieties of Table B – Table G2 also provide support for various limitations and provisos for excluding a specific moiety or set of moieties listed in Table B – Table G2 from the definitions of R1, L, R2, R3, and R4and their substituents, with respect to Formulas I, II, IIA, IIB, III, IV, V, VA, VI, and VII. 23 530.044WO1 USC 2024-132-02 Virtual Screening of a Chemically Diverse “Superscaffold” Library Enables Ligand Discovery for a key GPCR Target. Previously inaccessible sulfonamide functionalized heterocycles were generated by the regioselective synthesis of fluorosulfonyl 1,2,3-triazoles and isoxazoles from bromosulfonyl fluoride (Br-ESF) (Scheme 1). Scheme 1. Synthesis of sulfonamide functionalized heterocycles from Br-ESF. We used the reactions illustrated in Scheme 1 to generate a diverse virtual library of around 140 million compounds, which were subsequently screened in silico against the cannabinoid type II receptor (CB2). Both the CB2 and its psychotropically active counterpart, the cannabinoid receptor type I (CB1), have been found to play a key role in regulating the central nervous system and immune system signaling and are considered important targets for pain management, inflammation modulation, as well as potential treatments of fibrotic conditions and cancer. Our results demonstrate that even a single rationally designed “superscaffold” can generate a library with enough chemical diversity to lead to the discovery of new ligands for important drug targets, thus substantially contributing to expanding the diversity of searchable chemical space. Results. An On-Demand Virtual Library. The on-demand libraries were enumerated using combinatorial chemistry tools implemented in ICM-Pro (Figure 1; see also the Supporting Information of Grotsch et al., ACS Chem. Biol.2024, 19, 866−874, incorporated herein by reference). Building blocks for the on-demand libraries were retrieved from vendor servers including Enamine, ChemDiv, Life Chemicals, and ZINC15 Database, and the combinatorial library was generated as described the Methods section below. Following the two reaction protocols, for sulfonamide- functionalized triazoles and isoxazoles, two separate libraries totaling 140 million compounds were combined for virtual ligand screening (VLS). 24 530.044WO1 USC 2024-132-02 Benchmarking Receptor Models. For docking-based virtual screening of this compound library, we used the crystal structure of CB2R with antagonist AM10257. To account for binding site flexibility during the binding of different CB2ligands, we employed ligand-guided receptor optimization algorithm to refine the sidechains in 8Å radius from the co-crystallized ligand. Two diverse sets of high-affinity CB2R ligands were used as seed compounds to generate two distinct models of the binding site: known high-affinity agonists (Target ID: CHEMBL253, pAct > 9) and antagonists (Target ID: CHEMBL253, pAct > 8). Each set of ligands and a CB2 specific decoy compound library was used in benchmark docking to evaluate the performance of more than 100 structural conformers for their ability to discriminate between CB2binders and a decoy set. The receiver operating characteristic curve (ROC) area under curve (AUC) values were used as quantitative criteria for the selection of the best models. The two best structural models, corresponding to antagonist- and agonist-bound states, showed improved values of AUC in comparison to the CB2 crystal structure (Table 1, Figure 2). Moreover, optimized models showed better docking scores for 20 diverse high-affinity ligands compared to the CB2 crystal structure. Table 1. Receiver Operating Characteristics (ROC) for CB2 crystal structure and ligand-based optimized models. Docking poses of high-affinity ligands in the best models were similar to the conformation of the co-crystallized ligand. The two best structural models, corresponding to antagonist- (Model 1) and agonist-binding (Model 2) states, along with the crystal structure of CB2R (Model 3) were combined to generate a 4D structural model, allowing to screen several receptor conformations in a single screening run. The performance of the obtained 4D model was assessed in benchmark VLS and showed comparable docking scores and ROC values to that of individual structural models. Virtual Ligand Screening. The library of 140M on-demand triazole and isoxazole compounds that could be synthesized in-house was used in 4D docking into the CB2 receptor maps as described the Methods section below. Energy-based docking (with docking effort 1) was performed and a binding score for the best conformation of each ligand was predicted. Molecules with binding scores better than -30 (score threshold) were saved and the top 340K (170K from each reaction 25 530.044WO1 USC 2024-132-02 library) compounds with the lowest docking score were re-docked into the structural model with a higher effort (effort 2) to ensure comprehensive conformational sampling. For each model from 4D docking, the top 10K (5K from each reaction library) compounds with the lowest docking score were selected for further evaluation. They were clustered for diversity based on their chemical scaffold and filtered to ensure their novelty compared to known CB1 and CB2 ligands. A total of 500 compounds from all three models were nominated for synthesis and experimental testing based on docking score, predicted binding pose, chemical novelty, and diversity. Compounds with potential hydrogen bonds to residues T114, S285, S90, H95 and K109 were given priority in the selection process. Compound Selection and Synthesis. The top 500 compounds selected from the VLS campaigns were sorted and scored based on synthetic tractability. In order to ensure the most efficient synthesis timeline, only the most accessible molecules were selected for the validation of this method. Among the factors that were taken into consideration were (a) azides synthesized from halide precursors were preferred over alcohol precursors, (b) primary amines received preferential treatment over secondary amines, and (c) possible complications due to sterics and stability of the final product were taken into account. Out of this batch, 14 compounds were selected for synthesis by also taking the price of the building block into account. Of the 14 selected compounds, 11 were fully synthesized in-house with >95% purity. Due to the highly conjugated aromatic system formed in BRI-13107 (59141), this compound was obtained as the chlorinated isoxazole. Detailed synthetic procedures can be found in the Examples below. Mixtures of stereoisomers, when formed, were tested without separation, and their composition was confirmed by chiral HPLC analysis. Experimental Identification and Validation of CB2Binders. The 11 synthesized compounds were tested in CB2functional assays, which identified 6 compounds with CB2antagonist potency better than 10 μM. Full dose-response assays confirmed antagonist potency for all initial hits with functional Ki values below 10 μM. Of those, 2 compounds had potency in the sub-micromolar range (Table 2 and Figures 3 and 4). In addition, a radioligand binding assay with human CB2receptors was also used to validate six initial hits. Here, 2 compounds showed affinities better than 10 μM to CB2receptor, with the best affinity for compound BRI-13912. 26 530.044WO1 USC 2024-132-02 Table 2. Results of testing of hits from virtual ligand screening in binding and functional assays (Ki values for all active compounds). Conformational Diversity of CB2 Hits. Compounds from both triazole and isoxazole libraries were represented in experimentally confirmed hits. Hit compounds represent 5 new unique chemical scaffolds with a Tanimoto distance of >0.4 (Table 2) from known CB1and CB2ligands found in ChEMBL for Cannabinoid receptor family (Target ID: CHEMBL253, CHEMBL218, CHEMBL3571, CHEMBL3037, CHEMBL5373; negative logarithm of the activity pAct > 5.0, release ChEMBL24) and Tanimoto distance >0.35 between each other (Chart 1, Figure 3). Notably, although the compounds tested share a similar reaction scaffold, namely a triazole or isoxazole ring and sulfonamide moiety, chemical diversity is easily achievable through variations of R1, R2, and R3 substituents in the final molecules. Chart 1. Chemical structures of the CB2 hits. Analysis of predicted docking poses shows a similar position of triazole or isoxazole ring with sulfonamide moiety in the middle of the binding pocket for all experimentally confirmed hits, while the R1, R2, and R3substituents add diversity to ligand-receptor binding pocket interactions (Figure 5 and Figure 6). All compounds except BRI-13911 fill the hydrophobic subpocket formed by residues F183, I186, Y190, L191, and W194 with the aromatic moiety (Figure 6). Three compounds have H-bond interaction with different residues of the binding pocket. The hydroxy 27 530.044WO1 USC 2024-132-02 group of compound BRI-13901 forms a H-bond with the backbone of residue F87 and the pyrrole moiety of compound BRI-13907 forms a H-bond with the backbone of residue Y25 in the upper part of the binding pocket. The hydroxy group of compound BRI-13911 forms a H-bond with the sidechain of K109 and the backbone of S90. Compounds BRI-13901 and BRI-13911 explore the bottom part of the binding pocket, forming hydrophobic interactions with residues W258 and F117. All of the hits described above are promising lead candidates with MW below 500 Da and logP less than 5, which is especially important for CB2 receptors as their hydrophobic pockets tend to favor lipophilic molecules. Discussion. Given the recent advances in biology, chemistry, and computational science, we have better tools than ever to expand the known chemical space in a time- and cost-effective manner by generating and docking ultra-large libraries of compounds that are obtained by a sequence of orthogonal chemical reactions. Using the judiciously chosen transformations, the generation of such libraries can lead to the discovery of new hits for important biological targets. Here, we utilized two multistep reactions involving SuFEx chemistry to generate a virtual combinatorial library of 140 million drug-like compounds for prospective screening and discovery of potent CB2receptor antagonists. Accordingly, we demonstrated that even the enumeration of one single scaffold can generate enough chemical diversity to enable the discovery of promising lead compounds. Previous prospective screenings for CB2 resulted in hit rates between 15-33%. Given this value, which is on the higher end of the range observed for GPCRs, we can conclude that the receptor model at hand provides a strong basis for our work. In addition, the experimental hit rate of 55% for this library suggests that the scaffold at hand may be privileged for cannabinoid receptors. With Tanimoto distances >0.3 between compounds, the hits retain appreciable chemical diversity for this rationally designed “superscaffold.” Interestingly, recent screening of the virtual library of 75 million tetrahydropyridines for serotonin 5-HT(2A) receptor agonists resulted in the discovery of 4 micromolar-level agonists out of 17 synthesized and tested, with further optimization yielding nanomolar-range leads with an unusual pharmacological profile. This result supports the conclusion of our study that ultra-large virtual combinatorial libraries, even built around one highly versatile scaffold, can deliver chemical diversity for the discovery of new hits and leads