Urea derivatives for inhibiting NLRP3 and their use

Abstract

This disclosure relates to Ring A, Ring B, and R 1 , R 2a , R 2b , R 3 , R 4 This disclosure relates to compounds of formula (IB), where m, n, and p are as described herein, as well as pharmaceutically acceptable salts and tautomers thereof, as well as methods for preparing, treating, and prophylactically treating the same, and pharmaceutical compositions comprising them. This disclosure further relates to the use of compounds of formula (IB), as well as pharmaceutically acceptable salts and tautomers thereof, in the treatment or prophylaxis of NLRP3-related diseases and disorders. JPEG2026510922000351.jpg68170

Description

[Technical Field]

[0001] Related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 490,962, filed on 17 March 2023, and U.S. Provisional Patent Application No. 63 / 519,069, filed on 11 August 2023, the contents of each of those applications being incorporated herein by reference in their entirety. [Background technology]

[0002] Innate immune responses are mediated by different types of receptors called pattern recognition receptors (PRRs). PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) and injury-associated molecular patterns (DAMPs). When these receptors are involved, it triggers the activation of downstream inflammatory pathways that help resolve injury. However, in many cases, this activation can become uncontrolled and lead to disease.

[0003] Inflammasomes represent a class of PRRs, which are crucial components of the innate immune response. Activation of inflammasomes triggers a cascade of events that promote an inflammatory form of cell death called pyroptosis, which is induced by the activation of gasdermin and releases IL-1β and IL-18. Pyroptosis is a unique form of inflammatory cell death that leads to the release of not only cytokines but also other intracellular components that promote a broader immune response in both the innate and acquired immune systems. Therefore, inflammasome activation is a major regulator of the inflammatory cascade.

[0004] NLRP3 is the most distinctive inflammasome and has been shown to be important in innate immune and inflammatory responses. While some other NLR complexes, such as NLRC4, are activated under very specific circumstances, NLRP3 can be activated by a wide range of stimuli and should be considered a sensor of intracellular homeostatic imbalance. Therefore, its precise function is essential. In addition to playing a role in host immune defense, abnormal regulation of NLRP3 is associated with the pathogenesis of many inflammatory disorders. These include genetic disorders such as cryopyrin-associated periodic syndromes (CAPS) caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, NLRP3 hyperactivation has been preclinically demonstrated to play a crucial role in numerous inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes mellitus, gout, and many other autoinflammatory diseases. For example, see Li et al., European Journal of Pharmacology (2022) 928:175091, Nguyen et al., Journal of Parkinson's Disease (2022) 12:2117-2133, Su et al., Current Medicinal Chemistry (2021) 28:569-582, and Zahid et al., Frontiers in Immunology (2019) 10:2538. Therefore, there is an unmet need in this field to develop small molecules to modulate NLRP3 activity in order to treat various diseases and disorders. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Li et al.,European Journal of Pharmacology(2022)928:175091 [Non-Patent Document 2] Nguyen et al., Journal of Parkinson's Disease (2022) 12:2117-2133 [Non-Patent Document 3] u et al.,Current Medicinal Chemistry(2021)28:569-582 [Non-Patent Document 4] Zahid et al.,Frontiers in Immunology(2019)10:2538 [Overview of the project] [Problems that the invention aims to solve]

[0006] NLRP3 inhibitors of formula (IB): [ka] As well as pharmaceutically acceptable salts and tautomers thereof, are provided herein, wherein the formula, ring A, ring B, R 1 , R 2a , R 2b , R 3 , R 4 m, n, and p are described herein.

[0007] Methods for preparation, methods for treatment and prevention, and pharmaceutical compositions containing the same are further provided. [Means for solving the problem]

[0008] definition The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. thIdentified according to the Ed. endpapers, specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are referred to in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito, 1999, and *Smith and March March's Advanced Organic Chemistry*, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0009] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The compounds described herein are substantially free of other isomers, and alternatively, individual isomers may be further included as mixtures of various isomers.

[0010] For example, a compound described in this specification may be referred to as "Rac-X", which, for the purposes of the examples, means a mixture of two or more stereoisomers, such as compounds X’X”, X”, X””, XA, XB, XC, XD, XE, XF, XG, and / or XH, including the data provided in the assay method section. For the purpose of claiming the "Rac-X" molecule, the claims may encompass the racemic composition of the substance, but may also encompass compositions of enantiomerically enriched substances, for example, enriched in one stereoisomer over other stereoisomers that may be produced. For example, the claims may encompass a pharmaceutical composition comprising a "Rac-X" compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the "Rac-X" compound is enantiomerically enriched at >80%, >85%, >90%, >95%, or >99%.

[0011] Unless otherwise specified, a compound described in this specification also means including compounds that differ only in the presence of one or more isotope-enriched atoms. For example, substitution of hydrogen with deuterium or tritium, 18 substitution of 19 with 13 F, or [[ID=U11]] 14 substitution of carbon with 1-6 C or 1-6 C-enriched carbon, compounds having the structure of the present invention are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0012] When ranges of values are recited, it is intended to include each value and sub-range within the range. For example, "C 1-6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 [[ID=4〗2]], C 4-6 , C 4-5 , and C 5-6It is intended to include alkyl groups.

[0013] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms ("C"). 1-6 "alkyl" refers to an alkyl group consisting of 1 to 5 carbon atoms. In some embodiments, an alkyl group consists of 1 to 5 carbon atoms ("C"). 1-5 The alkyl group has 1 to 4 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 The alkyl group has 1 to 3 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3 The alkyl group has 1 to 2 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 The alkyl group has an alkyl group ("C1 alkyl"). In some embodiments, the alkyl group has an alkyl group ("C1 alkyl"). In some embodiments, the alkyl group has an alkyl group ("C1 alkyl"). 2-6 It has an alkyl group. 1-6 Examples of alkyl groups include methyl (-CH3, C1), ethyl (-CH2CH3, C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6).

[0014] "Haloalkyl" refers to a substituted alkyl group as defined herein, in which one or more hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodine. "Perhaloalkyl" is a subset of haloalkyls, in which all hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodine. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms ("C"). 1-6 Haloalkyl group has 1 to 5 carbon atoms ("C"). In some embodiments, the haloalkyl group has 1 to 5 carbon atoms ("C"). 1-5The haloalkyl group has 1 to 4 carbon atoms ("C"). In some embodiments, the haloalkyl group has 1 to 4 carbon atoms ("C"). 1-4 Haloalkyl group has 1 to 3 carbon atoms ("C"). In some embodiments, the haloalkyl group has 1 to 3 carbon atoms ("C"). 1-3 Haloalkyl group has 1-2 carbon atoms ("C"). In some embodiments, the haloalkyl group has 1-2 carbon atoms ("C"). 1-2 The group has a "haloalkyl" group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro atoms to provide a perfluoroalkyl group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro atoms to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, and -CF2Cl.

[0015] A "carbocyrill" or "carbocyclic" is a non-aromatic ring system containing 3-4 ring carbon atoms ("C"). 3-4 This refers to a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms ("carbocyclyl"). In some embodiments, the carbocyclyl group has 3 ring carbon atoms ("C3 carbocyclyl"). In some embodiments, the carbocyclyl group has 4 ring carbon atoms ("C4 carbocyclyl"). Exemplary C 3-4 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), and cyclobutenyl (C4).

[0016] "C3-C4 Carbocyclyl-C 1-3 "Alkyl" is defined as C as defined herein. 1-3 This refers to a C3-C4 carbocyclic group bonded to an alkyl group, with the bond site to the parent molecule located on the alkyl group.

[0017] A "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 4-membered non-aromatic ring system having a ring carbon atom and one ring heteroatom, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 4-membered heterocyclyl"). In a heterocyclyl group containing one nitrogen atom, the bond site can be a carbon atom or a nitrogen atom, if the valence allows. Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxyranyl, and thiranyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.

[0018] "Heteroaryl" refers to a radical of a five-membered monocyclic aromatic ring system having a ring carbon atom and one or two ring heteroatoms, where each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur ("five-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon atom or a nitrogen atom, if the valence allows. Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.

[0019] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I) radicals.

[0020] Adding the suffix "-en" indicates that the group is a divalent part; for example, alkylene is the divalent part of alkyl, and haloalkylene is the divalent part of haloalkyl. Examples include C, which can be linear or branched. 1-3Examples of alkylenes include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, and -CH2CH2CH2-.

[0021] An alkylene or haloalkylene "crosslinking group" refers to a group in which the two ends of the divalent moiety are bonded to different carbon atoms that are not adjacent to each other. Exemplary crosslinking groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and their corresponding halogenated (haloalkylene) groups. For clarity, "two R 3 The groups are linked together with the atoms to which they are bonded, C 1-3 Alkylene crosslinking group or C 1-3 The phrase "can form a haloalkylene crosslinking group" is used herein to mean "two R 3 The groups are linked together, with C between the two atoms they bond to. 1-3 Alkylene crosslinking group or C 1-3 The phrase "may form a haloalkylene crosslinking group" is used interchangeably with the phrase "may form a haloalkylene crosslinking group," and both phrases are linked together, with C on ring B. 1-3 Alkylene crosslinking group or C 1-3 Two non-adjacent R groups form a haloalkylene crosslinking group. 3 This means there is a group (bonded to the two carbon atoms of ring B). An example of this bridging group is the variable L in compounds of formula (IB-bridging).

[0022] Compounds of formula (IB), each containing a terminal tetrazolyl group, and their pharmaceutically acceptable salts are mixtures of tautomer isomers, for example, [ka] It can exist as such.

[0023] Amino and oxygen protecting groups are described in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rdDetails are provided in edition, John Wiley & Sons, 1999.

[0024] Examples of oxygen (hydroxyl) protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranil (THP), 3-bromotrahydropyranil, tetrahydropyranil, tetrahydropyranil, 1-metoxycyclohexyl, 4-methoxytetrahydropyranil (MTHP), 4-methoxytetrahydrothiopyranil Examples include, but are not limited to, lanyl, 4-methoxytetrahydrothiopyranyl S,S-oxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypepyridine-4-yl (CTMP), tetrahydrofuranyl, benzyl (Bn), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), diethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-ethyl carbonate (trimethylsilyl) (TMSEC), allyl carbonate, t-butyl carbonate (BOC), methanesulfonate (mesylate), benzyl sulfonate and tosylate (Ts).

[0025] Examples of amino protecting groups include, but are not limited to, amino protecting groups that protect amines as amides, such as formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, and phenylacetamide; amino protecting groups that protect amines as carbamates, such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), and benzyl carbamate (Cbz); and amino protecting groups that protect amines as sulfonamides, such as p-toluenesulfonamide (Ts), benzenesulfonamide, methanesulfonamide (Ms), and benzylsulfonamide.

[0026] Salts, pharmaceutically acceptable salts, and free bases of compounds of formula (IB) are intended herein.

[0027] "Salt" refers to any and all salts.

[0028] A "pharmaceutically acceptable salt" is a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that provides a reasonable benefit-risk ratio. Examples of pharmaceutically acceptable acid-added salts include, but are not limited to, salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchlorates, or salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malic acid, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons, where appropriate.

[0029] "Free base" refers to the neutral, non-ionized form of a compound that is not a salt or a pharmaceutically acceptable salt.

[0030] "Patient" or "subject" are used synonymously herein and refer to mammals, such as humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates, such as monkeys, chimpanzees, baboons, or rhesus monkeys. In certain embodiments, the patient or subject is a human.

[0031] "Effective dose" or "therapeutically effective dose" are used synonymously herein and refer to the amount of a compound, or a pharmaceutically acceptable salt or tautomer thereof, that is sufficient to produce a therapeutic benefit in the treatment of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder in a subject in need of such benefit. The effective dose may include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of the disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent. The effective dose of a compound, or a pharmaceutically acceptable salt or tautomer thereof, may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0032] The terms "disease" and "disorder" are used synonymously in this specification.

[0033] "To treat" or "to cure" or "to treat" describes the management and care of an object in need of it for the purpose of combating the disease or disorder of the subject, and includes the administration of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to reduce the symptoms or complications of the disease or disorder, or to eliminate the disease or disorder. The term "to treat" may also include the treatment of cells in vitro or the treatment of animal models (in vivo). A reference to "to treat" or "to treat" includes the relief of established symptoms of the disease or disorder in an object in need of it, and therefore includes (1) delaying the onset of at least one clinical or subclinical symptom of the disease or disorder that develops in an object suffering from the disease or disorder, (2) stopping, reducing or delaying the onset of the disease or its relapse in the object (e.g., in the case of maintenance treatment), or delaying the onset of at least one clinical or subclinical symptom thereof, or (3) alleviating or attenuating the disease in the object, i.e., causing regression of the disease or disorder, or at least one clinical or subclinical symptom thereof.

[0034] As used herein, the terms “prevention,” “prevent,” or “prevention” describe the management and care of a subject who is predisposed to a disease or disorder, or who is predisposed to a disease or disorder but has not yet experienced or shown any symptoms or complications of the disease or disorder (e.g., clinical or subclinical symptoms of the disease or disorder), for the purpose of preventing the appearance of such symptoms or complications of the disease or disorder in the subject, and include the administration of the compounds described herein, or their pharmaceutically acceptable salts or tautomers.

[0035] "Inhibition," "the act of inhibiting," "to inhibit," and "inhibitor" refer to the ability of a compound, or a pharmaceutically acceptable salt or tautomer thereof, to reduce, delay, halt, or prevent the activity of a specific intracellular biological process (e.g., NLRP3 activity) compared to a vehicle.

[0036] The phrase "at least one" refers to one example or two or more examples.