for a variety of therapeutic targets. Based on chemical intuition, the scaffold used for the design of this library is favored by the presence of two entities that appear abundantly in small molecule drugs: a) an electron-deficient sulfonamide and b) a 5-membered heterocycle moiety. Sulfonamides have long been known to possess useful properties in medicinal chemistry and are present in more than 30 drugs that are currently in clinical use. In our compounds, the electron density is localized on the oxygen atoms, 28 530.044WO1 USC 2024-132-02 essentially creating an “O–charge”, making the nitrogen atom inductively electron-deficient yet weakly basic. Similarly, triazoles have gained increasing popularity in drug discovery and have been used as antifungal, antiepileptic, and anticonvulsant agents. In part, this is due to their facile synthesis and the popularity of CuAAC in high throughput screening (HTS). However, they also possess interesting electronic properties, including two hydrogen bond acceptors and one hydrogen bond donor. Similar properties are observed for the isoxazole moiety, with the exception that the oxygen atom is more electronegative and is a more potent hydrogen bond than the nitrogen in its triazole counterpart. Even though the combination of a triazole / isoxazole ring with the sulfonamide moiety results in a highly hydrophilic scaffold, it does not create a barrier for the development of ligands for a hydrophobic pocket, as shown in our study. Even though CB2 receptors have highly hydrophobic binding pockets that favor the binding of lipophilic ligands, hit compounds based on the triazole and isoxazole moieties show a good fit into the binding pocket as R1, R2, and R3add the necessary interactions for strong binding. The combination of these effects supports the existence of a privileged scaffold, suggesting that the library can provide useful ligands for other clinical targets. Pharmaceutical Formulations. The compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier. The compounds may be added to a carrier in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and β-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods. The compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms. 29 530.044WO1 USC 2024-132-02 The forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes. The compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compounds can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained. The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms. Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the 30 530.044WO1 USC 2024-132-02 conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and / or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and / or gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution. For topical administration, compounds may be applied in pure form, e.g., when they are liquids. However, it will generally be desirable to administer the active agent to the skin as a composition or formulation, for example, in combination with a dermatologically acceptable carrier, which may be a solid, a liquid, a gel, or the like. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol / glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of dermatological compositions for delivering active agents to the skin are known to the art; for example, see U.S. Patent Nos.4,992,478 (Geria), 4,820,508 (Wortzman), 4,608,392 (Jacquet et al.), and 4,559,157 (Smith et al.). Such dermatological compositions can be used in combinations with the compounds described herein where an ingredient of such compositions can optionally be replaced by a compound described herein, or a compound described herein can be added to the composition. 31 530.044WO1 USC 2024-132-02 Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg / kg, e.g., from about 10 to about 75 mg / kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg / kg / day, most preferably in the range of 15 to 60 mg / kg / day. The compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg / m2, conveniently 10 to 750 mg / m2, most conveniently, 50 to 500 mg / m2of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations, such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The invention provides therapeutic methods of treating pain in a mammal, which involve administering to a mammal having cancer an effective amount of a compound or composition described herein. A mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like. The ability of a compound of the invention to treat pain may be determined by using assays well known to the art. For example, the design of treatment protocols, toxicity evaluation, data analysis, and the biological significance of the use of various screens are known. The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention. 32 530.044WO1 USC 2024-132-02 EXAMPLES Example 1. Synthesis of Sulfonamide-functionalized Heterocycles. General Information.1H,13C, and19F NMR spectra were recorded on Varian 400-MR, Varian VNMRS-500, and Varian VNMRS-600 instruments at 295K unless otherwise noted. Chemical shifts (δ) are expressed in parts per million, relative to the residual solvent signals as internal standards. Multiplicities are noted as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; sex, sextet; sept, septet. High resolution mass spectra were measured using Agilent 6545XT qToF instrument coupled with 1290 LC system. The qToF mass spectrometer was equipped with an atmospheric pressure chemical ionization source. Measurements were performed in positive ion mode with following ionization parameters: Capillary Voltage –3.5 kV, Corona current 4 µA, vaporization at 350 °C, nitrogen was applied as a nebulizer gas 35 psi, dry gas 13 L × min−1, 325 °C, and collision gas. Spectra were recorded in m / z 100 – 1700 range. For external calibration and tuning, a low-concentration tuning mix solution by Agilent Technologies was utilized. For sample injection (1 µL injection of ca.10–4M solution in MeOH) LC system was used. Injected compounds were passed through XDB-C18, 2.1 × 50 mm, 1.8 µm column at 40 °C with gradient H2O / MeOH (0.1% formic acid) elution. UV / Vis DAD detection was also applied (190 – 900 nm). All the MS spectra were recorded at 1 Hz. Spectra were processed using Agilent MassHunter 10.0 software package. Precoated Merk F-254 silica gel plates were used for analysis by thin layer chromatography (TLC), visualized with short wave UV light, and stained with KMnO4 and PPh3 / Ninhydrin. Column chromatography was carried out employing EMD (Merk) Silica Gel 60 (40-63 μm). Reagents were obtained from AA BLOCKS, Enamine, One-click chemistry, Acros Organics, Fisher Scientific or Sigma Aldrich, and used without further purification, unless otherwise noted. All SFC data was collected using Agilent 1260 Hybrid SFC / UHPLC equipped with chiral columns ChiralPak IA-3, 4.6x250mm, 3 mic; ChiralPak IB N-3, 4.6x250mm, 3 mic; ChiralPak IC-3, 4.6x250mm, 3 mic; ChiralPak IH-3, 4.6x250mm, 3 mic; ChiralPak IG-3, 4.6x250mm, 3 mic; ChiralPak IJ-3, 4.6x250mm, 3 mic; ChiralPak IK-3, 4.6x250mm, 3 mic; InfinityLab Poroshell 120 Chiral-CF, 4.6x150mm, 2.7 mic. Synthesis of BRI-13900. A 50 mL round-bottom flask was charged with 1-([1,1'-biphenyl]-4-yl)ethan-1-ol (1.0 eq., 350 mg, 1.77 mmol) and dissolved in 5 mL of toluene. DPPA (1.2 eq., 583 mg, 2.12 mmol) and DBU (1.5 eq., 403 mg, 2.65 mmol) were added at room temperature. The reaction mixture was stirred for 33 530.044WO1 USC 2024-132-02 24 h and then additional DPPA (1.2 eq., 583 mg, 2.12 mmol) and DBU (1.5 eq., 403 mg, 2.65 mmol) were added. The reaction mixture was stirred for an additional 24 h then extracted with DCM (3x10 mL), and the combined organic layers were washed with H2O (3x10 mL) and brine (1x10 mL) then dried over sodium sulfate. After rotary evaporation of the solvent, the azide (1) was obtained as a clear oil in 96% (272 mg) yield.1H NMR (400 MHz, Chloroform-d; δ, ppm): 7.65 – 7.56 (m, 4H), 7.54 – 7.31 (m, 5H), 4.67 (d, J = 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 3H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 141.18, 140.67, 139.95, 128.93, 127.61, 127.57, 127.22, 126.94, 60.94, 21.69. APCI -MS (TOF): measured m / z 223.1107, calcd for C14H13N3[M]•+m / z 223.1104 (Δ = 1.3 ppm). In a 10 mL reaction tube, 1 (1.0 eq., 250 mg, 1.12 mmol) and Br-ESF (3.0 eq., 635 mg, 3.36 mmol) were suspended in 1 mL dimethyl formamide and stirred at 80˚C for 24 h. Subsequently, the reaction mixture was extracted with DCM (3x10 mL) and washed with brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent yielded the crude mixture. Subsequent purification by column chromatography (SiO2, 40% → 60% DCM in hexanes) yielded the triazole (2) as an off-white solid (80%, 296 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 8.09 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.60 – 7.56 (m, 2H), 7.50 – 7.36 (m, 5H), 5.96 (q, J = 7.1 Hz, 1H), 2.11 (d, J = 7.1 Hz, 3H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 142.69, 139.94, 136.48, 129.98 (d, J = 1.0 Hz), 129.05, 128.29, 128.02, 127.39, 127.23, 125.74 (d, J = 1.4 Hz), 61.88, 21.19.19F NMR (376 MHz, Chloroform-d; δ, ppm): 66.29. APCI -MS (TOF): measured m / z 331.0794, calcd for C16H14FN3O2S [M]•+m / z 331.0785 (Δ = 2.7 ppm). A 10 mL reaction tube was charged with 2 (1.0 eq., 100 mg, 0.30 mmol), 4-(pyrrolidin-2- yl)pyrimidine (2.0 eq., 90 mg, 0.60 mmol), and triethylamine (2.0 eq., 0.9 mL, 0.60 mmol). After addition of 1 mL acetonitrile, the reaction mixture was stirred for 24 h at 80˚C. The crude mixture was obtained by rotary evaporation of the solvent and subjected to purification by column chromatography (SiO2, 5% MeOH in DCM) to obtain the product (3, BRI-13900) as a mixture of two diastereomers with two enantiomers each, as an off-white solid (32%, 44 mg).1H NMR (400 MHz, DMSO-d6; δ, ppm): 9.15 (s, 1H), 9.11 (d, J = 1.3 Hz, 1H), 8.81 (d, J = 5.3, 0.8 Hz, 1H), 7.71 – 34 530.044WO1 USC 2024-132-02 7.62 (m, 5H), 7.49 – 7.43 (m, 4H), 7.40 – 7.33 (m, 1H), 6.12 (q, J = 7.1 Hz, 1H), 4.87 (apparent ddd, 1H), 3.68 – 3.59 (m, 1H), 3.51 – 3.39 (m, 1H), 2.09 – 1.97 (m, 4H), 1.95 – 1.86 (m, 1H), 1.85 – 1.76 (m, 1H), 1.69 – 1.58 (m, 1H).13C NMR (101 MHz, DMSO-d6; δ, ppm): 170.08, 158.08, 157.67, 143.91, 140.23, 139.47, 139.27, 128.95, 127.66, 127.17, 127.02, 126.90, 126.74, 118.53, 63.68, 60.11, 49.77, 33.13, 23.87, 20.66. APCI -MS (TOF): measured m / z 461.1773, calcd for C24H25N6O2S [M+H]+m / z 461.1754 (Δ = 4.1 ppm). Chiral SFC: 250 mm ChiralPak IG–3, 15% MeOH, 3.0 mL / min, λ = 270 nm, 35 °C, nozzle pressure = 140 bar CO2, tR1 (major) = 6.021 min, tR2 (major) = 6.578 min, tR3(minor) = 8.547 min, tR4(minor) = 11.424 min. Synthesis of BRI-13901. A 50 mL round bottomed flask was charged with 1-chloro-4-(chloro(phenyl)methyl)benzene (1.0 eq., 1.00 g, 4.22 mmol) in 10 mL dimethyl formamide. Sodium azide (2.0 eq., 548 mg, 8.43 mmol) was added to the solution at room temperature and stirred for 10 h. Upon completion, the reaction mixture was extracted to Et2O (3x20 mL), and the combined organic layers were washed with water (3x10mL) and brine (1x10mL) then dried over sodium sulfate. The crude mixture was obtained by rotary evaporation of the solvent and subjected to purification by column chromatography (SiO2, 30% DCM in hexanes) to obtain the product (4) as a yellow oil (75%, 770 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 7.55 – 7.06 (m, 9H), 5.68 (s, 