[0037] In this disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of an article.

[0038] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean either "and" or "or". [Modes for carrying out the invention]

[0039] (i) Compound Compounds of formula (IB): [ka] Furthermore, pharmaceutically acceptable salts and tautomers thereof, During the ceremony, Ring A is a ring system, G1 is CR G1 Or N, and G2 is CR G2 Or N, and G3 is CR G3 Or N, and G4 is CR G4 Or N, provided that at least two of G1, G2, G3, and G4 are N. R 1 But, hello, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , -N(R G5 )2, C3-C4 carbocyclyl, or 3-4 member heterocyclyl, wherein the carbocyclyl and heterocyclyl independently have 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) Is it replaced with 2? or R 1 And G2 are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R G7forms a 5-membered heteroaryl ring independently substituted, R G1 、R G2 、R G3 、and R G4 are each independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, and -OR G6 selected from the group consisting of, R G5 and R G6 are each independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl, each instance of R G7 is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, -OR G5 、-SR G5 、and -N(R G5 )2, ring B is a ring system, n is 0 or 1, p is 1 or 2, m is 0, 1, 2, or 3, R 2a and R 2b each instance of is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C3-C4 carbocyclic, or 3-4 member heterocyclic, where the carbocyclic or heterocyclic is independently substituted with 0, 1, 2, or 3 halos, or R 2a and R 2b are linked to form a C3 carbocyclic independently substituted with 0, 1, 2, or 3 halos, each instance of R 3 is independently halo, C 1-6 alkyl or C 1-6 haloalkyl, or two R 3 groups are linked to form a C 1-3 alkylene bridging group or C 1-3 haloalkylene bridging group, R 4 is hydrogen, C 1-3Alkyl, C3-C4 carbocyrill, or C3-C4 carbocyrill-C 1-3 It is alkyl-, and the alkyl and carbocyryl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos, and the carbocyryl is further independently substituted with 0, 1, or 2 C 1-3 Alkyl or C 1-3 Compounds substituted with haloalkyl groups, or pharmaceutically acceptable salts or tautomers thereof, are provided herein.

[0040] In some embodiments of formula (IB), the compound is of the following formula: [ka] or a pharmaceutically acceptable salt or tautomer thereof.

[0041] In some embodiments of formula (IB), the compound is of the following formula: [ka] or a pharmaceutically acceptable salt or tautomer thereof.

[0042] In some embodiments of formula (IB), the compound is of the following formula: [ka] or a pharmaceutically acceptable salt or tautomer thereof, where L is C 1-3 Alkylene crosslinking group or C 1-3 It is a haloalkylene crosslinking group. In some embodiments, L is -CH2CH2-.

[0043] In some embodiments of formula (IB), the compound is of the following formula: [ka] or a pharmaceutically acceptable salt or tautomer thereof, where L is C 1-3Alkylene crosslinking group or C 1-3 It is a haloalkylene crosslinking group. In some embodiments, L is -CH2CH2-.

[0044] In some embodiments of formula (IB), the compound is of the following formula: [ka] [ka] or a pharmaceutically acceptable salt or tautomer thereof.

[0045] Additional embodiments are described below and further herein. (a) Ring A, G1, G2, G3, G4, R 1 , R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , and R G7

[0046] As generally described herein, G1 is CR G1 Or N, and G2 is CR G2 Or N, and G3 is CR G3 Or N, and G4 is CR G4 Or N, provided that at least two of G1, G2, G3, and G4 are N.

[0047] In some embodiments, G1 is CR G1 In some embodiments, G1 is N.

[0048] In some embodiments, G2 is CR G2 In some embodiments, G2 is N.

[0049] In some embodiments, G3 is CR G3In some embodiments, G3 is N.

[0050] In some embodiments, G4 is CR G4 In some embodiments, G4 is N.

[0051] In some embodiments, G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is CR G4 That is the case.

[0052] In some embodiments, at least one of G1, G2, G3, and G4 is N.

[0053] In some embodiments, G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is N. In some embodiments, G1 is CR G1 And G2 is CR G2 G3 is N, and G4 is CR G4 In some embodiments, G1 is CR G1 G2 is N, and G3 is CR G3 And G4 is CR G4 In some embodiments, G1 is N and G2 is CR. G2 And G3 is CR G3 And G4 is CR G4 That is the case.

[0054] In some embodiments, two of G1, G2, G3, and G4 are N.

[0055] For example, in some embodiments, G1 is CR G1 And G2 is CR G2 G3 is N, and G4 is N. In some embodiments, G1 is CR G1 G2 is N, and G3 is CR G3And G4 is N. In some embodiments, G1 is N and G2 is CR G2 And G3 is CR G3 And G4 is N. In some embodiments, G1 is N, G2 is N, and G3 is CR G3 And G4 is CR G4 In some embodiments, G1 is N and G2 is CR. G2 G3 is N, and G4 is CR G4 In some embodiments, G1 is CR G1 G2 is N, G3 is N, and G4 is CR G4 That is the case.

[0056] In some embodiments, G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is CR G4 Either G1 is N and G2 is CR G2 And G3 is CR G3 And G4 is CR G4 Is G1 CR? G1 G2 is N, and G3 is CR G3 And G4 is CR G4 Is G1 CR? G1 And G2 is CR G2 G3 is N, and G4 is CR G4 Is G1 CR? G1 And G2 is CR G2 And G3 is CR G3 And G4 is N, G1 is N, and G2 is CR G2 And G3 is CR G3 And G4 is N, G1 is N, and G2 is CR G2 G3 is N, and G4 is CR G4 Is G1 CR? G1 G2 is N, G3 is N, and G4 is CR G4 Either G1 is CR G1And G2 is CR G2 Therefore, G3 is N, and G4 is N.

[0057] In some embodiments, G1 is CH, G2 is CH, G3 is CH, and G4 is CH; or G1 is N, G2 is CH, G3 is CH, and G4 is CH; or G1 is CH, G2 is N, G3 is CH, and G4 is CH; or G1 is N, G2 is CH, G3 is CH, and G4 is CH; or G1 is CH, G2 is CH, G3 is CH, and G4 is N; or G1 is CH, G2 is CH, G3 is N, and G4 is CH.

[0058] As generally described herein, R 1 Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , -N(R G5 )2, C3-C4 carbocyclyl, or 3-4 member heterocyclyl, and carbocyclyl and heterocyclyl independently have 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 -haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) is replaced with 2, or R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) Select 0, 1, 2, or 3 R from the group consisting of 2 G7 They independently form a 5-membered heteroaryl ring.

[0059] In some embodiments, R 1 It is a halo.

[0060] In some embodiments, R 1 is F, Cl, Br, or I. In some embodiments, R 1 is F, Cl, or Br. In some embodiments, R 1 It is either F or Cl.

[0061] In some embodiments, R 1 F is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 It is I.

[0062] In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )C independently substituted in 2 1-6 It is alkyl.

[0063] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )C independently substituted in 2 1-6 It is alkyl.

[0064] In some embodiments, R 1 is unsubstituted C 1-6 It is alkyl.

[0065] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is butyl. In some embodiments, R1 is pentill. In some embodiments, R 1 is hexyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 isobutyl. In some embodiments, R 1 is isopentyl. In some embodiments, R 1 is isohexyl. In some embodiments, R 1 secbutyl is used in some embodiments. 1 secpentyl is used in some embodiments. 1 sec hexyl is used in some embodiments. 1 It is tert-butyl.

[0066] In some embodiments, R 1 C 1-6 It is a haloalkyl group.

[0067] In some embodiments, R 1 is a halomethyl. In some embodiments, R 1 is haloethyl. In some embodiments, R 1 is a halopropyl. In some embodiments, R 1 is halobutyl. In some embodiments, R 1 is halopentyl. In some embodiments, R 1 It is a halohexyl.

[0068] In some embodiments, R 1 is -OR G5 That is the case.

[0069] In some embodiments, R 1 -SR G5 That is the case.

[0070] In some embodiments, R 1 is -N(R G5 )2.

[0071] In some embodiments, R 1 These are C3-C4 carbocyclils or 3-4 member heterocyclils, and each carbocyclil or heterocyclil independently has 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) is replaced by 2.

[0072] In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C3-C4 carbocyclyl independently substituted with )2.

[0073] In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C3 carbocyclyl independently substituted with )2.

[0074] In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C4 carbocyclyl independently substituted with )2.

[0075] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5It is a C3-C4 carbocyclyl independently substituted with )2.

[0076] In some embodiments, R 1 These are independently 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C3 carbocyclyl substituted with )2.

[0077] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C4 carbocyclyl independently substituted with )2.

[0078] In some embodiments, R 1 It is an unsubstituted C3-C4 carbocyclyl.

[0079] In some embodiments, R 1 R is an unsubstituted C3 carbocykyl. In some embodiments, R 1 It is an unsubstituted C4 carbocykyl.

[0080] In some embodiments, R 1 This is one halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C3-C4 carbocyclyl substituted with )2.

[0081] In some embodiments, R 1 This is one halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5It is a C3 carbocykyl substituted with )2. In some embodiments, R 1 This is one halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C4 carbocykrill substituted with )2.

[0082] In some embodiments, R 1 This is two halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C3-C4 carbocyclyl independently substituted with )2.

[0083] In some embodiments, R 1 This is two halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a C3 carbocykyl independently substituted with R. In some embodiments, 1 This is two halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C4 carbocyclyl independently substituted with )2.

[0084] In some embodiments, R 1 It has three halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C3-C4 carbocyclyl independently substituted with )2.

[0085] In some embodiments, R 1 It has three halos, C 1-6 Alkyl, C1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a C3 carbocykyl independently substituted with R. In some embodiments, 1 It has three halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a C4 carbocyclyl independently substituted with )2.

[0086] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 A C3-C4 carbocyric molecule independently substituted with )2, provided that at least one substituent is a halo.

[0087] In some embodiments, R 1 is a C3 carbocykyl substituted with at least one halo. In some embodiments, R 1 This is a C4 carbocykrill substituted with at least one halo.

[0088] In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one of F, Cl, or Br. In some embodiments, R 1 It is a C3-C4 carbocykyl substituted with at least one of F or Cl.

[0089] In some embodiments, R 1 is a C3 carbocykyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R1 is a C3 carbocykyl substituted with at least one of F, Cl, or Br. In some embodiments, R 1 It is a C3 carbocykyl substituted with at least one of F or Cl.

[0090] In some embodiments, R 1 is a C4 carbocykyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 1 is a C4 carbocykyl substituted with at least one of F, Cl, or Br. In some embodiments, R 1 It is a C4 carbocykyl substituted with at least one of F or Cl.

[0091] In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one F. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one Cl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one Br. In some embodiments, R 1 It is a C3-C4 carbocyclyl substituted with at least one I.

[0092] In some embodiments, R 1 is a C3 carbocykyl substituted with at least one F. In some embodiments, R 1 is a C3 carbocykyl substituted with at least one Cl. In some embodiments, R 1 is a C3 carbocykyl substituted with at least one Br. In some embodiments, R 1 It is a C3 carbocykrill substituted with at least one I.

[0093] In some embodiments, R 1 is a C4 carbocykyl substituted with at least one F. In some embodiments, R1 is a C4 carbocykyl substituted with at least one Cl. In some embodiments, R 1 is a C4 carbocykyl substituted with at least one Br. In some embodiments, R 1 It is a C4 carbocykrill substituted with at least one I.

[0094] In some embodiments, R 1 is at least one C 1-6 It is an alkyl-substituted C3-C4 carbocyric.

[0095] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted C3-C4 carbocyric, provided that at least one substituent is C 1-6 The condition is that it must be alkyl.

[0096] In some embodiments, R 1 is a C3-C4 carbocyric substituted with at least one methyl group. In some embodiments, R 1 is a C3-C4 carbocyric substituted with at least one ethyl group. In some embodiments, R 1 is a C3-C4 carbocyric substituted with at least one propyl group. In some embodiments, R 1 is a C3-C4 carbocyrill substituted with at least one butyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one pentyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one hexyl. In some embodiments, R 1is a C3-C4 carbocyrill substituted with at least one isopropyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one isobutyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one isopentyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one isohexyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one secbutyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one secpentyl. In some embodiments, R 1 is a C3-C4 carbocyclyl substituted with at least one sechexyl. In some embodiments, R 1 It is a C3-C4 carbocykyl substituted with at least one tert-butyl.

[0097] In some embodiments, R 1 is a C3 carbocyric substituted with at least one methyl group. In some embodiments, R 1 is a C3 carbocyric substituted with at least one ethyl group. In some embodiments, R 1 is a C3 carbocyric substituted with at least one propyl group. In some embodiments, R 1 is a C3 carbocyric substituted with at least one butyl. In some embodiments, R 1 is a C3 carbocykyl substituted with at least one pentyl. In some embodiments, R 1 is a C3 carbocyrill substituted with at least one hexyl. In some embodiments, R 1 is a C3 carbocyric substituted with at least one isopropyl. In some embodiments, R 1is a C3 carbocyric substituted with at least one isobutyl. In some embodiments, R 1 is a C3 carbocyrill substituted with at least one isopentyl. In some embodiments, R 1 is a C3 carbocyrill substituted with at least one isohexyl. In some embodiments, R 1 is a C3 carbocyrill substituted with at least one secbutyl. In some embodiments, R 1 is a C3 carbocykyl substituted with at least one secpentyl. In some embodiments, R 1 is a C3 carbocyrill substituted with at least one sechexyl. In some embodiments, R 1 It is a C3 carbocyrill substituted with at least one tert-butyl molecule.