1H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 138.90, 137.95, 133.68, 128.65, 128.63, 128.49, 128.11, 127.15, 67.59. APCI -MS (TOF): measured m / z 243.0558, calcd for C13H10N3Cl [M]•+m / z 243.0558 (Δ = 0 ppm). In a 10 mL reaction tube, 4 (1.0 eq., 770 mg, 3.16 mmol) and mmol) were suspended in 4 mL dimethyl formamide and stirred at 80˚C for 24 h. Subsequently, the reaction mixture was extracted with DCM (3x20 mL) and washed with brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent yielded the crude mixture. Subsequent purification by column chromatography (SiO2, 40% DCM in Hexanes) yielded the triazole (5) as a yellow oil (81%, 1.17 g).1H NMR (400 MHz, Chloroform-d; δ, ppm): 8.13 (s, 1H), 7.44 – 7.39 (m, 3H), 7.39 – 7.35 (m, 2H), 7.18 – 7.12 (m, 3H), 7.11 – 7.03 (m, 2H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 135.87, 135.70, 134.96, 129.88, 129.76, 129.74, 129.37, 128.82, 128.12, 127.48, 68.96.19F NMR (376 MHz, Chloroform-d; δ, ppm): 66.58. APCI -MS (TOF): 35 530.044WO1 USC 2024-132-02 measured m / z 351.0243, calcd for C15H11ClFN3O2S [M]•+m / z 351.0239 (Δ = 1.1 ppm). A 10 mL reaction tube was charged with 5 (1.0 eq., 100 mg, 0.28 mmol), ((2R,3aR,7aR)- octahydro-1H-indol-2-yl)methanol (2.0 eq., 88 mg, 0.57 mmol), and triethylamine (2.0 eq., 0.8 mL, 0.57 mmol). After addition of 1 mL acetonitrile, the reaction mixture was stirred for 20 h at 80˚C. The crude mixture was obtained by rotary evaporation of the solvent and subjected to purification by column chromatography (SiO2, 5% → 10% MeOH in DCM) to obtain the product (6, BRI 13901) as two diastereomers as an off-white solid (23%, 32 mg).1H NMR (400 MHz, DMSO-d6; δ, ppm): 8.91 (s, 1H), 7.52 – 7.47 (m, 2H), 7.46 – 7.38 (m, 4H), 7.33 – 7.26 (m, 2H), 7.26 – 7.19 (m, 2H), 3.73 – 3.60 (m, 4H), 3.49 (dd, J = 10.4, 6.5 Hz, 1H), 2.03 – 1.85 (m, 1H), 1.78 – 1.65 (m, 2H), 1.63 – 1.52 (m, 2H), 1.51 – 1.30 (m, 4H), 1.27 – 1.05 (m, 2H).13C NMR (101 MHz, DMSO-d6; δ, ppm): 144.66, 137.54, 136.14, 133.35, 130.10, 128.95, 128.87, 128.65, 127.85, 127.68, 66.64, 64.49, 61.74, 60.35, 35.88, 30.51, 29.76, 25.26, 23.82, 19.67. APCI -MS (TOF): measured m / z 487.1578, calcd for C24H28ClN4O3S [M+H]+m / z 487.1565 (Δ = 2.7 ppm). Chiral SFC: 250 mm ChiralPak IC–3, 20% MeOH, 3.0 mL / min, λ = 210 nm, 35 °C, nozzle pressure = 140 bar CO2, tR1= 13.170 min, tR2= 14.037 min. Synthesis of BRI-13902. In a 10 mL reaction tube, 5 (1.0 eq., 100 mg, 0.28 mmol) was dissolved in 1 mL acetonitrile and 2-amino-2-phenylethan-1-ol (2.0 eq., 78 mg, 0.57 mmol) was added. DBU (2.0 eq., 87 mg, 0.57 mmol) was added and the reaction mixture was stirred at rt for 24 hours. After evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, 5% → 10% MeOH in DCM) to obtain the product (7, BRI 13902) as an off-white solid (15%, 19 mg).1H NMR (600 MHz, DMSO-d6, 20 of 211H signals observed; δ, ppm): 7.96 (s, 1H), 7.50 – 7.18 (m, 14H), 3.56 – 3.52 (m, 1H), 3.47 (t, J = 5.9 Hz, 1H), 3.33 (s, 1H), 3.24 (dd, J = 6.6, 5.0 Hz, 1H), 2.66 – 2.60 (m, 1H).13C 36 530.044WO1 USC 2024-132-02 NMR (101 MHz, DMSO-d6; δ, ppm): 165.41, 153.50, 138.28, 137.62, 132.96, 129.95, 128.84, 128.75, 128.52, 128.39, 128.25, 127.99, 127.31, 123.06, 65.77, 53.40, 47.89. MS (TOF): measured m / z 201.0467, calcd for C13H10Cl [M]•+m / z 201.0466 (Δ = 0.5 ppm). A 50 mL round bottomed flask was charged with 4-(bromomethyl)-1,1'-biphenyl (1.0 eq., 250 mg, 1.01 mmol) in 2.5 mL dimethyl formamide. Sodium azide (2.0 eq., 132 mg, 2.02 mmol) was added to the solution at room temperature and stirred for 24 h. Upon completion, the reaction mixture was extracted to Et2O (3x10 mL) and the combined organic layers were washed with water (3x10mL) and brine (1x10mL) then dried over sodium sulfate. The crude mixture was obtained by rotary evaporation of the solvent and purified by column chromatography (SiO2, 20% DCM in Hexanes) to obtain the product (9) as a white solid (96%, 203 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 7.67 – 7.60 (m, 4H), 7.53 – 7.45 (m, 2H), 7.43 – 7.37 (m, 3H), 4.38 (s, 2H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 141.74, 140.98, 134.80, 129.30, 129.14, 128.04, 127.98, 127.58, 55.01. APCI -MS (TOF): measured m / z 209.0947, calcd for C13H11N3[M]•+m / z 209.0947(Δ = 0.0 ppm). In a 10 mL reaction tube, 9 (1.0 eq., 300 mg, 1.34 mmol) and Br-ESF (3.0 eq., 762 mg, 4.03 mmol) were suspended in 2 mL dimethyl formamide and stirred at 80˚C for 24 h. Subsequently, the reaction mixture was extracted with DCM (3x 20 mL) and washed with brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent yielded the crude mixture. Purification by column chromatography (SiO2, 50% DCM in Hexanes) yielded the triazole (10) as a yellow oil (87%, 387 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 8.13 (s, 1H), 7.74 – 7.64 (m, 2H), 7.64 – 7.55 (m, 2H), 7.54 – 7.36 (m, 5H), 5.68 (s, 2H).13C NMR (151 MHz, Chloroform-d; δ, ppm): 142.91, 139.73, 130.95, 129.04, 128.92, 128.32, 127.96, 127.89, 127.10, 127.06, 55.02.19F NMR (376 MHz, Chloroform-d; δ, ppm): 66.33. APCI -MS (TOF): measured m / z 317.0634, calcd for C15H12N3O2SF [M]•+m / z 317.0629 (Δ = 1.6 ppm). In a 10 mL reaction tube, 10 (1.0 eq., 100 mg, 0.32 mmol) was dissolved in 1 mL acetonitrile 37 530.044WO1 USC 2024-132-02 and 4-(pyrrolidin-2-yl)pyrimidine (2.0 eq., 94 mg, 0.63 mmol) was added. Triethylamine (2.0 eq., 64 mg, 0.63 mmol) was added and the reaction mixture was stirred at 80˚C for 24 hours. After evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, 5% MeOH in DCM) to obtain the product (11, BRI 13903) as a mixture of two enantiomers as an off-white solid (49%, 68 mg).1H NMR (600 MHz, DMSO-d6; δ, ppm): 9.12 (d, J = 1.4 Hz, 1H), 9.06 (s, 1H), 8.81 (d, J = 5.2 Hz, 1H), 7.73 – 7.69 (m, 2H), 7.68 – 7.64 (m, 3H), 7.49 – 7.44 (m, 4H), 7.39 – 7.35 (m, 1H), 5.76 (s, 2H), 4.86 (dd, J = 8.5, 4.3 Hz, 1H), 3.65 (ddd, J = 10.0, 7.1, 5.0 Hz, 1H), 3.51 – 3.41 (m, 1H), 2.13 – 2.02 (m, 1H), 1.95 – 1.88 (m, 1H), 1.85 – 1.76 (m, 1H), 1.69 – 1.61 (m, 1H).13C NMR (151 MHz, DMSO-d6; δ, ppm): 170.10, 158.09, 157.68, 143.93, 140.33, 139.47, 134.25, 129.07, 128.86, 128.65, 128.33, 127.20, 126.73, 118.53, 63.73, 53.27, 49.85, 33.18, 23.88. APCI -MS (TOF): measured m / z 447.1610, calcd for C23H23N6O2S [M+H]+m / z 447.1598 (Δ = 2.7 ppm). Chiral SFC: 250 mm ChiralPak IJ–3, 40% MeOH, 3.0 mL / min, λ = 270 nm, 35 °C, nozzle pressure = 140 bar CO2, tR1 = 4.773 min, tR2 = 6.211 min. Synthesis of BRI-13904. Sodium borohydride (0.35 eq., 26 mg, 691.13 µmol) was added to a solution of 4- (diethylamino)benzaldehyde (1.0 eq., 350 mg, 1.97 mmol) in 3 mL ethanol and stirred at room temperature for 1.5 h. The reaction mixture was extracted with Et2O (3x10 mL) and the combined organic layers were washed with water (3x10mL) and brine (1x10mL) then dried over sodium sulfate. After rotary evaporation of the solvent, the product (12) was obtained as a white solid (96%, 339 mg).1H NMR (400 MHz, Chloroform-d, 16 of 171H signals observed; δ, ppm): 7.24 – 7.19 (m, 2H), 6.69 – 6.65 (m, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.36 (q, J = 7.1 Hz, 4H), 1.16 (d, J = 7.1 Hz, 6H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 147.16, 128.67, 127.49, 111.56, 64.96, 44.14, 12.24. APCI -MS (TOF): measured m / z 179.1306, calcd for C11H17NO [M]•+m / z 179.1305 (Δ = 0.56 ppm). In a 50 mL round bottom flask, 12 (1.0 eq., 189 mg, 1.05 mmol) was dissolved in 10mL toluene. DPPA (1.2 eq., 348 mg, 1.27 mmol) and DBU (1.5 eq., 241 mg, 1.58 mmol) were added and stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc (3x10 mL), and the combined organic layers were washed with water (3x10mL) and brine (1x10mL) then dried over sodium sulfate. After rotary evaporation of the solvent the product (13) was obtained as a yellow oil (81%, 174 mg).1H NMR (400 MHz, Acetonitrile-d3; δ, ppm): 7.17 – 7.05 (m, 2H), 6.70 – 6.62 (m, 38 530.044WO1 USC 2024-132-02 2H), 4.16 (s, 2H), 3.32 (q, J = 7.0 Hz, 4H), 1.09 (t, J = 7.0 Hz, 6H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 129.99, 125.74 (d, J = 1.2 Hz), 120.25 (d, J = 5.1 Hz), 111.73, 54.93, 44.47, 12.65. APCI -MS (TOF): measured m / z 204.1368, calcd for C11H16N4[M]•+m / z 205.1453(Δ = - 0.49 ppm). In a 10 mL reaction tube, 13 (1.0 eq., 150 mg, 0.73 mmol) and Br-ESF (3.0 eq., 416 mg, 2.20 mmol) were suspended in 1 mL dimethyl formamide and stirred at 80˚C for 24 h. Subsequently, the reaction mixture was extracted with DCM (3x 20 mL) and washed with brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent yielded the crude mixture. Purification by column chromatography (SiO2, 50% DCM in Hexanes → 60% DCM in Hexanes) yielded the triazole (14) as a yellow oil (63%, 146 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 7.97 (s, 1H), 7.14 – 7.05 (m, 2H), 6.67 – 6.48 (m, 2H), 5.39 (s, 2H), 3.28 (q, J = 7.3, 6.7 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H).13C NMR (101 MHz, Chloroform-d; δ, ppm): 171.25, 148.60, 130.50, 127.99, 117.65, 111.93, 55.37, 44.46, 12.51.19F NMR (376 MHz, Chloroform-d; δ, ppm): 66.28. APCI -MS (TOF): measured m / z 312.1061, calcd for C13H17N4O2SF [M]•+m / z 312.1051 (Δ = 3.2 ppm). In a 10 mL reaction tube, 14 (1.0 eq., 100 mg, 0.32 mmol) was dissolved in 1 mL acetonitrile, and (1H-pyrazol-5-yl)methanamine (2.0 eq., 62 mg, 0.64 mmol) and DBU (2.0 eq., 97 mg, 0.64 mmol) were added. DMAP (0.2 eq., 7.82 mg, 0.064 mmol) was added and the reaction mixture was stirred at rt for 3 h. After evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, 2% MeOH in DCM) to obtain the product (15, BRI 13904) as an off-white solid (49%, 68 mg).1H NMR (400 MHz, DMSO-d6, 22 of 231H signals observed; δ, ppm): 9.23 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.31 – 7.16 (m, 2H), 6.71 – 6.47 (m, 3H), 5.49 (s, 2H), 3.67 (s, 2H), 3.29 (q, J = 7.0 Hz, 5H), 1.05 (t, J = 7.0 Hz, 6H).13C NMR (101 MHz, DMSO-d6; δ, ppm): 161.40, 147.56, 143.00, 133.56, 129.97, 129.05, 120.33, 111.27, 108.95, 53.84, 43.58, 39.44, 12.31. APCI - MS (TOF): measured m / z 390.1703, calcd for C17H24N7O2S [M+H]+m / z (Δ = 1.0 ppm). Synthesis of BRI-13905. 39 530.044WO1 USC 2024-132-02 Sodium borohydride (0.35 eq., 27 mg, 713 µmol) was added to a solution of 4- benzylbenzaldehyde (1.0 eq., 400 mg, 2.04 mmol) in 3 mL ethanol and stirred at room temperature for 2 h. The reaction mixture was extracted with Et2O (3x10 mL) and the combined organic layers were washed with H2O (3x10 mL) and brine (1x10 mL) then dried over sodium sulfate. After rotary evaporation of the solvent the product was obtained (8) as a white solid (98%, 397 mg).1H NMR (400 MHz, Chloroform-d, 13 of 141H signals observed; δ, ppm): 7.33 – 7.27 (m, 4H), 7.24 – 7.17 (m, 5H), 4.66 (s, 2H), 3.99 (s, 2H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 141.47, 141.12, 139.09, 129.59, 129.34, 128.94, 127.73, 126.56, 65.65, 42.08. APCI -MS (TOF): measured m / z 198.1041, calcd for C14H14O [M]•+m / z 198.1039 (Δ = 1.0 ppm). In a 50 mL round bottom flask, (4-benzylphenyl)methanol (1.0 eq., 325 mg, 1.64 mmol) was dissolved in 12 mL toluene. DPPA (1.2 eq., 541 mg, 1.97 mmol) and DBU (1.5 eq., 374 mg, 2.46 mmol) were added and the reaction was stirred at room temperature for 23 h. The reaction mixture was extracted to EtAOc (3x 10 mL), the combined organic layers were washed with H2O (3x10 mL) and brine (1x10 mL) then dried over sodium sulfate. After rotary evaporation of the solvent, the azide (16) was obtained as an off-white solid (82%, 302 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 7.39 – 6.85 (m, 9H), 4.29 (s, 2H), 3.99 (s, 2H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 141.46, 140.85, 133.23, 129.48, 129.02, 128.63, 128.52, 126.30, 54.65, 41.70. APCI -MS (TOF): measured m / z 223.1106, calcd for C14H13N3 [M]•+m / z 223.1104 (Δ = 0.9 ppm). In a 10 mL reaction tube, 16 (1.0 eq., 200 mg, 0.89 mmol) and Br-ESF (3.0 eq., 508 mg, 2.69 mmol) were suspended in 2 mL dimethyl formamide and stirred at 80˚C for 4 h. Subsequently, the reaction mixture was extracted with DCM (3x 20 mL) and washed with brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent yielded the crude mixture. Purification by column chromatography (SiO2, 50% DCM in Hexanes) yielded the triazole (17) as a yellow oil (96%, 284 mg).1H NMR (400 MHz, Methanol-d4; δ, ppm): 8.99 (s, 1H), 7.34 – 7.29 (m, 2H), 7.28 – 7.21 (m, 4H), 7.19 – 7.13 (m, 3H), 5.67 (s, 2H), 3.96 (s, 2H).13C NMR (100 MHz, Methanol-d4; δ, ppm): 142.69, 139.94, 136.48, 129.98 (d, J = 1.0 Hz), 129.05, 128.29, 128.02, 127.39, 127.23, 125.74 (d, J = 1.4 Hz), 61.88, 21.19.19F NMR (376 MHz, Methanol-d4; δ, ppm): 64.49. APCI -MS (TOF): measured m / z 331.0791, calcd for C16H14N3O2SF [M]•+m / z 331.0785 (Δ = 1.8 ppm). 