[0098] In some embodiments, R 1 is a C4 carbocyric substituted with at least one methyl group. In some embodiments, R 1 is a C4 carbocyric substituted with at least one ethyl group. In some embodiments, R 1 is a C4 carbocyric substituted with at least one propyl group. In some embodiments, R 1 is a C4 carbocyrill substituted with at least one butyl. In some embodiments, R 1 is a C4 carbocykyl substituted with at least one pentyl. In some embodiments, R 1 is a C4 carbocykyl substituted with at least one hexyl. In some embodiments, R 1 is a C4 carbocyric substituted with at least one isopropyl. In some embodiments, R 1 is a C4 carbocyric substituted with at least one isobutyl. In some embodiments, R 1 is a C4 carbocyrill substituted with at least one isopentyl. In some embodiments, R 1is a C4 carbocyrill substituted with at least one isohexyl. In some embodiments, R 1 is a C4 carbocyrill substituted with at least one secbutyl. In some embodiments, R 1 is a C4 carbocykyl substituted with at least one secpentyl. In some embodiments, R 1 is a C4 carbocykyl substituted with at least one sechexyl. In some embodiments, R 1 It is a C4 carbocyrill substituted with at least one tert-butyl.

[0099] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted C3-C4 carbocyric, provided that at least one substituent is C 1-6 The condition is that it must be a haloalkyl group.

[0100] In some embodiments, R 1 is at least one C 1-6 It is a C3 carbocyryl substituted with a haloalkyl group. In some embodiments, R 1 is at least one C 1-6 It is a C4 carbocyric substituted with a haloalkyl group.

[0101] In some embodiments, R 1 is a C3-C4 carbocyclyl substituted with at least one halomethyl group. In some embodiments, R 1 is a C3-C4 carbocyric substituted with at least one haloethyl. In some embodiments, R 1 is a C3-C4 carbocyrill substituted with at least one halopropyl. In some embodiments, R 1is a C3-C4 carbocykyl substituted with at least one halobutyl. In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one halopentyl. In some embodiments, R 1 It is a C3-C4 carbocyclyl substituted with at least one halohexyl.

[0102] In some embodiments, R 1 is a C3 carbocyclyl substituted with at least one halomethyl group. In some embodiments, R 1 is a C3 carbocyric substituted with at least one haloethyl. In some embodiments, R 1 is a C3 carbocyric substituted with at least one halopropyl. In some embodiments, R 1 is a C3 carbocyric substituted with at least one halobutyl. In some embodiments, R 1 is a C3 carbocyrill substituted with at least one halopentyl. In some embodiments, R 1 It is a C3 carbocyrill substituted with at least one halohexyl.

[0103] In some embodiments, R 1 is a C4 carbocyclyl substituted with at least one halomethyl group. In some embodiments, R 1 is a C4 carbocyric substituted with at least one haloethyl. In some embodiments, R 1 is a C4 carbocyric substituted with at least one halopropyl. In some embodiments, R 1 is a C4 carbocyrill substituted with at least one halobutyl. In some embodiments, R 1 is a C4 carbocykyl substituted with at least one halopentyl. In some embodiments, R 1 It is a C4 carbocyrill substituted with at least one halohexyl.

[0104] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted C3-C4 carbocyric, provided that at least one substituent is -OR G5 This is conditional on the following:

[0105] In some embodiments, R 1 is at least one -OR G5 It is a C3 carbocykyl substituted with R. In some embodiments, R 1 is at least one -OR G5 It is a C4 carbocykyl substituted with [the specified compound].

[0106] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted C3-C4 carbocyric, provided that at least one substituent is -SR G5 This is conditional on the following:

[0107] In some embodiments, R 1 is at least one -SR G5 It is a C3 carbocykyl substituted with R. In some embodiments, R 1 is at least one -SR G5 It is a C4 carbocykyl substituted with [the specified compound].

[0108] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5A C3-C4 carbocyric independently substituted with )2, provided that at least one substituent is -N(R G5 ) Provided that it is 2.

[0109] In some embodiments, R 1 is at least one -N(R G5 It is a C3 carbocykyl substituted with )2. In some embodiments, R 1 is at least one -N(R G5 It is a C4 carbocykrill substituted with )2.

[0110] In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a 3-4 member heterocycline that is independently substituted.

[0111] In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) is a three-membered heterocyclyl substituted with 2. In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a four-membered heterocycline independently substituted at )2.

[0112] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5)2 is a 3-4 member heterocycline that is independently substituted.

[0113] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a three-membered heterocycline independently substituted. In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a four-membered heterocycline independently substituted at )2.

[0114] In some embodiments, R 1 It is an unsubstituted 3-4 member heterocyclyl.

[0115] In some embodiments, R 1 R is an unsubstituted three-membered heterocyclyl. In some embodiments, R 1 It is an unsubstituted four-membered heterocyclyl.

[0116] In some embodiments, R 1 This is one halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a 3-4 member heterocycline that is independently substituted.

[0117] In some embodiments, R 1 This is one halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) is a three-membered heterocyclyl substituted with 2. In some embodiments, R1 This is one halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a four-membered heterocyclyl substituted with )2.

[0118] In some embodiments, R 1 This is two halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a 3-4 member heterocycline that is independently substituted.

[0119] In some embodiments, R 1 This is two halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a three-membered heterocycline independently substituted. In some embodiments, R 1 This is two halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a four-membered heterocycline independently substituted at )2.

[0120] In some embodiments, R 1 It has three halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a 3-4 member heterocycline that is independently substituted.

[0121] In some embodiments, R 1 It has three halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SRG5 , or -N(R G5 )2 is a three-membered heterocycline independently substituted. In some embodiments, R 1 It has three halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 It is a four-membered heterocycline independently substituted at )2.

[0122] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 is a 3-4 member heterocycline independently substituted, provided that at least one substituent is a halo.

[0123] In some embodiments, R 1 is a three-membered heterocycline substituted with at least one halo. In some embodiments, R 1 It is a four-membered heterocyclyl substituted with at least one halo.

[0124] In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one of F, Cl, Br, or I. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one of F, Cl, or Br. In some embodiments, R 1 It is a 3-4 member heterocycline substituted with at least one of F or Cl.

[0125] In some embodiments, R 1 is a three-membered heterocycline substituted with at least one of F, Cl, Br, or I. In some embodiments, R 1is a three-membered heterocycline substituted with at least one of F, Cl, or Br. In some embodiments, R 1 It is a three-membered heterocycline substituted with at least one of F or Cl.

[0126] In some embodiments, R 1 is a four-membered heterocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one of F, Cl, or Br. In some embodiments, R 1 It is a four-membered heterocyclyl substituted with at least one of F or Cl.

[0127] In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one F. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one Cl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one Br. In some embodiments, R 1 It is a 3-4 member heterocycline substituted with at least one I.

[0128] In some embodiments, R 1 is a three-membered heterocycline substituted with at least one F. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one Cl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one Br. In some embodiments, R 1 It is a three-membered heterocycline substituted with at least one I.

[0129] In some embodiments, R 1 is a four-membered heterocyclyl substituted with at least one F. In some embodiments, R 1is a four-membered heterocyclyl substituted with at least one Cl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one Br. In some embodiments, R 1 It is a four-membered heterocycline substituted with at least one I.

[0130] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted 3-4 member heterocyclyl, provided that at least one substituent is C 1-6 The condition is that it must be alkyl.

[0131] In some embodiments, R 1 is at least one C 1-6 It is an alkyl-substituted three-membered heterocycline. In some embodiments, R 1 is at least one C 1-6 It is a four-membered heterocycline substituted with an alkyl group.

[0132] In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one methyl group. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one ethyl group. In some embodiments, R 1 is a 3-4 membered heterocycline substituted with at least one propyl group. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one butyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one pentyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one hexyl. In some embodiments, R1 is a 3-4 member heterocycline substituted with at least one isopropyl group. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one isobutyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one isopentyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one isohexyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one secbutyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one secpentyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one sechexyl. In some embodiments, R 1 It is a 3-4 member heterocycline substituted with at least one tertbutyl molecule.

[0133] In some embodiments, R 1 is a three-membered heterocycline substituted with at least one methyl group. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one ethyl group. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one propyl group. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one butyl. In some embodiments, R 1 is a three-membered heterocyclyl substituted with at least one pentyl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one hexyl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one isopropyl group. In some embodiments, R 1is a three-membered heterocycline substituted with at least one isobutyl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one isopentyl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one isohexyl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one secbutyl. In some embodiments, R 1 is a three-membered heterocyclyl substituted with at least one secpentyl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one sechexyl. In some embodiments, R 1 It is a three-membered heterocycline substituted with at least one tert-butyl molecule.

[0134] In some embodiments, R 1 is a four-membered heterocycline substituted with at least one methyl group. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one ethyl group. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one propyl group. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one butyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one pentyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one hexyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one isopropyl group. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one isobutyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one isopentyl. In some embodiments, R 1is a four-membered heterocycline substituted with at least one isohexyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one secbutyl. In some embodiments, R 1 is a four-membered heterocyclyl substituted with at least one secpentyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one sechexyl. In some embodiments, R 1 It is a four-membered heterocycline substituted with at least one tert-butyl molecule.

[0135] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted 3-4 member heterocyclyl, provided that at least one substituent is C 1-6 The condition is that it must be a haloalkyl group.

[0136] In some embodiments, R 1 is at least one C 1-6 It is a three-membered heterocycline substituted with a haloalkyl group. In some embodiments, R 1 is at least one C 1-6 It is a four-membered heterocycline substituted with a haloalkyl group.

[0137] In some embodiments, R 1 is a 3-4 membered heterocycline substituted with at least one halomethyl group. In some embodiments, R 1 is a 3-4 membered heterocycline substituted with at least one haloethyl group. In some embodiments, R 1 is a 3-4 membered heterocycline substituted with at least one halopropyl. In some embodiments, R 1is a 3-4 member heterocycline substituted with at least one halobutyl. In some embodiments, R 1 is a 3-4 member heterocycline substituted with at least one halopentyl. In some embodiments, R 1 It is a 3-4 member heterocycline substituted with at least one halohexyl.

[0138] In some embodiments, R 1 is a three-membered heterocycline substituted with at least one halomethyl group. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one haloethyl group. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one halopropyl. In some embodiments, R 1 is a three-membered heterocycline substituted with at least one halobutyl. In some embodiments, R 1 is a three-membered heterocyclyl substituted with at least one halopentyl. In some embodiments, R 1 It is a three-membered heterocycline substituted with at least one halohexyl.

[0139] In some embodiments, R 1 is a four-membered heterocycline substituted with at least one halomethyl group. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one haloethyl group. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one halopropyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one halobutyl. In some embodiments, R 1 is a four-membered heterocycline substituted with at least one halopentyl. In some embodiments, R 1 It is a four-membered heterocycline substituted with at least one halohexyl.

[0140] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted 3-4 member heterocyclyls, provided that at least one substituent is -OR G5 This is conditional on the following:

[0141] In some embodiments, R 1 is at least one -OR G5 It is a three-membered heterocycline substituted with R. In some embodiments, 1 is at least one -OR G5 It is a four-membered heterocycline that has been substituted with [a specific compound].

[0142] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2 independently substituted 3-4 member heterocyclines, provided that at least one substituent is -SR G5 This is conditional on the following:

[0143] In some embodiments, R 1 is at least one -SR G5 It is a three-membered heterocycline substituted with R. In some embodiments, 1 is at least one -SR G5 It is a four-membered heterocycline that has been substituted with [a specific compound].

[0144] In some embodiments, R 1 This is 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5)2 independently substituted 3-4 member heterocyclyl, provided that at least one substituent is -N(R G5 ) Provided that it is 2.

[0145] In some embodiments, R 1 is at least one -N(R G5 ) is a three-membered heterocyclyl substituted with 2. In some embodiments, R 1 is at least one -N(R G5 It is a four-membered heterocyclyl substituted with )2.

[0146] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7 They independently form a 5-membered heteroaryl ring.

[0147] In some embodiments, R 1 G2 and G2 are linked together with the atoms to which they are bonded to form an unsubstituted five-membered heteroaryl ring.

[0148] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 ) One R selected from the group consisting of 2 G7 It forms a 5-membered heteroaryl ring substituted with [the specified compound].

[0149] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -ORG5 , -SR G5 , and -N(R G5 Two R selected from the group consisting of )2 G7 They independently form a 5-membered heteroaryl ring.

[0150] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 Three R selected from the group consisting of )2 G7 They independently form a 5-membered heteroaryl ring.

[0151] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7 These molecules independently form a five-membered heteroaryl ring, provided that at least one substituent is a halo.

[0152] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one of F, Cl, Br, or I. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one of F, Cl, or Br. In some embodiments, R 1 G2 and G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one of F or Cl.

[0153] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one F. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one Cl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one Br. In some embodiments, R 1 G2 and G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one I.

[0154] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7 They form independently substituted 5-membered heteroaryl rings, provided that at least one substituent is C 1-6 The condition is that it must be alkyl.

[0155] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one methyl group. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one ethyl atom. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one propyl atom. In some embodiments, R 1And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one butyl atom. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one pentyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one hexyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one isopropyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one isobutyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one isopentyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one isohexyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one secbutyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one secpentyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one sec hexyl. In some embodiments, R 1 G2 and G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one tertbutyl atom.

[0156] In some embodiments, R 1And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7 They form independently substituted 5-membered heteroaryl rings, provided that at least one substituent is C 1-6 The condition is that it must be a haloalkyl group.