40 530.044WO1 USC 2024-132-02 In a 10 mL reaction tube, 17 (1.0 eq., 50 mg, 0.15 mmol) was dissolved in 1 mL acetonitrile, and (1H-pyrazol-5-yl)methanamine (2.0 eq., 29 mg, 0.30 mmol) and DBU (2.0 eq., 45 mg, 0.30 mmol) were added. DMAP (0.2 eq., 3.69 mg, 0.030 mmol) was added and the reaction mixture was stirred at rt for 4 h. After evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, 10% MeOH in DCM) to obtain the product (18, BRI 13905) as an off-white solid (38%, 47 mg).1H NMR (400 MHz, DMSO-d6; δ, ppm): 9.26 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 7.41 – 7.11 (m, 10H), 6.60 (d, J = 2.8 Hz, 1H), 5.60 (s, 2H), 3.89 (s, 2H), 3.60 (s, 2H).13C NMR (101 MHz, DMSO-d6; δ, ppm): 162.05, 143.10, 141.89, 140.90, 133.54, 132.35, 129.64, 129.20, 128.69, 128.52, 128.45, 126.04, 108.96, 53.58, 40.69, 39.22. APCI -MS (TOF): measured m / z 409.1459, calcd for C20H21N6O2S [M+H]+m / z 409.1441 (Δ = 4.4 ppm). Synthesis of BRI-13906. In a 50 mL round bottom flask, 3-(methoxymethyl)aniline (1.0 eq., 1.11 g, 8.12 mmol) was dissolved in 5 mL of 5 M HCl. A solution of sodium nitrite (1.5 eq., 840 mg, 12.18 mmol) in 20 mL H2O was added dropwise at 0˚C and stirred at room temperature for 20 h. Upon completion, the reaction mixture was quenched with NaHCO3and extracted with EtOAC (3x 100 mL). After evaporation of the solvent, the azide (19) was obtained as a yellow oil (99%, 1.32 g).1H NMR (400 MHz, Chloroform-d; δ, ppm): 7.39 – 7.30 (m, 1H), 7.14 – 7.08 (m, 1H), 7.08 – 7.02 (m, 1H), 6.99 – 6.93 (m, 1H), 4.45 (s, 2H), 3.40 (s, 3H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 140.16, 139.99, 129.54, 123.80, 118.05, 117.77, 73.85, 58.07. APCI -MS (TOF): measured m / z 135.0677, calcd for C8H9NO [M-N2]•+m / z 135.0679 (Δ = -1.5 ppm). In a 10 mL reaction tube, 19 (1.0 eq., 500 mg, 3.06 mmol) and Br-ESF (3.0 eq., 1.74 g, 9.19 mmol) were suspended in 5 mL dimethyl formamide and stirred at 80˚C for 24 h. Subsequently, the reaction mixture was extracted with DCM (3x 50 mL) and washed with brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent yielded the crude mixture. Purification by column chromatography (SiO2, 10% EtOAc in Hexanes → 50% EtOAc in Hexanes) yielded the triazole (20) as a yellow oil (59%, 520 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 41 530.044WO1 USC 2024-132-02 8.72 (s, 1H), 7.77 – 7.74 (m, 1H), 7.71 – 7.67 (m, 1H), 7.60 – 7.55 (m, 1H), 7.52 – 7.49 (m, 1H), 4.56 (s, 2H), 3.46 (s, 3H).13C NMR (151 MHz, Chloroform-d; δ, ppm): 140.21 (d, J = 21.2 Hz), 130.18, 129.68, 129.10, 123.95, 120.06, 119.63, 118.20, 117.92, 58.21.19F NMR (376 MHz, Chloroform-d; δ, ppm): 66.64. APCI -MS (TOF): measured m / z 271.0427, calcd for C10H10FN3O3S [M]•+m / z 271.0421 (Δ = 2.2 ppm). In a 10 mL reaction tube, 20 (1.0 eq., 100 mg, 0.35 mmol) was dissolved in 1 mL acetonitrile, and (4-chloro-6-(piperazin-1-yl)pyrimidine (2.0 eq., 139 mg, 0.70 mmol) and DBU (2.0 eq., 106 mg, 0.70 mmol) were added. DMAP (0.2 eq., 8.56 mg, 0.07 mmol) was added and the reaction mixture was stirred at rt for 4 h. After evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, 5% MeOH in DCM) to obtain the product (21, BRI 13906) as an off-white solid (56%, 90 mg).1H NMR (600 MHz, DMSO-d6; δ, ppm): 9.55 (s, 1H), 8.31 (s, 1H), 7.93 – 7.91 (m, 1H), 7.90 – 7.86 (m, 1H), 7.61 – 7.56 (m, 1H), 7.50 – 7.46 (m, 1H), 6.96 (s, 1H), 4.51 (s, 2H), 3.83 – 3.77 (m, 4H), 3.33 (s, 3H), 3.24 – 3.19 (m, 4H).13C NMR (151 MHz, DMSO-d6; δ, ppm): 161.95, 159.24, 157.92, 143.54, 140.61, 135.96, 129.83, 128.35, 126.46, 119.86, 119.68, 119.54, 102.09, 72.78, 57.78, 45.22. APCI -MS (TOF): measured m / z 450.1129, calcd for C18H21ClN7O3S [M+H]+m / z 450.1110 (Δ = 4.2 ppm). Synthesis of BRI-13907. A 50 mL dry round bottom flask was charged with 3-methoxy-2-napthaldehyde (1.0 equiv., 500 mg, 2.68 mmol) and was dissolved in 5 mL ethanol. Triethylamine (2.0 equiv., 750 µL, 5.37 mmol) and hydroxylamine•HCl (2.0 equiv., 373 mg, 5.37 mmol) were disdsolved in 5 mL of water and added dropwise to aldehyde solution. The reaction was stirred at room temperature (r.t.; ~22oC) for 5 h and extracted with EtOAc (3x10) to obtain 22 as an off-white solid (85%, 425 mg).1H NMR (400 MHz, Chloroform-d, 10 of 111H signals observed; δ, ppm): 8.60 (s, 1H), 8.17 (d, J = 2.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.47 (ddt, J = 8.3, 6.8, 1.6 Hz, 1H), 7.35 (ddt, J = 8.1, 6.9, 1.1 Hz, 1H), 7.16 (s, 1H), 3.99 (s, 3H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 155.49, 135.40, 128.54, 128.49, 127.79, 127.59, 126.65, 124.71, 124.44, 121.84, 105.95, 55.75. APCI -MS (TOF): measured m / z 201.0787, calcd for C12H11NO2[M]•+m / z 201.0787 (Δ = 1.5 ppm). 42 530.044WO1 USC 2024-132-02 A 100 mL dry round bottom flask was charged with 22 (1.0 equiv., 337 mg, 1.67 mmol) and 22 mL DMF. The flask was covered with aluminuum foil and N-chlorosuccinimide (1.05 equiv., 235 mg, 1.75 mmol) was added portionwise over 30 min. The reaction mixture was stirred at r.t. for 48 h and then extracted with diethyl ether (20 mL). The organic layer was washed with water (10 mL x 3) and brine (10mL), and then concentrated in vacuo to obtain the desired product (23) as a pale yellow solid (99%, 390 mg).1H NMR (400 MHz, DMSO-d6; δ, ppm): 11.65 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.14 (dq, J = 8.5, 0.9 Hz, 1H), 8.09 – 8.05 (m, 1H), 7.71 – 7.66 (m, 1H), 7.58 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 3.88 (s, 3H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 155.49, 135.40, 128.54, 128.49, 127.79, 127.59, 126.65, 124.71, 124.44, 121.84, 105.95, 55.75. APCI -MS (TOF): measured m / z 235.0399, calcd for C12H10ClNO2 [M]•+m / z 235.0395 (Δ = 1.7 ppm). A 25 mL dry round bottom flask was charged with 23 (1.0 equiv., 150 mg, 1.67 mmol) and was dissolved in 3 mL of tert-butanol and DIPEA (2.5 equiv., 277 µL, 1.59 mmol) was added. The reaction mixture was vigorously stirred. Alongside, 1-bromoethene-1-sulfonyl fluoride (4 equiv., 481mg, 2.55mmol) was dissolved in 3 mL tert-butanol and was added dropwise to the reaction mixture over a period of 20 min. The solution ws stirred for 2 h. The reaction mixture was washed with water (10 mL). The aqueous layer was washed with DCM (3 x 10mL) and finally the organic layer was washed with brine (10 mL). The organic layer was concentrated, and the residue was purified by silica gel chromatography with 0% to 3% ethyl acetate in hexanes to obtain the desired product (24) as an off white solid (18%, 27 mg)1H NMR (600 MHz, Chloroform-d; δ, ppm): 8.36 (d, J = 3.0 Hz, 1H), 8.29 (dd, J = 8.5, 1.0 Hz, 1H), 7.95 – 7.92 (m, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.71 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.58 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 3.90 (s, 3H).13C NMR (151 MHz, Chloroform-d; δ, ppm): 162.78, 140.66, 138.18, 137.88, 128.01, 127.13, 125.32, 125.07, 124.82, 123.20, 122.12, 121.25, 110.88, 30.22.19F NMR (376 MHz, CDCl3; δ, ppm): 64.70. In a 10 mL reaction tube, 24 (1.0 eq., 20 mg, 0.06 mmol) was dissolved in 0.5 mL of 43 530.044WO1 USC 2024-132-02 acetonitrile, and then piperazin-1-yl(1H-pyrrol-2-yl)methanone (3.0 eq., 31 mg, 0.18 mmol) was added. Triethylamine (2.0 eq., 12 mg, 0.12 mmol) was added, and the reaction mixture was stirred at 80˚C for 6 hours. After evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, 5% MeOH in DCM) to obtain the product (25, BRI 13907) as an off-white solid (49%, 68 mg).1H NMR (400 MHz, DMSO-d6; δ, ppm): 11.47 (s, 1H), 8.52 (s, 1H), 8.39 – 8.18 (m, 1H), 8.18 – 8.07 (m, 1H), 7.83 – 7.77 (m, 1H), 7.72 (s, 1H), 7.71 – 7.64 (m, 1H), 7.06 – 6.78 (m, 1H), 6.73 – 6.52 (m, 1H), 6.26 – 5.92 (m, 1H), 3.94 – 3.73 (m, 7H), 3.40 – 3.35 (m, 4H).13C NMR (101 MHz, DMSO-d6; δ, ppm): 163.33, 161.67, 160.14, 151.01, 131.80, 130.32, 129.72, 129.48, 129.16, 126.93, 123.73, 123.63, 123.33, 121.59, 121.45, 112.31, 109.49, 108.49, 61.44, 45.74, 27.10. APCI-MS (TOF): measured m / z 501.1005, calcd for C23H22ClN4O5S [M-H]+m / z 501.0994 (Δ = 1.8 ppm). Synthesis of BRI-13910. A 50 mL round bottom flask was charged with hydroxylamine hydrochloride (1.2 eq., 148 mg, 2.1 mmol) and sodium carbonate (1.2 eq., 226 mg, 2.1 mmol) and dissolved in 2.5 mL of a 5:1 water:ethanol mixture and the solution was mixed for 15 min. The aldehyde (1.0 eq., 500 mg, 1.8 mmol) was added portionwise over 5 minutes followed by10 mL more of EtOH, and the reaction was stirred for 45 min. Reaction progress was monitored via LC-DAD. After 72 h the reaction was complete. Product was extracted with EtOAc (3 × 10 mL), washed with water (3 × 10 mL) and brine (2 × 10 mL), and dried over sodium sulfate. Solvents were evaporated under vacuum and the product, initially an oil, was cooled crashed out with hexanes to afford white solid. Solvent was removed under vacuum, yielding the product (26) as a white solid in 94% (504 mg). Purity was confirmed by LC-UV-APCI-MS.1H NMR (499.8 MHz, DMSO-d6; δ, ppm): 11.25 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.14 (s, 2H).13C NMR (125.7 MHz, DMSO-d6; δ, ppm): 158.1, 147.9, 138.2, 134.5, 131.1, 130.7, 130.4, 129.9, 129.4, 127.8, 119.5, 115.9, 112.2, 67.6. APCI-MS (TOF): exact for C14H12Cl2NO2[M + H]+m / z 296.0240, accurate m / z 296.0242 (Δ = 0.7 ppm). In a 20 mL scintillation vial, oxime 26 (1.0 eq., 496 mg, 1.7 mmol) was dissolved in 2 mL of 44 530.044WO1 USC 2024-132-02 DMF and placed in a 15 °C water bath with continuous stirring. NCS (1.05 eq, 235 mg, 1.8 mmol) was added portionwise over 30 minutes to the stirring reaction. The mixture was stirred in the dark at 15 °C. Reaction progress was monitored via LC-DAD. After 2 h the reaction was complete. The reaction was quenched with 2 mL of water and the product was extracted to DCM (3 × 10 mL). The combined organic layer was washed with a 5:1 brine:water mixture (3 × 10 mL), and brine (1 × 10 mL), and dried over sodium sulfate. Solvents were evaporated under vacuum to yield the product (27) as a light yellow solid in 98% (545 mg). Purity was confirmed by LC-UV-APCI-MS.1H NMR (499.8 MHz, DMSO-d6; δ, ppm): 12.42 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.59 – 7.34 (m, 4H), 7.25 – 7.12 (m, 1H), 5.18 (s, 2H).13C NMR (125.7 MHz, DMSO-d6; δ, ppm): 158.0, 138.0, 135.1, 134.0, 131.1, 130.7, 130.4, 130.0, 129.5, 127.8, 119.5, 116.9, 112.8, 67.8. APCI-MS (TOF): measured for C14H11Cl3NO2 [M + H]+m / z 