[0157] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one halomethyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one haloethyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one halopropyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one halobutyl. In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one halopentyl. In some embodiments, R 1 G2 and G2 are linked together with the atoms to which they are bonded to form a five-membered heteroaryl ring substituted with at least one halohexyl.

[0158] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5)0, 1, 2, or 3 R selected from the group consisting of 2 G7 They form independently substituted 5-membered heteroaryl rings, provided that at least one substituent is -OR G5 This is conditional on the following:

[0159] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7 The substituted 5-membered heteroaryl rings are formed independently, provided that at least one substituent is -SR G5 This is conditional on the following:

[0160] In some embodiments, R 1 And G2 are linked together with the atoms to which they are bonded, forming a halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7 The 5-membered heteroaryl ring is independently substituted, provided that at least one substituent is -N(R G5 ) Provided that it is 2.

[0161] As generally defined herein, R G7 Each case is independent of Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2.

[0162] In some embodiments, R G7 It is a halo.

[0163] In some embodiments, R G7 is F, Cl, Br, or I. In some embodiments, R G7 is F, Cl, or Br. In some embodiments, R G7 It is either F or Cl.

[0164] In some embodiments, R G7 F is F. In some embodiments, R G7 is Cl. In some embodiments, R G7 is Br. In some embodiments, R G7 It is I.

[0165] In some embodiments, R G7 C 1-6 It is alkyl.

[0166] In some embodiments, R G7 is methyl. In some embodiments, R G7 is ethyl. In some embodiments, R G7 is propyl. In some embodiments, R G7 is butyl. In some embodiments, R G7 is pentill. In some embodiments, R G7 is hexyl. In some embodiments, R G7 is isopropyl. In some embodiments, R G7 isobutyl. In some embodiments, R G7 is isopentyl. In some embodiments, R G7 is isohexyl. In some embodiments, R G7 secbutyl is used in some embodiments. G7 secpentyl is used in some embodiments. G7 sec hexyl is used in some embodiments. G7 It is tert-butyl.

[0167] In some embodiments, RG7 C 1-6 It is a haloalkyl group.

[0168] In some embodiments, R G7 is a halomethyl. In some embodiments, R G7 is haloethyl. In some embodiments, R G7 is a halopropyl. In some embodiments, R G7 is halobutyl. In some embodiments, R G7 is halopentyl. In some embodiments, R G7 It is a halohexyl.

[0169] In some embodiments, R G7 is -OR G5 That is the case.

[0170] In some embodiments, R G7 -SR G5 That is the case.

[0171] In some embodiments, R G7 is -N(R G5 )2.

[0172] As generally defined herein, R G1 , R G2 , R G3 , and R G4 However, each is independent of hydrogen, halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0173] In some embodiments, R G1 is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0174] In some embodiments, R G1 It is hydrogen.

[0175] In some embodiments, R G1 is a halo.

[0176] In some embodiments, R G1 is F, Cl, Br, or I. In some embodiments, R G1 is F, Cl, or Br. In some embodiments, R G1 is F or Cl.

[0177] In some embodiments, R G1 is F. In some embodiments, R G1 is Cl. In some embodiments, R G1 is Br. In some embodiments, R G1 is I.

[0178] In some embodiments, R G1 is C 1-6 alkyl.

[0179] In some embodiments, R G1 is methyl. In some embodiments, R G1 is ethyl. In some embodiments, R G1 is propyl. In some embodiments, R G1 is butyl. In some embodiments, R G1 is pentyl. In some embodiments, R G1 is hexyl. In some embodiments, R G1 is isopropyl. In some embodiments, R G1 is isobutyl. In some embodiments, R G1 is isopentyl. In some embodiments, R G1 is isohexyl. In some embodiments, R G1 is sec-butyl. In some embodiments, R G1 is sec-pentyl. In some embodiments, R G1sec hexyl is used in some embodiments. G1 It is tert-butyl.

[0180] In some embodiments, R G1 C 1-6 It is a haloalkyl group.

[0181] In some embodiments, R G1 is a halomethyl. In some embodiments, R G1 is haloethyl. In some embodiments, R G1 is a halopropyl. In some embodiments, R G1 is halobutyl. In some embodiments, R G1 is halopentyl. In some embodiments, R G1 It is a halohexyl.

[0182] In some embodiments, R G1 is -OR G6 That is the case.

[0183] In some embodiments, R G2 is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0184] In some embodiments, R G2 It is hydrogen.

[0185] In some embodiments, R G2 It is a halo.

[0186] In some embodiments, R G2 is F, Cl, Br, or I. In some embodiments, R G2 is F, Cl, or Br. In some embodiments, R G2 It is either F or Cl.

[0187] In some embodiments, RG2 F is F. In some embodiments, R G2 is Cl. In some embodiments, R G2 is Br. In some embodiments, R G2 It is I.

[0188] In some embodiments, R G2 C 1-6 It is alkyl.

[0189] In some embodiments, R G2 is methyl. In some embodiments, R G2 is ethyl. In some embodiments, R G2 is propyl. In some embodiments, R G2 is butyl. In some embodiments, R G2 is pentill. In some embodiments, R G2 is hexyl. In some embodiments, R G2 is isopropyl. In some embodiments, R G2 isobutyl. In some embodiments, R G2 is isopentyl. In some embodiments, R G2 is isohexyl. In some embodiments, R G2 secbutyl is used in some embodiments. G2 secpentyl is used in some embodiments. G2 sec hexyl is used in some embodiments. G2 It is tert-butyl.

[0190] In some embodiments, R G2 C 1-6 It is a haloalkyl group.

[0191] In some embodiments, R G2 is a halomethyl. In some embodiments, R G2 is haloethyl. In some embodiments, R G2is halopropyl. In some embodiments, R G2 is halobutyl. In some embodiments, R G2 is halopentyl. In some embodiments, R G2 is halohexyl.

[0192] In some embodiments, R G2 is -OR G6 .

[0193] In some embodiments, R G3 is hydrogen, halo, C<000096​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​is methyl. In some embodiments, R G3 is ethyl. In some embodiments, R G3 is propyl. In some embodiments, R G3 is butyl. In some embodiments, R G3 is pentill. In some embodiments, R G3 is hexyl. In some embodiments, R G3 is isopropyl. In some embodiments, R G3 isobutyl. In some embodiments, R G3 is isopentyl. In some embodiments, R G3 is isohexyl. In some embodiments, R G3 secbutyl is used in some embodiments. G3 secpentyl is used in some embodiments. G3 sec hexyl is used in some embodiments. G3 It is tert-butyl.

[0200] In some embodiments, R G3 C 1-6 It is a haloalkyl group.

[0201] In some embodiments, R G3 is a halomethyl. In some embodiments, R G3 is haloethyl. In some embodiments, R G3 is a halopropyl. In some embodiments, R G3 is halobutyl. In some embodiments, R G3 is halopentyl. In some embodiments, R G3 It is a halohexyl.

[0202] In some embodiments, R G3 is -OR G6 That is the case.

[0203] In some embodiments, R G4is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0204] In some embodiments, R G4 It is hydrogen.

[0205] In some embodiments, R G4 It is a halo.

[0206] In some embodiments, R G4 is F, Cl, Br, or I. In some embodiments, R G4 is F, Cl, or Br. In some embodiments, R G4 It is either F or Cl.

[0207] In some embodiments, R G4 F is F. In some embodiments, R G4 is Cl. In some embodiments, R G4 is Br. In some embodiments, R G4 It is I.

[0208] In some embodiments, R G4 C 1-6 It is alkyl.

[0209] In some embodiments, R G4 is methyl. In some embodiments, R G4 is ethyl. In some embodiments, R G4 is propyl. In some embodiments, R G4 is butyl. In some embodiments, R G4 is pentill. In some embodiments, R G4 is hexyl. In some embodiments, R G4 is isopropyl. In some embodiments, R G4 isobutyl. In some embodiments, R G4is isopentyl. In some embodiments, R G4 is isohexyl. In some embodiments, R G4 secbutyl is used in some embodiments. G4 secpentyl is used in some embodiments. G4 sec hexyl is used in some embodiments. G4 It is tert-butyl.

[0210] In some embodiments, R G4 C 1-6 It is a haloalkyl group.

[0211] In some embodiments, R G4 is a halomethyl. In some embodiments, R G4 is haloethyl. In some embodiments, R G4 is a halopropyl. In some embodiments, R G4 is halobutyl. In some embodiments, R G4 is halopentyl. In some embodiments, R G4 It is a halohexyl.

[0212] In some embodiments, R G4 is -OR G6 That is the case.

[0213] As generally defined herein, R G5 and R G6 These are, independently, hydrogen and C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0214] In some embodiments, R G5 It is hydrogen.

[0215] In some embodiments, R G5 C 1-6 It is alkyl.

[0216] In some embodiments, R G5 is methyl. In some embodiments, R G5 is ethyl. In some embodiments, R G5 is propyl. In some embodiments, R G5 is butyl. In some embodiments, R G5 is pentill. In some embodiments, R G5 is hexyl. In some embodiments, R G5 is isopropyl. In some embodiments, R G5 isobutyl. In some embodiments, R G5 is isopentyl. In some embodiments, R G5 is isohexyl. In some embodiments, R G5 secbutyl is used in some embodiments. G5 secpentyl is used in some embodiments. G5 sec hexyl is used in some embodiments. G5 It is tert-butyl.

[0217] In some embodiments, R G5 C 1-6 It is a haloalkyl group.

[0218] In some embodiments, R G5 is a halomethyl. In some embodiments, R G5 is haloethyl. In some embodiments, R G5 is a halopropyl. In some embodiments, R G5 is halobutyl. In some embodiments, R G5 is halopentyl. In some embodiments, R G5 It is a halohexyl.

[0219] In some embodiments, R G6 It is hydrogen.

[0220] In some embodiments, RG6 C 1-6 It is alkyl.

[0221] In some embodiments, R G6 is methyl. In some embodiments, R G6 is ethyl. In some embodiments, R G6 is propyl. In some embodiments, R G6 is butyl. In some embodiments, R G6 is pentill. In some embodiments, R G6 is hexyl. In some embodiments, R G6 is isopropyl. In some embodiments, R G6 isobutyl. In some embodiments, R G6 is isopentyl. In some embodiments, R G6 is isohexyl. In some embodiments, R G6 secbutyl is used in some embodiments. G6 secpentyl is used in some embodiments. G6 sec hexyl is used in some embodiments. G6 It is tert-butyl.

[0222] In some embodiments, R G6 C 1-6 It is a haloalkyl group.

[0223] In some embodiments, R G6 is a halomethyl. In some embodiments, R G6 is haloethyl. In some embodiments, R G6 is a halopropyl. In some embodiments, R G6 is halobutyl. In some embodiments, R G6 is halopentyl. In some embodiments, R G6 It is a halohexyl.

[0224] In some embodiments, the ring A of the formula: [ka] This is based on the following formula: [ka] That is the case.

[0225] In some embodiments, ring A is of formula (a-2), (a-3), (a-4), (a-5), or (a-6), where R G1 , R G2 , R G3 , and R G4 These are, independently, Haro and C. 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0226] In some embodiments, ring A is of formula (a-2), (a-4), (a-5), or (a-6), where R G1 is -OR G6 That is the case.

[0227] In some embodiments, ring A is of the following formula: [ka] That is the case.

[0228] In some embodiments, ring A is of formula (a-2), (a-4), (a-5), or (a-6), where R G1 It is fluoro.

[0229] In some embodiments, ring A is of the following formula: [ka] That is the case.

[0230] In some embodiments, the ring A of the formula: [ka] This is based on the following formula: [ka] That is the case.

[0231] In some embodiments, ring A is of the formula (a-1N), (a-2N), (a-3N), (a-4N), (a-5N), (a-6N), (a-7N), (a-8N), or (a-9N), where R G1 Hello, C 1-6 Alkyl, C 1-6 Haloalkyl or -OR G6 That is the case.

[0232] In some embodiments, ring A is of formula (a-7N), (a-8N), or (a-9N), where R G1 is -OR G6 That is the case.

[0233] In some embodiments, ring A is of the following formula: [ka] That is the case.

[0234] In some embodiments, ring A is of the following formula: [ka] And R 1 And G2, together with the atoms to which they are bonded, form a 5-membered heteroaryl ring, where ring A, R 1 , and G 2 This is based on the following formula: [ka] Obtained, During the ceremony, X is O, S, NH, or NR G7 And, Y is N, CH, or CR G7And, z is either 0 or 1, However, R G7 If R is a group bonded to a nitrogen (N) atom, G7 However, C 1-6 Alkyl or C 1-6 The condition is that it must be a haloalkyl group.

[0235] In some embodiments, X is O or S.

[0236] In some embodiments, X is O. In some embodiments, X is S.

[0237] In some embodiments, X is NH or NR G7 That is the case.

[0238] In some embodiments, X is NH. In some embodiments, X is NR G7 That is the case.

[0239] In some embodiments, Y is N.

[0240] In some embodiments, Y is CH or CR G7 That is the case.

[0241] In some embodiments, Y is CH. In some embodiments, Y is CR G7 That is the case.

[0242] In some embodiments, z is 0.

[0243] In some embodiments, z is 1.

[0244] In some embodiments, R G7 If R is a group bonded to a nitrogen (N) atom, G7 C 1-6 It is alkyl.

[0245] In some embodiments, R G7If R is a group bonded to a nitrogen (N) atom, G7 C 1-6 It is a haloalkyl group.

[0246] In some embodiments, ring A is R 1 And G2 are linked together with the atoms to which they are bonded to form a 5-membered heteroaryl ring, ring A, R 1 , and G 2 This is based on the following formula: [ka] To obtain.

[0247] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[0248] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[0249] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[0250] In some embodiments, ring A is based on the following formula: [ka] [ka] That is the case.

[0251] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[0252] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[0253] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[0254] In some embodiments, ring A is based on the following formula: [ka] That is the case. (b) Ring B, n, p, m, R 3 , R 4 , R 2a , and R 2b

[0255] As is generally described herein, n is either 0 or 1.

[0256] In some embodiments, n is 0 or 1.

[0257] In some embodiments, n is 0. In some embodiments, n is 1.

[0258] As is generally described herein, p is 1 or 2.

[0259] In some embodiments, p is 1. In some embodiments, p is 2.

[0260] As is generally described herein, m is 0, 1, 2, or 3.

[0261] In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 1 or 3.

[0262] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0263] As generally described herein, R 2a and R 2b Each of these cases is independent of hydrogen, halo, and C. 1-6 Alkyl, C 1-6 They are haloalkyls, C3-C4 carbocyclyls, or 3-4 membered heterocyclyls, where each carbocyclyl or heterocyclyl is independently substituted with 0, 1, 2, or 3 halos, or R 2a and R 2b These are linked together to form a C3 carbocykrill independently substituted with 0, 1, 2, or 3 halos.

[0264] In some embodiments, R 2a These are, independently, hydrogen, halo, and C. 1-6 Alkyl, C 1-6 They are haloalkyl, C3-C4 carbocyrill, or 3-4 membered heterocyclyl.

[0265] In some embodiments, R 2a It is, independently, hydrogen.

[0266] In some embodiments, R 2a It is, independently, a halo.

[0267] In some embodiments, R 2a Independently, are F, Cl, Br, or I. In some embodiments, R 2a These are independently F, Cl, or Br. In some embodiments, R2a These are independently either F or Cl.

[0268] In some embodiments, R 2a Independently, F. In some embodiments, R 2a Independently, is Cl. In some embodiments, R 2a In some embodiments, R 2a It is independently I.

[0269] In some embodiments, R 2a Independently, C 1-6 It is alkyl.

[0270] In some embodiments, R 2a R is independently methyl. In some embodiments, R 2a is independently ethyl. In some embodiments, R 2a In some embodiments, R 2a is independently butyl. In some embodiments, R 2a In some embodiments, R 2a is independently hexyl. In some embodiments, R 2a is independently isopropyl. In some embodiments, R 2a is independently isobutyl. In some embodiments, R 2a is independently isopentyl. In some embodiments, R 2a is independently isohexyl. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a is independently sec hexyl. In some embodiments, R 2a It is independently tertbutyl.

[0271] In some embodiments, R2a Independently, C 1-6 It is a haloalkyl group.

[0272] In some embodiments, R 2a R is independently a halomethyl compound. In some embodiments, R 2a Independently, is haloethyl. In some embodiments, R 2a is independently a halopropyl. In some embodiments, R 2a Independently, is halobutyl. In some embodiments, R 2a In some embodiments, R is independently a halopentyl. 2a It is independently a halohexyl.

[0273] In some embodiments, R 2a It is independently a C3-C4 carbocycline.

[0274] In some embodiments, R 2a is independently C3 carbocykyl. In some embodiments, R 2a It is independently C4 carbocyclyl.

[0275] In some embodiments, R 2a These are independently 3-4 member heterocyclines.

[0276] In some embodiments, R 2a R is independently a three-membered heterocycline. In some embodiments, R 2a It is an independent four-membered heterocycline.

[0277] In some embodiments, R 2b Each of these cases is independent of hydrogen, halo, and C. 1-6 Alkyl, C 1-6 They are haloalkyl, C3-C4 carbocyrill, or 3-4 membered heterocyclyl.

[0278] In some embodiments, R 2bIt is, independently, hydrogen.

[0279] In some embodiments, R 2b It is, independently, a halo.

[0280] In some embodiments, R 2b Independently, are F, Cl, Br, or I. In some embodiments, R 2b These are independently F, Cl, or Br. In some embodiments, R 2b These are independently either F or Cl.

[0281] In some embodiments, R 2b Independently, F. In some embodiments, R 2b Independently, is Cl. In some embodiments, R 2b In some embodiments, R 2b It is independently I.

[0282] In some embodiments, R 2b Independently, C 1-6 It is alkyl.

[0283] In some embodiments, R 2b R is independently methyl. In some embodiments, R 2b is independently ethyl. In some embodiments, R 2b In some embodiments, R 2b is independently butyl. In some embodiments, R 2b In some embodiments, R 2b is independently hexyl. In some embodiments, R 2b is independently isopropyl. In some embodiments, R 2b is independently isobutyl. In some embodiments, R 2b is independently isopentyl. In some embodiments, R 2bis independently isohexyl. In some embodiments, R 2b In some embodiments, R 2b In some embodiments, R 2b is independently sec hexyl. In some embodiments, R 2b It is independently tertbutyl.

[0284] In some embodiments, R 2b Independently, C 1-6 It is a haloalkyl group.

[0285] In some embodiments, R 2b R is independently a halomethyl compound. In some embodiments, R 2b Independently, is haloethyl. In some embodiments, R 2b is independently a halopropyl. In some embodiments, R 2b Independently, is halobutyl. In some embodiments, R 2b In some embodiments, R is independently a halopentyl. 2b It is independently a halohexyl.

[0286] In some embodiments, R 2b It is independently a C3-C4 carbocycline.

[0287] In some embodiments, R 2b is independently C3 carbocykyl. In some embodiments, R 2b It is independently C4 carbocyclyl.

[0288] In some embodiments, R 2b These are independently 3-4 member heterocyclines.

[0289] In some embodiments, R 2b R is independently a three-membered heterocycline. In some embodiments, R 2bIt is an independent four-membered heterocycline.

[0290] In some embodiments, R 2a and R 2b They are the same. In some embodiments, R 2a and R 2b They are different.

[0291] In some embodiments, R 2a and R 2b These are linked together to form a C3 carbocykrill independently substituted with 0, 1, 2, or 3 halos.

[0292] As generally described herein, R 3 Each case is independent of Halo, C 1-6 Alkyl, or C 1-6 It is either a haloalkyl or two Rs. 3 The base is connected, C 1-3 Alkylene crosslinking group or C 1-3 Forms haloalkylene crosslinking groups.

[0293] In some embodiments, R 3 It is a halo.

[0294] In some embodiments, R 3 is F, Cl, Br, or I. In some embodiments, R 3 is F, Cl, or Br. In some embodiments, R 3 It is either F or Cl.

[0295] In some embodiments, R 3 F is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 It is I.

[0296] In some embodiments, R 3 C 1-6 It is alkyl.

[0297] In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is pentill. In some embodiments, R 3 is hexyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 isobutyl. In some embodiments, R 3 is isopentyl. In some embodiments, R 3 is isohexyl. In some embodiments, R 3 secbutyl is used in some embodiments. 3 secpentyl is used in some embodiments. 3 sec hexyl is used in some embodiments. 3 It is tert-butyl.

[0298] In some embodiments, R 3 C 1-6 It is a haloalkyl group.

[0299] In some embodiments, R 3 is a halomethyl. In some embodiments, R 3 is haloethyl. In some embodiments, R 3 is a halopropyl. In some embodiments, R 3 is halobutyl. In some embodiments, R 3 is halopentyl. In some embodiments, R 3 It is a halohexyl.

[0300] As is generally described herein, two R 3 The base is connected, C1-3 Alkylene crosslinking group or C 1-3 Forms haloalkylene crosslinking groups.

[0301] In some embodiments, two R's are linked together to form a crosslinking group. 3 The base is defined as L.

[0302] In some embodiments, two R 3 The base is connected, C 1-3 Forms alkylene crosslinking groups.

[0303] In some embodiments, two R 3 The groups are linked together to form a methylene crosslinking group. In some embodiments, two R 3 The groups are linked together to form an ethylene crosslinking group. In some embodiments, two R groups 3 The groups are linked together to form propylene crosslinking groups.

[0304] In some embodiments, two R 3 The base is connected, C 1-3 Forms haloalkylene crosslinking groups.

[0305] In some embodiments, two R 3 The groups are linked together to form a halomethylene crosslinking group. In some embodiments, two R 3 The groups are linked together to form a haloethylene crosslinking group. In some embodiments, two R 3 The groups are linked together to form halopropylene crosslinking groups.

[0306] As generally described herein, R 4 is hydrogen, C 1-3 Alkyl, C3-C4 carbocyrill, or C3-C4 carbocyrill - C 1-3 The alkyl group and the carbocyclyl group are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos, and the carbocyclyl group has 0, 1, or 2 C 1-3 Alkyl, or C1-3 It is further independently substituted with a haloalkyl group.

[0307] In some embodiments, R 4 is hydrogen. In other embodiments, R 4 It is not hydrogen.

[0308] In some embodiments, R 4 C 1-3 It is alkyl.

[0309] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 It is isopropyl.

[0310] In some embodiments, R 4 C is replaced with 0, 1, 2, 3, 4, 5, or 6 halos. 1-3 It is alkyl.

[0311] In some embodiments, R 4 is a methyl molecule substituted with 0, 1, 2, or 3 halos. In some embodiments, R 4 is ethyl substituted with 0, 1, 2, 3, 4, 5, or 6 halos. In some embodiments, R 4 is a propyl substituted with 0, 1, 2, 3, 4, 5, or 6 halos. In some embodiments, R 4 isopropyl is substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0312] In some embodiments, R 4 C is replaced by one halo. 1-3 It is alkyl.

[0313] In some embodiments, R 4 is a methyl molecule substituted with one halo. In some embodiments, R4 is ethyl substituted with one halo. In some embodiments, R 4 is a propyl substituted with one halo. In some embodiments, R 4 This is isopropyl substituted with one halo.

[0314] In some embodiments, R 4 This is C, which is independently substituted by two halos. 1-3 It is alkyl.

[0315] In some embodiments, R 4 R is a methyl molecule independently substituted with two halos. In some embodiments, R 4 is ethyl substituted independently with two halos. In some embodiments, R 4 R is a propyl derivative independently substituted with two halos. In some embodiments, R 4 This is isopropyl is independently substituted with two halos.

[0316] In some embodiments, R 4 This is C, which is independently substituted by three halos. 1-3 It is alkyl.

[0317] In some embodiments, R 4 R is a methyl molecule independently substituted with three halos. In some embodiments, R 4 is ethyl substituted independently with three halos. In some embodiments, R 4 R is a propyl derivative independently substituted with three halos. In some embodiments, R 4 This is isopropyl is independently substituted with three halos.

[0318] In some embodiments, R 4 This is C, which is independently substituted by four halos. 1-3 It is alkyl.

[0319] In some embodiments, R 4is ethyl substituted independently with four halos. In some embodiments, R 4 R is independently a propyl substituted with four halos. In some embodiments, R 4 This is isopropyl is independently substituted with four halos.

[0320] In some embodiments, R 4 This is C replaced by 5 halos. 1-3 It is alkyl.

[0321] In some embodiments, R 4 is ethyl substituted independently with five halos. In some embodiments, R 4 is a propyl derivative independently substituted with five halos. In some embodiments, R 4 This is isopropyl is independently substituted with five halos.

[0322] In some embodiments, R 4 C is replaced by 6 halos. 1-3 It is alkyl.

[0323] In some embodiments, R 4 is ethyl substituted independently with six halos. In some embodiments, R 4 R is independently a propyl substituted with six halos. In some embodiments, R 4 This is independently isopropyl substituted with six halos.

[0324] In some embodiments, R 4 C is substituted with at least one of F, Cl, Br, or I. 1-3 It is alkyl. In some embodiments, R 4 C is a carbon atom substituted with at least one of F, Cl, or Br. 1-3 It is alkyl. In some embodiments, R 4 C is a C substituted with at least one of F or Cl. 1-3 It is alkyl.

[0325] In some embodiments, R 4 is a methyl molecule substituted with at least one of F, Cl, Br, or I. In some embodiments, R 4 is a methyl molecule substituted with at least one of F, Cl, or Br. In some embodiments, R 4 This is a methyl molecule substituted with at least one of F or Cl.

[0326] In some embodiments, R 4 is ethyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 4 is ethyl substituted with at least one of F, Cl, or Br. In some embodiments, R 4 This is ethyl substituted with at least one of F or Cl.

[0327] In some embodiments, R 4 is a propyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 4 is a propyl substituted with at least one of F, Cl, or Br. In some embodiments, R 4 This is a propyl compound substituted with at least one of F or Cl.

[0328] In some embodiments, R 4 is an isopropyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 4 is an isopropyl substituted with at least one of F, Cl, or Br. In some embodiments, R 4 isopropyl is substituted with at least one of F or Cl.

[0329] In some embodiments, R 4 is a C substituted with at least one F. 1-3 It is alkyl. In some embodiments, R 4is a C substituted with at least one Cl. 1-3 It is alkyl. In some embodiments, R 4 is a C substituted with at least one Br. 1-3 It is alkyl. In some embodiments, R 4 is a C substituted with at least one I. 1-3 It is alkyl.

[0330] In some embodiments, R 4 is a methyl molecule substituted with at least one F. In some embodiments, R 4 is a methyl molecule substituted with at least one Cl. In some embodiments, R 4 is a methyl group substituted with at least one Br. In some embodiments, R 4 This is a methyl group substituted with at least one I.

[0331] In some embodiments, R 4 is ethyl substituted with at least one F. In some embodiments, R 4 is ethyl substituted with at least one Cl. In some embodiments, R 4 is ethyl substituted with at least one Br. In some embodiments, R 4 It is ethyl substituted with at least one I.