329.9850, calcd m / z 329.9844 (Δ = 1.8 ppm). In a 20 mL scintillation vial, the chloro-oxime 27 (1.0 eq., 331 mg, 1 mmol) were dissolved in 10 mL of DCM. Br-ESF (2.0 eq., 378 mg, 2 mmol) was added and the mixture was stirred at r.t. for 5 min. While the mixture was stirring, triethylamine (2.0 eq., 202 mg, 2.0 mmol) was slowly added dropwise over 1 min (white fume formed immediately above the solution and the solution gradually changed color to dark orange). After 2 h of stirring, the reaction was quenched with 10 mL of water. The product was extracted to DCM (3 x 10 mL), washed with water (3 × 10 mL) and brine (2 × 10 mL), and dried over sodium sulfate. The solution was passed through a short pad of silica and solvents were evaporated under vacuum, until the product (28) crystalized as beige crystals in a yield of 78% (316 mg). Purity was confirmed by LC-UV-APCI-MS.1H NMR (499.8 MHz, DMSO-d6; δ, ppm): 8.71 (s, 1H), 7.76 (s, 1H), 7.69 – 7.65 (m, 2H), 7.64 – 7.60 (m, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.22 (s, 2H)13C NMR (125.7 MHz, DMSO-d6; δ, ppm): 163.3, 158.6, 137.9, 131.7, 131.2, 130.8, 130.7, 130.5, 129.6, 127.9, 127.3, 119.8, 118.3, 113.4, 112.8 (d, J = 3.5 Hz), 67.9.19F NMR (470.3 MHz, DMSO-d6; δ, ppm): 65.5. APCI-MS (TOF): measured for C16H11Cl2FNO4S [M + H]+m / z 401.9764, calcd m / z 401.9771 (Δ = 1.7 ppm). In a 20 mL scintillation vial, 28 (1.0 eq., 201 mg, 0.5 mmol) was dissolved in 5 mL MeCN, and methyl(1H-pyrazol-3-yl)methylamine (2.0 eq., 111 mg, 1 mmol) and DBU (2.0 eq., 152 mg, 45 530.044WO1 USC 2024-132-02 1 mmol) were added. DMAP (0.2 eq., 12 mg, 0.1 mmol) was added and the reaction mixture was stirred at r.t. for 3 h. Solvent was evaporated until 3 mL total volume and product was purified by MS-guided HPLC in MeCN / H2O / formic acid system. Removal of solvent resulted in formate salt of the product (29, BRI 13910) as an off-white solid in a yield of 8% (22 mg). Purity was confirmed by LC-UV-APCI-MS.1H NMR (499.8 MHz, DMSO-d6; δ, ppm): 8.61 (s, 1H), 8.39 (s, 1H), 8.22 (br s, 3H), 7.75 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 6.81 (s, 1H), 5.21 (s, 2H), 3.87 (s, 2H), 2.33 (s, 3H).13C NMR (125.7 MHz, DMSO-d6; δ, ppm): 163.9, 163.0, 161.9, 158.5, 157.7, 138.0, 134.8, 131.2, 130.8, 130.7, 130.5, 129.5, 127.9, 127.5, 119.7, 118.2, 113.3, 111.2, 110.2, 67.9, 46.4, 34.1. APCI-MS (TOF): measured for C21H19Cl2N4O4S [M + H]+m / z 493.0499, calcd m / z 493.0501 (Δ = 0.4 ppm). Synthesis of BRI-13911. A round bottom flask (50 mL) was charged with hydroxylamine hydrochloride (1.2 eq., 80 mg 1.15 mmol) and sodium carbonate (1.2 eq., 122 mg, 1.15 mmol) and dissolved in 6 mL of a 5:1 water: ethanol mixture and the solution was mixed for 15 min. The aldehyde (1.0 eq., 250 mg, 0.961 mmol) was added portion wise over 5 minutes. Reaction progress was monitored via TLC in 3:1 hexanes: EtOAc. After 120 h the reaction was complete. Product was extracted in EtOAc (3 × 10 mL), washed with water (3 × 10 mL) and brine (2 × 10 mL), and dried over sodium sulfate. Solvents were evaporated under vacuum and the remaining solvent was removed under vacuum and product dried overnight to yield the product (30) as an off-white solid in 98% (259 mg).1H NMR (600 MHz, Chloroform-d; δ, ppm): 9.83 (s, 1H), 8.04 (s, 1H), 7.44 – 7.40 (m, 2H), 7.10 – 7.02 (m, 4H), 6.88 (d, J = 8.3 Hz, 1H), 5.11 (s, 2H), 3.90 (s, 3H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 164.22, 161.77, 151.99, 148.75, 129.90 (d, J = 3.8 Hz), 125.01, 122.77, 115.96 (d, J = 21.6 Hz), 111.74, 111.15, 70.75, 56.45, 30.17.19F NMR (564 MHz, Chloroform-d; δ, ppm): -113.74 (ddd, J = 13.8, 8.9, 5.3 Hz), -114.27 (ddd, J = 14.0, 8.9, 5.4 Hz). APCI -MS (TOF): measured m / z 275.0956, calcd for C15H14NO3F [M]•+m / z 275.0952 (Δ = 1.5 ppm). In a 50 mL round bottom flask oxime 30 (1.0 eq., 254 mg, 923 mmol) was dissolved in 10 mL of DMF and placed in a 15 °C water bath covered in foil with continuous stirring. NCS (1.05 eq., 129 mg, 969 mmol) was added portion wise over 30 minutes to the stirring reaction. The mixture was left stirring in the dark at 15 °C. Reaction progress was monitored via TLC in 3:1 hexanes: EtOAc. 46 530.044WO1 USC 2024-132-02 After 24h, 13 mg of NCS was added to push the reaction to completion. After an additional 5 h the reaction was complete. The reaction was quenched with 5 mL of water and the product was extracted to ether (3 × 10 mL). The combined organic layer was washed with a 5:1 brine: water mixture (3 × 10 mL), and brine (1 × 10 mL), and dried over sodium sulfate. Solvents were evaporated under vacuum and the product was left on a vacuum line overnight to yield the product (31) as an off-white solid in 99% (282 mg).1H NMR (600 MHz, Chloroform-d; δ, ppm): 7.47 – 7.40 (m, 4H), 7.08 – 7.04 (m, 3H), 6.93 – 6.89 (m, 1H), 5.12 (s, 2H), 3.91 (s, 3H).13C NMR (151 MHz, Chloroform-d; δ, ppm): 163.31, 161.75, 151.49, 148.25, 130.85, 129.42 (d, J = 8.3 Hz), 126.54, 120.86, 115.43 (d, J = 21.4 Hz), 111.96, 102.15, 70.38, 55.94.19F NMR (564 MHz, Chloroform-d; δ, ppm): -113.79 (td, J = 8.7, 4.3 Hz), -114.16 (ddd, J = 14.1, 8.8, 5.4 Hz). APCI-MS (TOF): measured m / z 309.0562, calcd for C15H13NO3ClF [M]•+m / z 309.0563 (Δ = -0.32 ppm). In a 20 mL scintillation vial chloro-oxime 31 (1.0 eq., 310 mg, 1 mmol) was dissolved in 20 mL of DCM. Br-ESF (2.0 eq., 378 mg, 2 mmol) was added and the mixture was stirred at r.t. for 5 min. While the mixture was stirring, triethylamine (2.0 eq., 202 mg, 2 mmol) was slowly added dropwise over 1 min (white fumes formed immediately above the solution and the solution gradually changed color). After 4 h of stirring, the reaction was complete and quenched with 10 mL of water. The product was extracted to DCM 3×10 mL, washed with water (3 × 10 mL) and brine (2 × 10 mL), dried over sodium sulfate. Solution was passed through a short pad of silica, and solvents were evaporated under vacuum to yield the product (32) as an off-white solid in 62% yield (236 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 7.48 – 7.42 (m, 3H), 7.38 – 7.36 (m, 1H), 7.33 (dd, J = 8.3, 2.0 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 5.16 (s, 2H), 3.94 (s, 3H).19F NMR (376 MHz, Chloroform-d; δ, ppm): 64.31, -113.85 (ddd, J = 14.0, 8.8, 5.3 Hz).13C NMR (100 MHz, Chloroform-d; δ, ppm): 163.99, 162.85, 161.53, 152.69, 148.73, 132.19 (d, J = 3.1 Hz), 129.57 (d, J = 8.3 Hz), 121.29, 118.77, 115.86, 115.65, 111.87 (d, J = 2.3 Hz), 110.24 (d, J = 3.6 Hz), 70.66, 56.20. APCI-MS (TOF): measured m / z 382.1, calcd for C17H14NO5SF2[M+H]+m / z 382.1 (Δ = 0.0 ppm). In a 10 mL reaction tube, isoxazole 32 (1.0 eq., 130 mg, 341 mmol) was dissolved in 0.5 mL 47 530.044WO1 USC 2024-132-02 DMSO. Subsequently, the amine (2.0 eq., 29 mg 284 mmol), HOBt (1 mol%), 1,1,3,3- tetramethyldisiloxane (2.0 eq., 76 mg, 568 mmol), and DIPEA (2.0 eq., 73 mg, 568 mmol) were added and the reaction was stirred at rt and the reaction was monitored by LCMS. After 24 h the reaction was complete and diluted with 10 mL of EtOAc. The reaction mixture was washed with water (2 x 10 mL) and 1M HCl (1 x 1 mL), then brine (1 x 10 mL) After rotary evaporation of the solvent, the crude mixture was purified by semi-preparative HPLC to obtain the final product (33, BRI 13911) as two enantiomers as an off-white solid in 10% (13 mg).1H NMR (600 MHz, Methylene Chloride-d2, 22 of 231H signals observed; δ, ppm): 7.61 – 7.57 (m, 3H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.25 – 7.20 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 5.45 – 5.44 (m, 1H), 5.39 (d, J = 6.7 Hz, 1H), 5.23 (s, 2H), 4.20 – 4.15 (m, 1H), 4.03 (s, 3H), 3.67 (tt, J = 7.9, 6.3 Hz, 1H), 2.22 (dtd, J = 13.1, 8.2, 4.8 Hz, 1H), 2.16 – 2.11 (m, 1H), 1.88 – 1.77 (m, 2H), 1.69 (ddt, J = 13.1, 9.5, 6.5 Hz, 1H), 1.60 (ddt, J = 13.4, 9.2, 7.9 Hz, 1H).13C NMR (151 MHz, Methylene Chloride-d2; δ, ppm): 166.59, 163.90, 162.80, 152.67, 149.04, 133.06 (d, J = 2.9 Hz), 130.22 (d, J = 8.1 Hz), 121.41, 120.23, 115.93, 115.79, 112.30, 106.50, 78.48, 70.93, 62.96, 56.39, 32.08, 30.80, 20.40.19F NMR (564 MHz, Methylene Chloride-d2; δ, ppm): -114.70 (tt, J = 8.9, 5.4 Hz). APCI-MS (TOF): exact for C22H24FN2O6S [M + H]+ m / z 463.1334, accurate m / z 463.1347 (Δ = 2.8 ppm). Chiral SFC: 250 mm ChiralPak IJ–3, 20% MeOH, 3.0 mL / min, λ = 270 nm, 35 °C, nozzle pressure = 140 bar CO2, tR1 = 6.854 min, tR2 = 8.219 min. Synthesis of BRI-13912. In a 50 mL round bottom flask, dibenzo[b,d]thiophene-4-carbaldehyde (1.0 eq., 500 mg, 2.36 mmol) was dissolved in 8 mL ethanol. Potassium carbonate (1.2 eq., 390 mg, 2.83 mmol) and hydroxylamine (2.0 eq., 327 mg, 4.71 mmol) were dissolved in 2 mL water and added dropwise to the aldehyde solution. After stirring at room temperature for 24 h, the reaction was quenched with cold water and dilute hydrochloric acid was added until the solution was brought down to a pH of 6- 7. After extraction to dichloromethane (3x 10), the combined organic layers were washed with brine and dried with sodium sulfate to obtain the product (34) as an off-white solid (92%, 490 mg) that was used for chlorination without further purification.1H NMR (400 MHz, Chloroform-d, 8 of 91H signals observed; δ, ppm): 8.48 (s, 1H), 8.27 – 8.18 (m, 2H), 7.94 – 7.89 (m, 1H), 7.56 – 7.52 (m, 2H), 7.51 – 7.47 (m, 2H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 150.39, 141.21, 136.84, 135.98, 134.80, 128.98, 127.14, 126.78, 124.69, 124.46, 122.99, 122.87, 121.65. APCI -MS (TOF): measured m / z 227.0401, calcd for C13H9NOS [M]•+m / z 227.0399 (Δ = 0.88 ppm). 48 530.044WO1 USC 2024-132-02 In a 50 mL round bottom flask, 34 (1.0 eq., 200 mg, 0.49 mmol) was dissolved in 6 mL DMF. NCS (1.1 eq., 109 mg, 1.07 mmol) was added at 0˚C and the reaction was warmed to room temperature and stirred at room temperature for 5 h. The resulting mixture was extracted with DCM (3x 10) and washed with water to obtain the product (35) as a yellow solid (86%, 101 mg).1H NMR (400 MHz, Chloroform-d, 7 of 81H signals observed; δ, ppm): 8.28 (dd, J = 7.9, 1.1 Hz, 1H), 8.22 – 8.17 (m, 1H), 8.12 (dd, J = 7.7, 1.1 Hz, 1H), 7.91 – 7.87 (m, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.52 – 7.47 (m, 2H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 141.06, 139.20, 136.89, 136.70, 134.82, 127.90, 127.27, 126.83, 124.75, 124.44, 123.70, 122.64, 121.68. APCI -MS (TOF): measured m / z 225.0245, calcd for C13H7NOS [M-HCl]•+m / z 225.0243 (Δ = 0.89 ppm). In a 20 mL scintillation vial, 35 (1.0 eq., 70 mg, 0.27 mmol) was dissolved in 7 mL DCM and cooled to 0˚C. NEt3(1.0 eq., 19 mg, 0.19 mmol) was added and the solution was stirred for 20 minutes. Br-ESF (2.0 eq., 72 mg, 0.38 mmol) was added dropwise at 0˚C and the solution was warmed to rt and stirred. After 1 hour, another equivalent of NEt3was added (1.0 eq., 19 mg, 0.19 mmol), and the reaction was stirred for 20 hours. After rotary evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, 25% DCM in Hexanes) to obtain the product (36) as a white crystalline solid (12%, 7.3 mg).1H NMR (400 MHz, Chloroform-d; δ, ppm): 8.37 (dd, J = 7.9, 0.9 Hz, 1H), 8.26 – 8.21 (m, 1H), 7.99 – 7.93 (m, 1H), 7.84 (dq, J = 7.6, 1.0 Hz, 1H), 7.72 (dd, J = 1.4, 0.8 Hz, 1H), 7.68 – 7.61 (m, 1H), 7.58 – 7.50 (m, 2H).13C NMR (100 MHz, Chloroform-d; δ, ppm): 140.39, 137.88, 137.59, 134.61, 127.75, 127.54, 126.86, 125.05, 124.80, 124.56, 123.18, 122.94, 121.86, 120.95, 110.62 (d, J = 3.6 Hz).19F NMR (564 MHz, Chloroform-d; δ, ppm): 64.74. APCI -MS (TOF): measured m / z 332.9931, calcd for C15H8FNO3S2 [M]•+m / z 332.9924 (Δ = 2.1 ppm). In a 10 mL reaction tube, 36 (1.2 eq., 7.3 mg, 0.02 mmol) was dissolved in 0.5 mL DMSO. Subsequently, 4-(pyrrolidin-2-yl)pyrimidine (1.0 eq., 2.7 mg, 0.018 mmol), HOBt (1 mol%), 1,1,3,3- 49 530.044WO1 USC 2024-132-02 tetramethyldisiloxane (2.0 eq., 4.9 mg, 0.036 mmol), and DIPEA (2.0 eq., 4.7 mg, 0.036 mmol) were added and the reaction was stirred at rt for 24 hours. After rotary evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2, DCM → 5% MeOH in DCM) to obtain the product (37, BRI 13912) as a mixture of two enantiomers as an off-white solid (12%, 7.3 mg).1H NMR (600 MHz, Methylene Chloride-d2; δ, ppm): 9.11 (d, J = 1.4 Hz, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.39 (dd, J = 7.9, 1.1 Hz, 1H), 8.33 – 8.25 (m, 1H), 8.08 – 7.93 (m, 1H), 7.87 (dd, J = 7.5, 1.1 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.62 – 7.51 (m, 3H), 7.38 (s, 1H), 5.03 (dd, J = 8.5, 3.8 Hz, 1H), 3.94 – 3.79 (m, 1H), 3.79 – 3.62 (m, 1H), 2.41 – 2.24 (m, 1H), 2.24 – 2.09 (m, 1H), 2.09 – 1.98 (m, 1H), 1.98 – 1.87 (m, 1H).13C NMR (151 MHz, Methylene Chloride-d2; δ, ppm): 169.82, 165.66, 162.34, 159.11, 158.16, 141.02, 138.01, 137.82, 135.23, 128.04, 127.46, 125.41, 125.30, 124.56, 123.29, 122.45, 122.30, 119.02, 107.76, 64.94, 50.74, 34.17, 24.85. APCI -MS (TOF): measured m / z 463.0901 calcd for C23H19N4O3S2 [M+H]+m / z 463.0893 (Δ = 1.7 ppm). Chiral SFC: 250 mm ChiralPak IJ–3, 40% MeOH, 3.0 mL / min, λ = 270 nm, 35 °C, nozzle pressure = 140 bar CO2, tR1 = 10.568 min, tR2 = 11.156 min. Example 2. Library Design, Screening, and Assays. Building blocks for the on-demand libraries were retrieved from vendor servers including Enamine, ChemDiv, Life Chemicals, and ZINC15 Database. For the generation of the on-demand virtual triazole library, these vendor libraries were first searched to select building blocks that contain azides, as well as alcohols and halides as azide precursors (Scheme 2a). This library was combined with existing azide building blocks from the retrieved vendor libraries, and exclusions based on functional group presence, molecular weight, and heteroatom count were applied to ensure appropriate safety and reactivity. Similarly, to create the on-demand virtual isoxazole library, the retrieved vendor libraries were searched for aldehyde precursors from which the respective oximes could be generated (Scheme 2b). See also, Figure 1. Scheme 2. Reaction scheme for a) generation of triazole library b) generation of isoxazole library. The compounds from this search were enumerated, and SMILES-based structural exclusions were applied to ensure synthetic feasibility. The respective compounds from each library were compiled and enumerated with Br-ESF to generate an intermediate library of sulfonyl-fluoride 50 530.044WO1 USC 2024-132-02 functionalized triazoles and isoxazoles. The building block libraries were then searched for primary and secondary amines, which were combinatorially enumerated with the triazole building blocks to generate the final compound library. At each enumeration step, structural exclusions were applied to the building blocks to ensure the feasibility of the particular reaction based on functional group reactivity. The library resulting from the final compound enumeration was then filtered using “Lipinski’s rule of 5” yielding ~140 million readily synthesizable drug-like compounds library for VLS screening. Receptor Model Preparation and Optimization. A multi-template structural model of CB2R, which includes crystal structure and ligand-guided refined structural models, was employed for prospective virtual ligand screening. The structural models were prepared using the crystal structure of CB2 receptor with a rationally designed antagonist AM10257 at 2.8 Å resolution (PDB ID 5ZTY). ICM-Pro conversion algorithm was used to generate a molecular object from the PDB coordinates. This algorithm involves the building of the hydrogen and missing heavy atoms, local minimization of polar hydrogens, optimization of His, Asn, and Gln side chain rotamers and protonation state, and assigning secondary structure. The sidechains in 8Å radius from the orthosteric ligand and water molecule in the binding pocket were optimized using ligand-guided receptor optimization algorithm. Two sets of high- affinity CB2 ligands from ChEMBL (release ChEMBL24), agonists (Target ID: CHEMBL253, pAct > 9) and antagonists (Target ID: CHEMBL253, pAct > 8), were employed to generate antagonist- (Model 1) and agonist-bound (Model 2) models of CB2 binding pocket. 200 diverse decoy molecules from CB2receptor decoy database (GDD) were docked into CB2models along with the high-affinity ligands to benchmark the generated models. The AUC (Area Under The Curve) ROC (Receiver Operating Characteristics) curves were used to quantitatively evaluate the models, where ROC curves were plotted based on the True Positive Rates (TPR) and False Positive Rates (FPR) from the docking of true binders and decoys. Virtual Ligand Screening. Docking / VLS simulations were performed using ICM-Pro3.8-7b molecular modeling software (Molsoft LLC). 4D docking algorithm was employed to sample generated antagonist- (Model 1) and agonist-bound (Model 2) models of CB2binding pocket and crystal structure (Model 3) in a single docking run, as implemented in ICM-Pro. Energy potential maps were calculated for each model and stored in a single multi-dimensional map file (4D grid). During docking, ligands were given full torsion flexibility in internal coordinates. Docking simulations used biased probability Monte Carlo (BPMC) optimization of the compound’s internal coordinates in the pre-calculated 4D grid energy potentials. In VLS, the exhaustive sampling of the molecule conformational space in the rectangular box of the CB2orthosteric binding pocket was performed and the best docking conformation of each molecule was stored with the corresponding predicted binding score. 51 530.044WO1 USC 2024-132-02 The initial screening of 140 million compounds thoroughness set to 1 was performed on Google Cloud Platform using ̴100K cores and took around 24 hours to complete. The 500,000 top- scoring compounds were re-docked on local servers two times with increased thoroughness set to 2 to ensure comprehensive ligand sampling. The Tanimoto coefficients were calculated for top hits in ICM-Pro (www.molsoft.com / icm / fingerprints.html) to select novel and diverse compounds for synthesis. Functional Potency in CB2 Tango Assays. The Tango arrestin recruitment assays were performed as previously described (Nat. Struct. Mol. Biol.2015, 22 (5), 362). Briefly, HTLA cells were transiently transfected with human CB2Tango DNA construct overnight in DMEM supplemented with 10 % FBS, 100 µg / ml streptomycin, and 100 U / ml penicillin. The transfected cells were then plated into Poly-L-Lysine coated 384-well white clear bottom cell culture plates in DMEM containing 1% dialyzed FBS at a density of 10,000-15,000 cells / well. After 6 hours of incubation, the plates were added with drug solutions prepared in DMEM containing 1% dialyzed FBS for overnight incubation. Especially for the antagonist assay, 100 nM of CP55940 was added after 30 minutes of incubation of the drugs. On the day of assay, medium and drug solutions were removed and 20 µL / well of BrightGlo reagent (Promega) was added. The plates were further incubated for 20 min at room temperature and counted using a Wallac TriLux Microbeta counter (PerkinElmer). Results were analyzed using GraphPad Prism 9. Radioligand Binding in CB2 Binding Assays. The affinities (Ki) of the new compounds for human CB2 receptors were obtained by using membrane preparations from HEK293 cells expressing hCB2receptors, and [3H]CP-55,940 as the radioligand. Results from the competition assays were analyzed using nonlinear regression to determine the IC50values for the ligand; Kivalues were calculated from the IC50using GraphPad Prism. Each experiment was performed in triplicate and Kivalues determined from three independent experiments and are expressed as the mean of the three values. Example 3. Method for Building a Click Chemistry Library. The virtual libraries were built using the Zbb “building block library” from ZINC database containing over 2.7 million compounds. The building block chemical entities with appropriate functional groups were identified using chemical fingerprint search, and final compounds were generated using the enumeration function. In the case of the fluorotriazole reaction library, appropriate precursor groups capable of generating functionalized azide intermediate were also included in the exercise, while the compounds containing secondary moieties predicted to limit the synthetic viability of the final compounds were eliminated for both reactions. All chemical fingerprint search and enumeration of the final compounds were performed in ICM Molsoft Pro v3.8. 52 530.044WO1 USC 2024-132-02 Figure 1 in combination with Scheme 2 above provides a schematic representation of the library design procedure employed to develop the two click chemistry libraries. Procedures with chemical fingerprinting searches are shown with solid arrows, and the steps involving chemical enumeration are shown with dotted arrows. Tables A-G2 below illustrate the reactions and exclusions included in the procedure. Steps for Fluorotriazole reaction: 1. Download building block library 2. Search for precursors to azides in the building block library: a) halides b) alcohols 3. Make reaction (enumeration / generation of compounds based on reaction): a) Halide-azide (1st row in Rxn1Reaction table (A1)) b) Alcohol-azide (2ndrow in Rxn1Reaction table (A2)) 4. Exclusion of compounds containing certain moieties from: a) Halide-azide b) Alcohol-azides 5. Search for azides in building block library with certain exclusions 6. Append azides from all three sources, and delete all azides with Mol weight > 350 and atom count < 5 7. Make reaction / enumeration / generation of intermediate compounds (3rdrow in Rxn1Reaction table (A3)) 8. Search for primary and secondary amines with respective exclusions in the building block library 9. Append primary and secondary amines and delete amines with Mol weight > 350 10. Final make reaction / enumeration / generation of final compounds and filter all molecules >500 Mol weight (4th row in Rxn1Reaction table (A4)) Steps for Isoxazole reaction: 1. Download building block library 2. Search for precursor aldehydes and filter out aldehydes with Mol weight > 350 3. Make reaction / enumeration / generation of intermediate compounds (1strow in Rxn2Reaction table (A1)) 4. Make reaction / enumeration / generation of intermediate compounds (2ndrow in Rxn2Reaction table (A2)) 5. Search for primary and secondary amines with respective exclusions in the building block library 53 530.044WO1 USC 2024-132-02 6. Append primary and secondary amines and delete amines with Mol weight > 350 7. Final make reaction / enumeration / generation of final compounds and filter all molecules >500 Mol weight (3rdrow in Rxn2Reaction table (A3)) Table A. Reactions tables (A1-A7). 54 530.044WO1 USC 2024-132-02 Table B. Moieties excluded from azide search from the building block library. Table C. Moieties excluded from azide intermediate generated after halide search from the building block library. Table D. Moieties excluded from azide intermediate generated after alcohol search from the building block library. 55 530.044WO1 USC 2024-132-02

[0002] Table E. Moieties excluded from carbonyl search from the building block library. Table F1. Moieties excluded from primary amines search from the building block library for fluorotriazole library. Table G1. Moieties excluded from secondary amines search from the building block library for fluorotriazole library. Table F2. Moieties excluded from primary amines search from the building block library for fluorotriazole library. 56 530.044WO1 USC 2024-132-02 Table G2. Moieties excluded from secondary amines search from the building block library for fluorotriazole library. (Legend: * : any atom; a : any aromatic atom; X : any halogen atom; ! : not; Q: any but not carbon or hydrogen). Example 4. Pharmaceutical Dosage Forms. The following formulations illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as 'Compound X'): (i) Tablet 1 mg / tablet 'Compound X' 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (ii) Tablet 2 mg / tablet 'Compound X' 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg / capsule 'Compound X' 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 57 530.044WO1 USC 2024-132-02 (iv) Injection 1 (1 mg / mL) mg / mL 'Compound X' (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg / mL) mg / mL 'Compound X' (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 0.1 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg / can 'Compound X' 20 Oleic acid 10 Trichloromonofluoromethane 5,000 Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000 (vii) Topical Gel 1 wt.% 'Compound X' 5% Carbomer 934 1.25% Triethanolamine q.s. (pH adjustment to 5-7) Methyl paraben 0.2% Purified water q.s. to 100g (viii) Topical Gel 2 wt.% 'Compound X' 5% Methylcellulose 2% Methyl paraben 0.2% Propyl paraben 0.02% Purified water q.s. to 100g (ix) Topical Ointment wt.% 'Compound X' 5% Propylene glycol 1% Anhydrous ointment base 40% Polysorbate 80 2% Methyl paraben 0.2% Purified water q.s. to 100g 58 530.044WO1 USC 2024-132-02 (x) Topical Cream 1 wt.% 'Compound X' 5% White bees wax 10% Liquid paraffin 30% Benzyl alcohol 5% Purified water q.s. to 100g (xi) Topical Cream 2 wt.% 'Compound X' 5% Stearic acid 10% Glyceryl monostearate 3% Polyoxyethylene stearyl ether 3% Sorbitol 5% Isopropyl palmitate 2 % Methyl Paraben 0.2% Purified water q.s. to 100g These formulations may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest. All publications, patents, and patent documents cited herein are incorporated by reference as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, many variations and modifications may be made while remaining within the spirit and scope of the invention. While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims. 59 530.044WO1 USC 2024-132-02