[0332] In some embodiments, R 4 is a propyl substituted with at least one F. In some embodiments, R 4 is a propyl substituted with at least one Cl. In some embodiments, R 4 is a propyl substituted with at least one Br. In some embodiments, R 4 This is a propyl compound substituted with at least one I.

[0333] In some embodiments, R 4is an isopropyl substituted with at least one F. In some embodiments, R 4 is an isopropyl substituted with at least one Cl. In some embodiments, R 4 is an isopropyl substituted with at least one Br. In some embodiments, R 4 is an isopropyl compound substituted with at least one I.

[0334] In some embodiments, R 4 This consists of 0, 1, 2, 3, 4, 5, or 6 halos and 0, 1, or 2 Cs. 1-3 Alkyl or C 1-3 It is a C3-C4 carbocyric substituted with a haloalkyl group.

[0335] In some embodiments, R 4 is a C3 carbocyrill substituted with 0, 1, 2, 3, 4, or 5 halos. In some embodiments, R 4 This is a C4 carbocyrill substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0336] In some embodiments, R 4 It is an unsubstituted C3-C4 carbocyclyl.

[0337] In some embodiments, R 4 R is an unsubstituted C3 carbocykyl. In some embodiments, R 4 It is an unsubstituted C4 carbocykyl.

[0338] In some embodiments, R 4 This is a C3-C4 carbocykyl substituted with a single halo.

[0339] In some embodiments, R 4 is a C3 carbocyrill substituted with one halo. In some embodiments, R 4 This is a C4 carbocyrill substituted with one halo.

[0340] In some embodiments, R 4 This is a C3-C4 carbocykyl molecule independently substituted by two halos.

[0341] In some embodiments, R 4 is a C3 carbocyrill independently substituted with two halos. In some embodiments, R 4 This is a C4 carbocyrill substituted with two halos.

[0342] In some embodiments, R 4 This is a C3-C4 carbocykyl molecule independently substituted by three halos.

[0343] In some embodiments, R 4 is a C3 carbocyrill independently substituted with three halos. In some embodiments, R 4 This is a C4 carbocyrill substituted with three halos.

[0344] In some embodiments, R 4 This is a C3-C4 carbocyclyl independently substituted by four halos.

[0345] In some embodiments, R 4 is a C3 carbocyrill independently substituted with four halos. In some embodiments, R 4 This is a C4 carbocyrill substituted with four halos.

[0346] In some embodiments, R 4 This is a C3-C4 carbocykyl molecule independently substituted by five halos.

[0347] In some embodiments, R 4 is a C3 carbocyrill independently substituted with five halos. In some embodiments, R 4 This is a C4 carbocyrill substituted with five halos.

[0348] In some embodiments, R 4 This is a C4 carbocyrill independently substituted by six halos.

[0349] In some embodiments, R 4 is a C3-C4 carbocykyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 4 is a C3-C4 carbocykyl substituted with at least one of F, Cl, or Br. In some embodiments, R 4 It is a C3-C4 carbocykyl substituted with at least one of F or Cl.

[0350] In some embodiments, R 4 is a C3 carbocykyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 4 is a C3 carbocykyl substituted with at least one of F, Cl, or Br. In some embodiments, R 4 It is a C3 carbocykyl substituted with at least one of F or Cl.

[0351] In some embodiments, R 4 is a C4 carbocykyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 4 is a C4 carbocykyl substituted with at least one of F, Cl, or Br. In some embodiments, R 4 It is a C4 carbocykyl substituted with at least one of F or Cl.

[0352] In some embodiments, R 4 is a C3-C4 carbocykyl substituted with at least one F. In some embodiments, R 4 is a C3-C4 carbocykyl substituted with at least one Cl. In some embodiments, R 4 is a C3-C4 carbocykyl substituted with at least one Br. In some embodiments, R4 It is a C3-C4 carbocyclyl substituted with at least one I.

[0353] In some embodiments, R 4 is a C3 carbocykyl substituted with at least one F. In some embodiments, R 4 is a C3 carbocykyl substituted with at least one Cl. In some embodiments, R 4 is a C3 carbocykyl substituted with at least one Br. In some embodiments, R 4 It is a C3 carbocykrill substituted with at least one I.

[0354] In some embodiments, R 4 is a C4 carbocykyl substituted with at least one F. In some embodiments, R 4 is a C4 carbocykyl substituted with at least one Cl. In some embodiments, R 4 is a C4 carbocykyl substituted with at least one Br. In some embodiments, R 4 It is a C4 carbocykrill substituted with at least one I.

[0355] In some embodiments, R 4 This is C3-C4 carbocyclyl-C 1-3 The alkyl group is alkyl-, and each alkyl and carbocyclyl group is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0356] To clarify, the number of substituents provided to the alkyl and carbocyrill groups should satisfy the valency requirements of those groups. Furthermore, if both the alkyl and carbocyrill groups are variable, either the alkyl or carbocyrill group may independently have up to 6 halos and up to 0, 1, or 2 carbon atoms. 1-3 Alkyl or C 1-3 It can be substituted with a haloalkyl group.

[0357] In some embodiments, R4 C3 Carbocyclyl-C 1-3 Alkyl, carbocyclyl has 0, 1, 2, 3, 4, or 5 halos and 0, 1, or 2 Cs. 1-3 Alkyl or C 1-3 It is substituted with a haloalkyl. In some embodiments, R 4 C4 carbocykrill - C 1-3 Alkyl, carbocyclyl independently contains 0, 1, 2, 3, 4, 5, or 6 halos and 0, 1, or 2 Cs. 1-3 Alkyl or C 1-3 It is substituted with a haloalkyl. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0358] In some embodiments, R 4 It is a C3-C4 carbocyclyl-C1 alkyl, where the carbocyclyl independently has 0, 1, 2, 3, 4, 5, or 6 halos and 0, 1, or 2 C 1-3 Alkyl or C 1-3 It is substituted with a haloalkyl. In some embodiments, R 4 It is a C3-C4 carbocyclyl-C2 alkyl, where the carbocyclyl independently has 0, 1, 2, 3, 4, 5, or 6 halos and 0, 1, or 2 C 1-3 Alkyl or C 1-3 It is substituted with a haloalkyl. In some embodiments, R 4 It is a C3-C4 carbocyclyl-C3 alkyl, where the carbocyclyl independently has 0, 1, 2, 3, 4, 5, or 6 halos and 0, 1, or 2 Cs. 1-3 Alkyl or C 1-3 It is substituted with a haloalkyl. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0359] In some embodiments, R 4 This is unsubstituted C3-C4 carbocyrill-C 1-3It is alkyl.

[0360] In some embodiments, R 4 This is unsubstituted C3 carbocyrill-C 1-3 It is alkyl. In some embodiments, R 4 This is unsubstituted C4 carbocyrill-C 1-3 It is alkyl.

[0361] In some embodiments, R 4 R is an unsubstituted C3-C4 carbocyryl-C1 alkyl. In some embodiments, R 4 R is an unsubstituted C3-C4 carbocyryl-C2 alkyl. In some embodiments, R 4 It is an unsubstituted C3-C4 carbocyryl-C3 alkyl group.

[0362] In some embodiments, R 4 This is C3-C4 carbocyclyl-C 1-3 It is alkyl, and the carbocyclyl is substituted with one halo. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0363] In some embodiments, R 4 C3 Carbocyclyl-C 1-3 It is alkyl, and the carbocyclyl is substituted with one halo. In some embodiments, R 4 C4 Carbocyclyl-C 1-3 It is alkyl, and the carbocyclyl is substituted with one halo. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0364] In some embodiments, R 4 R is a C3-C4 carbocykyl-C1 alkyl group, where the carbocykyl group is substituted with one halo. In some embodiments, R 4R is a C3-C4 carbocyrill-C2 alkyl group, where the carbocyrill is substituted with one halo. In some embodiments, R 4 This is a C3-C4 carbocykyl-C3 alkyl group, where the carbocykyl group is substituted with one halo. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0365] In some embodiments, R 4 This is C3-C4 carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with two halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0366] In some embodiments, R 4 C3 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with two halos. In some embodiments, R 4 C4 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with two halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0367] In some embodiments, R 4 R is a C3-C4 carbocyrill-C1 alkyl group, where the carbocyrill is independently substituted with two halos. In some embodiments, R 4 R is a C3-C4 carbocyrill-C2 alkyl group, where the carbocyrill is independently substituted with two halos. In some embodiments, R 4 This is a C3-C4 carbocyrill-C3 alkyl group, where the carbocyrill is independently substituted with two halos. In some embodiments, C 1-3Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0368] In some embodiments, R 4 This is C3-C4 carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with three halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0369] In some embodiments, R 4 C3 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with three halos. In some embodiments, R 4 C4 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with three halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0370] In some embodiments, R 4 R is a C3-C4 carbocykyl-C1 alkyl group, where the carbocykyl group is independently substituted with three halos. In some embodiments, R 4 R is a C3-C4 carbocyrill-C2 alkyl group, where the carbocyrill is independently substituted with three halos. In some embodiments, R 4 This is a C3-C4 carbocyryl-C3 alkyl group, where the carbocyryl is independently substituted with three halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0371] In some embodiments, R 4 This is C3-C4 carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with four halos. In some embodiments, C1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0372] In some embodiments, R 4 C3 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with four halos. In some embodiments, R 4 C4 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with four halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0373] In some embodiments, R 4 R is a C3-C4 carbocyrill-C1 alkyl group, where the carbocyrill is independently substituted with four halos. In some embodiments, R 4 is a C3-C4 carbocyrill-C2 alkyl group, where the carbocyrill is independently substituted with four halos. In some embodiments, R 4 This is a C3-C4 carbocyrill-C3 alkyl group, where the carbocyrill is independently substituted with four halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0374] In some embodiments, R 4 This is C3-C4 carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with five halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0375] In some embodiments, R 4 C3 Carbocyclyl-C 1-3The alkyl group, and the carbocyclyl, is independently substituted with five halos. In some embodiments, R 4 C4 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with five halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0376] In some embodiments, R 4 R is a C3-C4 carbocykyl-C1 alkyl group, where the alkyl and carbocykyl groups are independently substituted with five halos. In some embodiments, R 4 R is a C3-C4 carbocyrill-C2 alkyl group, where the carbocyrill is independently substituted with five halos. In some embodiments, R 4 This is a C3-C4 carbocyrill-C3 alkyl group, where the carbocyrill is independently substituted with five halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0377] In some embodiments, R 4 C4 Carbocyclyl-C 1-3 The alkyl group, and the carbocyclyl, is independently substituted with six halos. In some embodiments, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0378] In some embodiments, R 4 R is a C4 carbocyrill-C1 alkyl group, where the carbocyrill is independently substituted with six halos. In some embodiments, R 4 R is a C4 carbocyrill-C2 alkyl group, where the carbocyrill is independently substituted with six halos. In some embodiments, R 4is a C4 carbocyrill-C3 alkyl group, where the carbocyrill is independently substituted with six halos. In a particular embodiment, C 1-3 Alkyl groups are independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0379] In some embodiments, R 4 R is hydrogen, methyl, ethyl, cyclopropyl, or cyclopropyl-methyl. In some embodiments, R 4 These are methyl, ethyl, cyclopropyl, or cyclopropyl-methyl.

[0380] In some embodiments, the ring B of the formula: [ka] This is based on the following formula: [ka] That is the case.

[0381] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0382] In some embodiments, ring B is a base (b-1-i), (b-1-ii), (b-1-iii), or (b-1-iv) of the following formula, R 2a and R 2b Each case is independent of Halo, C 1-6 Alkyl, C 1-6 They are haloalkyl, C3-C4 carbocyrill, or 3-4 membered heterocyclyl.

[0383] In some embodiments, ring B is of formula (b-1), (b-2), (b-3), or (b-4), and has two R 3 The base is connected, C 1-3 Alkylene crosslinking group or C 1-3Forms haloalkylene crosslinking groups.

[0384] In some embodiments, ring B is based on the following formula: [ka] And, In the formula, L is C 1-3 Alkylene crosslinking group or C 1-3 It is a haloalkylene crosslinking group.

[0385] In some embodiments, L is C 1-3 It is an alkylene crosslinking group.

[0386] In some embodiments, L is C 1-3 It is a haloalkylene crosslinking group.

[0387] In some embodiments, ring B is based on the following formula: [ka] And, In the formula, L is C 1-3 Alkylene crosslinking group or C 1-3 It is a haloalkylene crosslinking group.

[0388] In some embodiments, ring B is a base of the following formula (b-1-BR-i), (b-1-BR-ii), or (b-1-BR-iii), R 2a and R 2b Each case is independent of Halo, C 1-6 Alkyl, C 1-6 They are haloalkyl, C3-C4 carbocyrill, or 3-4 membered heterocyclyl.

[0389] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0390] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0391] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula. [ka] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0392] In some embodiments, ring B is based on the following formula: [ka] [ka] [ka] That is the case.

[0393] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0394] In some embodiments, ring B is the base of the formula: [ka] That is the case.

[0395] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0396] (c) Subgenus The compounds disclosed herein have variable rings A, G1, G2, G3, G4, and R. 1 , R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , R G7 , ring B, n, p, m, R 3 , R 4 , R 2a , and R 2b Each of these is selected from the groups described herein, where applicable, and the variable rings A, G1, G2, G3, G4, R1 , R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , R G7 , ring B, n, p, m, R 3 , R 4 , R 2a , and R 2b Any of the groups described herein for any of the variable rings A, G1, G2, G3, G4, R, where applicable. 1 , R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , R G7 , ring B, n, p, m, R 3 , R 4 , R 2a , and R 2b It is understood that one or more of the remaining can be combined with any of the bases described herein. Additional exemplary combinations of the embodiments described above are further intended herein.