Claims

CLAIMS What is claimed is:

1. A compound of Formula I:wherein R1is aryl or heteroaryl; L is –CH(R11)– or a direct bond, wherein when present, R11is H, aryl, heteroaryl, heterocycle, or alkyl, each optionally substituted with one or more substituents; N-Het is triazole or isoxazole, optionally substituted with halo, nitro, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, –N(R12)2, –SR13, or –OR14, wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heteroaryl or heterocycle, each optionally substituted with one or more substituents, which substituents are optionally pyrimidine, halo-substituted pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H or alkyl and R3is alkyl, benzyl, or (C3-C8)cycloalkyl, optionally substituted with one or more substituents, which substituents are optionally hydroxy, hydroxyalkyl, phenyl, or heteroaryl; and wherein each aryl, heteroaryl, heterocycle, or alkyl is optionally substituted with one or more substituents, which substituents are optionally halo, nitro, –N(R12)2, –SR13, or –OR14, alkyl, alkoxy- alkyl, cycloalkyl, cycloalkoxy, benzyl, and benzyloxy optionally substituted with one or more halo, wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, as represented by Formula III:wherein R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered ring, wherein the ring system formed is a pyrrolidine, octahydro-1H- indole, or piperazine, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or 60 530.044WO1 USC 2024-132-02R2is H and R3is (C3-C8)cycloalkyl optionally substituted with one or more substituents, which substituents optionally include -OH; and wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, as represented by Formula IIIA:wherein Raand Rbtaken together with the nitrogen atom and carbon atom, respectively, to which they are attached form a pyrrolidine ring; and Rcis H, alkyl, or pyrimidine; or Rais H; and Rband Rctaken together with the carbon atom to which they are attached form a cycloalkyl ring; or Rais H; Rbis phenyl or pyrazole; and Rcis H, alkyl, or pyrimidine; Rdis H, alkyl, or phenyl; Reis amino alkyl, amino phenyl, benzyl, halo, or phenyl; and Rfis H or halo; wherein each alkyl, amino alkyl, amino phenyl, benzyl, cycloalkyl, phenyl, pyrazole, pyrimidine, and pyrrolidine ring is independently either substituted or unsubstituted; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein Raand Rbare taken together with the nitrogen atom to which they are attached to form a substituted pyrrolidine ring, and Rcis pyrimidine, wherein the substituted pyrrolidine ring is:. 61 530.044WO1 USC 2024-132-025. The compound of claim 3, wherein Raand Rbare taken together with the nitrogen atom to which they are attached to form a substituted pyrrolidine ring, and Rctaken together with Rbforms a cycloalkyl ring, wherein the substituted pyrrolidine ring is:.

6. The compound of claim 3, wherein Rbis phenyl substituted with CH2OH; or Rcis substituted alkyl and Rcis CH2OH.

7. The compound of claim 3, wherein Reis CH2Ph, N(Et2), NPhMe, or Ph.

8. The compound of claim 1, as represented by Formula IV:R1is biphenyl, phenyl, naphthyl, or dibenzothiophene; L is –CH(R11) – or a direct bond, wherein when present, R11is H, Ph, or (C1-C6)alkyl; R2and R3taken together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered ring, wherein the ring system formed is a pyrrolidine, octahydro-1H- indole, or piperazine, each optionally substituted with one or more substituents, which substituents optionally include pyrimidine, hydroxymethyl, or –C(=O)-imidazole; or R2is H and R3is (C3-C8)cycloalkyl optionally substituted with one or more substituents, which substituents optionally include -OH; and R4is H, halo, nitro, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, –N(R12)2, –SR13, or –OR14, wherein each R12, R13and R14is independently H, alkyl, aryl, heteroaryl, or heterocycle; wherein each biphenyl, phenyl, naphthyl, or dibenzothiophene is optionally substituted with one or more substituents, which substituents optionally include halo, hydroxy, alkoxy, and benzyloxy, optionally substituted with halo; or a pharmaceutically acceptable salt thereof. 62 530.044WO1 USC 2024-132-029. The compound of claim 1, as represented by Formula IVA:wherein Raand Rbtaken together with the nitrogen atom and carbon atom, respectively, to which they are attached form a pyrrolidine ring; and Rcis H, alkyl, or pyrimidine; or Rais H; and Rband Rctaken together with the carbon atom to which they are attached form a cycloalkyl ring; or Rais H; Rbis phenyl or pyrazole; and Rcis H, alkyl, or pyrimidine; Rfis independently H or halo; each Rgand Rhare independently H, alkoxy, cycloalkyloxy, or benzyloxy; or Rgand Rhform a 5-membered heterocycle; and Riis H; or Rhand Riform a benzo ring; wherein each alkyl, alkoxy, cycloalkyl ring, cycloalkyloxy, benzyloxy, cycloalkyl, 5-membered heterocycle, piperazine ring, phenyl, pyrazole, and pyrrolidine ring is independently either substituted or unsubstituted; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein Raand Rbare taken together with the nitrogen atom and carbon atom, respectively, to which they are attached to form a substituted piperazine ring, wherein the substituted piperazine ring is:.

11. The compound of claim 9, wherein Raand Rbare taken together with the nitrogen atom and carbon atom, respectively, to which they are attached to form a substituted pyrrolidine ring, and Rcis pyrimidine, wherein the substituted pyrrolidine ring is: 63 530.044WO1 USC 2024-132-02.

12. The compound of claim 9, wherein Rais CH3 or CH2OH; or Rbis tolyl.

13. The compound of claim 9, wherein Rctaken together with Rband the carbon atom to which they are attached forms a substituted cycloalkyl ring, wherein the substituted cycloalkyl ring is:.

14. The compound of claim 9, wherein Rgand Rhare each independently H, methoxy, cyclopentyloxy, or dichlorobenzyloxy.

15. The compound of claim 9, wherein Rgand Rhform a 5-membered heterocycle, wherein the substituted 5-membered heterocycle is:64 530.044WO1 USC 2024-132-02or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof. 65 530.044WO1 USC 2024-132-0218. A method for treating or reducing the symptoms of a condition that is responsive to CB2R modulation comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-17, thereby treating or reducing the symptoms of the condition that is responsive to CB2R modulation.

19. The method of claim 18, wherein the condition comprises an autoimmune disorder, a metabolic disorder, arthritis, chronic pain, fibrosis, multiple sclerosis, neuroinflammation, or cancer.

20. The method of claim 18, wherein the compound is:or a pharmaceutically acceptable salt thereof. 66 530.044WO1 USC 2024-132-02

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