[0397] For example, in a particular embodiment, the formulas are (IB′), (IBa), (IB′-bridge), (IB′′′-bridge), or (IB-bridge-a): [ka] The compound, Alternatively, pharmaceutically acceptable salts or tautomers thereof are provided.

[0398] In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), R 4 It is not hydrogen.

[0399] In some embodiments of formulas (IB'), (IBa), (IB'-crosslink), (IB''''-crosslink), or (IB-crosslink-a), G1 is CH, G2 is CH, G3 is CH, and G4 is CH. In some embodiments of formulas (IB'), (IBa), (IB'-crosslink), (IB''''-crosslink), or (IB-crosslink-a), G1 is CH, G2 is CH, G3 is CH, G4 is CH, and R 4 C 1-3 It is alkyl. In some embodiments of formula (IB'), (IBa), (IB'-crosslinked), (IB'''-crosslinked), or (IB-crosslinked-a), G1 is CH, G2 is CH, G3 is CH, G4 is CH, R 4 is a C3-C4 carbocyclyl. In some embodiments of formula (IB'), (IBa), (IB'-crosslinked), (IB'''-crosslinked), or (IB-crosslinked-a), G1 is CH, G2 is CH, G3 is CH, G4 is CH, and R 4 This is C3-C4 carbocyclyl-C 1-3 It is alkyl. In some embodiments of formula (IB′), (IBa), (IB′-crosslinked), (IB′′′-crosslinked), or (IB-crosslinked-a), G1 is CR G1 And G2 is CH, G3 is CH, and G4 is CH. In some embodiments of formula (IB'), (IBa), (IB'-bridged), (IB'''-bridged), or (IB-bridged-a), G1 is CR G1 G2 is CH, G3 is CH, G4 is CH, R 4 is hydrogen. In some embodiments of formula (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), G1 is CH and G2 is CR G2 And G3 is CH and G4 is CH. In some embodiments of formula (IB'), (IBa), (IB'-bridged), (IB'''-bridged), or (IB-bridged-a), G1 is CH and G2 is CR G2G3 is CH, G4 is CH, R 4 C 1-3 It is alkyl. In some embodiments of formula (IB′), (IBa), (IB′-crosslinked), (IB′′′-crosslinked), or (IB-crosslinked-a), G1 is CR G1 And G2 is CR G2 And G3 is CH and G4 is CH. In some embodiments of formula (IB'), (IBa), (IB'-bridged), (IB'''-bridged), or (IB-bridged-a), G1 is CR G1 And G2 is CR G2 G3 is CH, G4 is CH, R 4 C 1-3 It is alkyl. In some embodiments of formula (IB′), (IBa), (IB′-crosslinked), (IB′′′-crosslinked), or (IB-crosslinked-a), G1 is CR G1 G2 is CH, G3 is CH, and G4 is CR. G4 In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), G1 is CR G1 G2 is CH, G3 is CH, and G4 is CR. G4 And R 4 C 1-3 It is alkyl. In some embodiments of formula (IB′), (IBa), (IB′-crosslinked), (IB′′′-crosslinked), or (IB-crosslinked-a), G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is CR G4 In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is CR G4 And R 4 C 1-3It is alkyl.

[0400] In some embodiments of formula (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), and in any of the embodiments described in this section, n is 0 and p is 1. In some embodiments, n is 0 and p is 1, R 2a and R 2b At least one of them is C 1-6 It is alkyl. In some embodiments, n is 0, p is 1, and R 2a and R 2b At least one of them is a halo. In some embodiments, n is 0, p is 1, and R 2a and R 2b At least one of them is C 1-6 It is a haloalkyl. In some embodiments, n is 0, p is 1, and at least one R 3 C 1-6 It is alkyl. In some embodiments, n is 0, p is 1, and at least one R 3 This is a halo. In some embodiments, n is 0, p is 1, and there are two R 3 The base is connected, C 1-3 An alkylene (e.g., an ethylene crosslink) is formed. In some embodiments, n is 0, p is 1, and there are two R 3 The base is connected, C 1-3 Form an alkylene (e.g., an ethylene crosslink), R 2a and R 2b At least one of them is C 1-6 It is alkyl.

[0401] In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), R G1 It is a halo, and R 1 is -OR G5 In some embodiments, R G1 It is a halo, and R 1is a halo. In some embodiments, R G1 It is a halo, and R 1 C 1-6 It is a haloalkyl group.

[0402] In some embodiments, R G2 It is a halo, and R 1 is a halo. In some embodiments, R G2 It is a halo, and R 1 C 1-6 In some embodiments, R G2 It is a halo, and R 1 is C3-C4 carbocyclyl. In some embodiments, R G2 It is a halo, and R 1 is -OR G5 In some embodiments, R G2 is -OR G6 And R 1 is -OR G5 In some embodiments, R G1 It is a halo, and R G2 It is a halo, and R 1 C 1-6 In some embodiments, R G1 It is a halo, and R G2 It is a halo, and R 1 is -OR G5 In some embodiments, R G1 It is a halo, and R G4 is a halo. In some embodiments, R G1 It is a halo, and R G4 It is a halo, and R 1 is -OR G5 In some embodiments, R G1 It is a halo, and R G4 It is a halo, and R 1 It is C3-C4 carbocyclyl.

[0403] In some embodiments of formula (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), and in any of the embodiments described in this section, n is 1, p is 1, and R 2a and R 2b At least one of them is C 1-6 It is alkyl. In some embodiments, n is 1, p is 1, and R 2a and R 2b At least one of them is C 1-6 It is a haloalkyl. In some embodiments, n is 1, p is 1, and R 2a and R 2b At least one of them is C 1-6 It is alkyl. In some embodiments, n is 1, p is 1, and R 2a and R 2b At least one of them is a C3-C4 carbocyclyl. In some embodiments, n is 1, p is 1, and R 2a and R 2b At least one of them is a halo. In some embodiments, n is 1, p is 1, and R 2a H is R 2b H is. In some embodiments, n is 1, p is 1, and two R 3 The base is connected, C 1-3 An alkylene (e.g., an ethylene crosslink) is formed. In some embodiments, n is 1, p is 1, and two R 3 The base is connected, C 1-3 Form an alkylene (e.g., an ethylene crosslink), R 2a and R 2b At least one of them is C 1-6 It is alkyl.

[0404] In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), ring A is a ring system, R 1 But, hello, C 1-6 Haloalkyl, -ORG5 , or C3-C4 carbocyclyl, wherein the carbocyclyl independently contains 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) Is it replaced with 2? or R 1 And G2 are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R G7 They independently form a 5-membered heteroaryl ring, R G1 , R G2 , R G3 , and R G4 However, each independently produces hydrogen, halo, and -OR. G6 Selected from the group consisting of, R G5 and R G6 However, each independently, hydrogen or C 1-6 It is a haloalkyl, R G7 Each case is independent of Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )2.

[0405] In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), ring A is a ring system, R 1 However, is it Cl, cyclopropyl, CF3, CF2H, OCF3, or OCF2H? or R 1 And G2 are linked together with the atoms to which they are bonded to form an oxazole, isoxazole, pyrazole, or imidazole. R G1 , R G2 , R G3 , and R G4 However, each is independently selected from the group consisting of H, F, Cl, OH, and OCF2H.

[0406] In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), ring B is a ring system. R 2a and R 2b Each of these cases independently involved hydrogen or C 1-6 It is alkyl, Two R's 3 The bases are connected, C 1-3 Forms alkylene crosslinking groups, R 4 However, C 1-3 Alkyl, C3-C4 carbocyrill, or C3-C4 carbocyrill-C 1-3 It is an alkyl group, and the alkyl and carbocyrillic groups are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos.

[0407] In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), ring B is a ring system. R 2a and R 2b Each of these cases is independently hydrogen or methyl, Two R's 3 The groups are linked together to form an ethylene crosslinking group. R 4 However, these are methyl, ethyl, cyclopropyl, or cyclopropyl-methyl.

[0408] In some embodiments of formulas (IB′), (IBa), (IB′-bridged), (IB′′′-bridged), or (IB-bridged-a), R 4 is methyl. In a particular embodiment, R 4 It is ethyl.

[0409] In a particular embodiment of formula (IBa), n is 0, p is 1, and m is 0 (wherein R 3 (does not exist), and G1 is CR G1 And G2 is CRG2 G3 is CH, and G4 is CR G4 However, the compound of formula (II-B-a1), [ka] Or a pharmaceutically acceptable salt or tautomer thereof is provided. In a particular embodiment, R 2b and R 4 is not hydrogen. In a particular embodiment, R 4 is methyl or ethyl. In certain embodiments, R 2b is methyl. In a particular embodiment, R 1 is halogen, C3 carbocyryl, C 1-3 Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R 1 C 1-3 Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R G1 is hydrogen or a halogen (e.g., fluoro or chloro). In certain embodiments, R G1 is hydrogen or fluorocarbon. In certain embodiments, R G1 is fluoro. In a particular embodiment, R G2 is hydrogen, fluoro, or -OR G6 And R G6 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R G4 is hydrogen or fluorocarbon. In certain embodiments, R G1 is fluoro, and R G2 is hydrogen, and R G4 is hydrogen, and R 1 C 1-3Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl group.

[0410] n is 1, p is 1, and m is 0 (in the formula, R 3 However, it does not exist) and G1 is CR G1 And G2 is CR G2 G3 is CH, and G4 is CR G4 In a particular embodiment of formula (IBa), the compound of formula (II-B-a2) [ka] Or a pharmaceutically acceptable salt or tautomer thereof is provided. In a particular embodiment, R 2b and R 4 is not hydrogen. In a particular embodiment, R 4 is methyl or ethyl. In certain embodiments, R 2b is methyl. In a particular embodiment, R 1 is halogen, C3 carbocyryl, C 1-3 Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R 1 C 1-3 Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R G1 is hydrogen or a halogen (e.g., fluoro or chloro). In certain embodiments, R G1 is hydrogen or fluorocarbon. In certain embodiments, R G1 is fluoro. In a particular embodiment, RG2 is hydrogen, fluoro, or -OR G6 And R G6 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R G4 is hydrogen or fluorocarbon. In certain embodiments, R G1 is fluoro, and R G2 is hydrogen, and R G4 is hydrogen, and R 1 C 1-3 Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl group.

[0411] n is 0, p is 1, m is 0 (additional R in the formula) 3 However, it does not exist), G1 is CR G1 And G2 is CR G2 G3 is CH, and G4 is CR G4 In a particular embodiment of formula (IB-crosslink-a), the compound of formula (II-B-crosslink-a) is [ka] Or a pharmaceutically acceptable salt or tautomer thereof is provided. In a particular embodiment, R 2a and R 4 is not hydrogen. In a particular embodiment, R 4 is methyl or ethyl. In certain embodiments, R 2a is methyl. In a particular embodiment, R 1 is halogen, C3 carbocyryl, C 1-3 Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R 1 C 1-3Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R G1 is hydrogen or a halogen (e.g., fluoro or chloro). In certain embodiments, R G1 is hydrogen or fluorocarbon. In certain embodiments, R G1 is fluoro. In a particular embodiment, R G2 is hydrogen, fluoro, or -OR G6 And R G6 C 1-3 Alkyl or C 1-3 It is a haloalkyl. In a particular embodiment, R G4 is hydrogen or fluorocarbon. In certain embodiments, R G1 is fluoro, and R G2 is hydrogen, and R G4 is hydrogen, and R 1 C 1-3 Alkyl, C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl group.

[0412] In some embodiments, the compound of formula (IB) is selected from any one of the compounds in Table 1 or Table 2, or from a pharmaceutically acceptable salt or tautomer thereof.

[0413] In some embodiments, the compound of formula (IB) is a pharmaceutically acceptable salt of any one of the compounds in Table 1 or Table 2, or a tautomer thereof.

[0414] In some embodiments, the compound of formula (IB) is a free base selected from any one of the compounds in Table 1 or Table 2, or from its tautomers.

[0415] Tables 1 and 2 below also provide the location of the compounds provided in Example (Ex) by Example Number (Ex), or in Table A (TA) of the Examples. The asterisk (*) next to the compound number (#) indicates that any stereochemistry has been assigned. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 [Table 1-67] [Table 1-68] [Table 1-69] [Table 1-70] [Table 1-71] [Table 1-72] [Table 1-73] [Table 1-74] [Table 1-75] [Table 1-76] [Table 1-77] [Table 1-78] [Table 2-1] [Table 2-2]

[0416] In certain embodiments, the compound is selected from the group consisting of compound 6A and compound 39A, or any pharmaceutically acceptable salt or tautomer of either of the above.

[0417] In a particular embodiment, the compound is selected from the group consisting of compound 4A*, compound 5A*, compound 7A*, compound 8A*, compound 10A*, compound 11A*, compound 13A*, compound 15A*, compound 16A*, compound 17A*, compound 18A*, compound 19A*, compound 20A*, compound 21A*, compound 22A*, compound 23A*, compound 24A*, compound 25A*, compound 40A*, compound 41A*, and compound 43A*, or any pharmaceutically acceptable salt or tautomer of any of the above.

[0418] In a particular embodiment, the compound is selected from the group consisting of compound 42A*, compound 43A*, compound 45A*, compound 46A*, compound 47A*, compound 48A*, compound 49A*, compound 51A*, compound 52A*, compound 54A*, compound 55A*, compound 56A*, compound 57A*, compound 58A*, compound 60A*, compound 61A*, compound 62A*, compound 64A*, and compound 65A*, or any pharmaceutically acceptable salt or tautomer described above.

[0419] (ii) Pharmaceutical composition Pharmaceutical compositions comprising a compound of formula (IB), or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier are further intended herein.

[0420] For example, in some embodiments, a pharmaceutical composition is provided comprising a compound of formula (IB), or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0421] Exemplary pharmaceutically acceptable carriers may include diluents such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil such as EPA or DHA, or esters or triglycerides thereof, or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine.

[0422] Administration to the target can be achieved by any mode of administration, such as oral administration, topical administration, or injection. Depending on the intended mode of administration, the pharmaceutical composition comprising the compound of formula (IB), or a pharmaceutically acceptable salt or tautomer thereof, may be in solid, semi-solid, or liquid dosage forms.

[0423] Compounds of formula (IB), or their pharmaceutically acceptable salts or tautomers, may be administered alone in a pharmaceutical composition as a monotherapy, or in combination with other therapeutic agents. Combination therapy may be achieved by concurrent administration (e.g., two drugs administered simultaneously) or sequential administration (e.g., one drug administered first, followed by the other). In the case of concurrent administration, compounds of formula (IB), or their pharmaceutically acceptable salts or tautomers, may be administered in the same pharmaceutical composition as the other therapeutic agent, or in a different pharmaceutical composition. The specific selection of the other therapeutic agent depends on the physician's diagnosis, assessment of the patient's condition, and an appropriate treatment protocol.

[0424] (iii) Treatment method Compounds of formula (IB), as well as their pharmaceutically acceptable salts and tautomers, have been found to be useful as inhibitors of NLRP3 activity.

[0425] In some embodiments, methods are provided for treating a disease or disorder in a subject that requires treatment, comprising administering a compound of formula (IB), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing the same, to the subject. In some embodiments, methods are provided for treating a disease or disorder in a subject that requires treatment, comprising administering an effective amount of a compound of formula (IB), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing the same, to the subject. In some embodiments, the disease or disorder is associated with abnormal NLRP3 activity, and the method comprises inhibiting the abnormal NLRP3 activity so that the subject is treated.

[0426] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disorder of the muscle, an inflammatory disorder, an autoimmune disorder, cancer, an infection, obesity, a metabolic disorder, a cardiovascular disorder, a respiratory disorder, a kidney disorder, a liver disorder, an eye disorder, a skin disorder, a lymphatic disorder, a rheumatic disorder, a psychological disorder, a graft-versus-host disorder, pain (including disorders related to pain management such as allodynia), or an NLRP3-related disorder in a subject determined to have germline or somatic nonsilent mutations in NLRP3.

[0427] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system and / or peripheral nervous system ("PNS") such as dementia, Alzheimer's disease ("AD"), epilepsy, traumatic brain injury ("TBI"), multiple sclerosis ("MS"), developmental disorders, acute disseminated encephalopathy, transverse osteomyelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), Huntington's disease ("HD"), spinal cord injury, or neuroinflammation associated with obesity.

[0428] In some embodiments, the disease or disorder is a primary neurological disorder of the muscles, such as dystrophy or spinal muscular atrophy.

[0429] In some embodiments, the disease or disorder is an inflammatory disorder such as gout or inflammatory anemia.

[0430] In some embodiments, the disease or disorder is an autoimmune disease such as ulcerative colitis.

[0431] In some embodiments, the disease or disorder is a cancer such as skin cancer or colon cancer.

[0432] In some embodiments, the disease or disorder is an infection, such as a neurological infection.

[0433] In some embodiments, the disease or disorder is a metabolic disorder such as diabetes, for example, type 2 diabetes.

[0434] In some embodiments, the disease or disorder is obesity. In some embodiments, obesity is associated with neuroinflammation, such as hypothalamic inflammation and / or gliosis. In some embodiments, obesity is associated with metabolic disorders.

[0435] In some embodiments, the disease or disorder is a cardiovascular disease such as stroke, arteriosclerosis, or atherosclerotic cardiovascular disease (ASCVD).

[0436] In some embodiments, the disease or disorder is a respiratory disease such as asthma (e.g., steroid-resistant asthma, severe steroid-resistant asthma) or chronic obstructive pulmonary disease ("COPD").

[0437] In some embodiments, the disease or disorder is a kidney disease, such as acute kidney disease, chronic kidney disease, or a rare kidney disease. In certain embodiments, chronic kidney disease is chronic renal failure.

[0438] In some embodiments, the disease or disorder is a liver disease such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (also known as NASH, MASH, or metabolic disorder-associated steatohepatitis).

[0439] In some embodiments, the disease or disorder is an eye disease such as optic neuritis or macular degeneration.

[0440] In some embodiments, the disease or disorder is a skin condition such as psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0441] In some embodiments, the disease or disorder is a lymphatic system disorder.

[0442] In some embodiments, the disease or disorder is a rheumatic disease such as osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0443] In some embodiments, the disease or disorder is a psychological disorder such as a neuropsychiatric condition including depression, major depressive disorder, or treatment-resistant depression.

[0444] In some embodiments, the disease or disorder is a graft-versus-host disease.

[0445] In some embodiments, the disease or disorder is pain (including disorders related to pain management), such as pain management dependence, osteoarthritis pain, or allodynia.

[0446] In some embodiments, the NLRP3-related disorder in subjects determined to have germline or somatic nonsilent mutations in NLRP3 is cryopyrin-associated autoinflammatory syndrome. In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Macklewells syndrome, or neonatal onset multi-organ inflammatory disease (NOMID).

[0447] In some embodiments, the disease or disorder is dementia, Alzheimer's disease ("AD"), epilepsy, traumatic brain injury ("TBI"), multiple sclerosis ("MS"), developmental disorders, acute disseminated encephalomyelitis, transverse osteomyelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), spinal muscular atrophy, Huntington's disease ("HD"), spinal cord injury, dystrophy, neuroinfection, pain management dependence, neuropsychiatric disorders (e.g., depression, major depressive disorder, treatment-resistant depression), neonatal onset multi-organ inflammatory disease ("NOMID"), asthma, osteoarthritis, ulcerative colitis, gout, inflammatory anemia, Still's disease, chronic obstructive pulmonary disease ("COPD"), osteoarthritis pain, hidradenitis suppurativa, or neuroinflammation associated with obesity.

[0448] In other embodiments, methods are provided for modulating (e.g., inhibiting) NLRP3 activity (e.g., intracellularly or in vivo in a subject), comprising contacting cells with a compound of formula (IB), or a pharmaceutically acceptable salt or tautomer thereof, or administering them to a subject. In certain cases, the compound, or a pharmaceutically acceptable salt or tautomer thereof, is administered to cells or a subject in an effective amount.

[0449] (iv) Preparation method Compounds of formula (IB), as well as their salts and tautomers, can be synthesized according to general scheme A or B, as provided below. The examples further illustrate non-limiting examples of this general synthesis.

[0450] General method, Protocol A A preferred general route for the preparation of the compounds described herein follows Protocol A, as shown in General Scheme A.

[0451] General Scheme A. [ka] Step 1 involves the reaction of an amine (i) reagent, or a salt or tautomer thereof, with phenylcarbonochloride (ii), where R' is -NO2 or a halogen, and x is 0, 1, or 2, or diphosgene, to provide a carbamate (iii), or a salt or tautomer thereof. Step 2 involves coupling the carbamate (iii), or a salt thereof, with an aniline (iv) reagent, or a salt thereof, to provide a compound of formula (IB), or a salt or tautomer thereof.

[0452] General method, Protocol B Another preferred general route for the preparation of the compounds described herein follows Protocol B shown in General Scheme B.

[0453] General Scheme B. [ka] Step 1 involves the reaction of an aniline(iv) reagent or a salt thereof with a phenylcarbonochloride(ii) or a salt thereof, where R' is -NO2 or a halogen, and x is 0, 1, or 2, or diphosgene, to provide a carbamate(iii) or a salt thereof. Step 2 involves coupling the carbamate(iii) or a salt thereof with an amine(i) reagent, or a salt thereof or a tautomer, to provide a compound of formula (IB), or a salt thereof or a tautomer.

[0454] (v) Biological assays Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of this disclosure. These in vitro or in vivo biological assays include, but are not limited to, binding assays, cell assays (cell lines, primary cells, and whole blood), in vitro cell viability assays, and assays for determining the binding activity and potency, unbinding clearance, solubility, and permeability of NLRP3.

[0455] In some embodiments, the compounds of this disclosure can be tested for their human-NLRP3 inhibitory activity / potency using known procedures, such as the methodology reported in Coll et al. Nat Med. (2015) 21(3):248-255. See also the sections on Examples and Biological Assay Methods.

[0456] In some embodiments, compounds can be tested for unbound clearance (Clu) according to known procedures, such as those described in Miller et al., J.Med.Chem. (2020) 63:12156-12170. For example, unbound clearance (Clu) can be calculated by dividing the total clearance (in mL / min / kg units, "CL") measured in blood or plasma by the unbound fraction (fu) in plasma.

[0457] In some embodiments, the solubility of a compound can be determined by known procedures, as described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567 and Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, the dynamic solubility in a physiologically relevant medium can be measured using serial dilution and a 2-hour incubation period, followed by filtration, and may be reported in mM units by LC-MS / MS. The thermodynamic solubility in a physiologically relevant medium can be measured by LC-MS / MS after a 24-hour incubation, followed by filtration, and may be reported in mg / mL units.

[0458] (vi) Exemplary Embodiments Additional exemplary embodiments are as described below. Other embodiments are contemplated in the claims.

[0459] Exemplary Embodiment 1. Compound of formula (IB): [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, Ring A is a ring system, G1 is CR G1 Or N, and G2 is CR G2 Or N, and G3 is CR G3 Or N, and G4 is CR G4 Or N, provided that at least two of G1, G2, G3, and G4 are N. R 1 But, hello, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , -N(R G5 )2, C3-C4 carbocyclyl, or 3-4 member heterocyclyl, wherein the carbocyclyl and the heterocyclyl independently have 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) Is it replaced with 2? or R 1 And G2 are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R G7 They independently form a 5-membered heteroaryl ring, R G1 , R G2 , R G3 , and R G4 However, each is independent of hydrogen, halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 Selected from the group consisting of, R G5 and R G6 However, each independently, hydrogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl, R G7 Each case is independent of Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SRG5 , and -N(R G5 )2, Ring B is a ring system, n is 0 or 1, p is 1 or 2, m is 0, 1, 2, or 3, R 2a and R 2b Each of these cases independently involved hydrogen, halo, and C. 1-6 Alkyl, C 1-6 A haloalkyl, a C3-C4 carbocykyl, or a 3-4 membered heterocycline, wherein the carbocykyl or heterocycline is independently substituted with 0, 1, 2, or 3 halos, or R 2a and R 2b These are linked together to form a C3 carbocykrill independently substituted with 0, 1, 2, or 3 halos. R 3 Each case is independent of Halo, C 1-6 Alkyl or C 1-6 It is either a haloalkyl or two Rs. 3 The groups are linked together, and between the two atoms they bond, there is C 1-3 Alkylene crosslinking group or C 1-3 A haloalkylene crosslinking group can be formed, R 4 However, hydrogen, C 1-3 Alkyl, C3-C4 carbocyrill, or C3-C4 carbocyrill-C 1-3 It is alkyl-, and the alkyl and the carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos, and the carbocyclyl is further independently substituted with 0, 1, or 2 C 1-3 Alkyl or C 1-3 The compound, or a pharmaceutically acceptable salt or tautomer thereof, that is substituted with a haloalkyl group.

[0460] Exemplary Embodiment 2. The compound is of the following formula: [ka] The compound described in Exemplary Embodiment 1, or a pharmaceutically acceptable salt or tautomer thereof.

[0461] Exemplary Embodiment 3. The compound is of the following formula: [ka] The compound described in Exemplary Embodiment 2, or a pharmaceutically acceptable salt or tautomer thereof.

[0462] Exemplary Embodiment 4. The compound is of the following formula: [ka] And in the formula, L is C 1-3 Alkylene crosslinking group or C 1-3 A compound described in Exemplary Embodiment 1, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

[0463] Exemplary Embodiment 5. The compound is of the following formula: [ka] [ka] The compound described in Exemplary Embodiment 4, or a pharmaceutically acceptable salt or tautomer thereof.

[0464] Exemplary Embodiment 6.R 4 However, the compound described in any one of the exemplary embodiments 1 to 5, which is not hydrogen, or a pharmaceutically acceptable salt or tautomer thereof.

[0465] Exemplary Embodiment 7. Ring A is a ring system, in formula, R 1 But, hello, C 1-6 Haloalkyl, -OR G5 , or C3-C4 carbocyclyl, wherein the carbocyclyl independently contains 0, 1, 2, or 3 halos, C 1-6Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) Is it replaced with 2? or R 1 And G2 are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R G7 They independently form a 5-membered heteroaryl ring, R G1 , R G2 , R G3 , and R G4 However, each independently produces hydrogen, halo, and -OR. G6 Selected from the group consisting of, R G5 and R G6 However, each independently, hydrogen or C 1-6 It is a haloalkyl, R G7 Each case is independent of Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , and -N(R G5 )2, the compound described in any one of the exemplary embodiments 1 to 6, or a pharmaceutically acceptable salt or tautomer thereof.

[0466] Exemplary Embodiment 8. Ring A is a ring system, in formula, R 1 However, is it Cl, cyclopropyl, CF3, CF2H, OCF3, or OCF2H? or R 1 And G2 are linked together with the atoms to which they are bonded to form an oxazole, isoxazole, pyrazole, or imidazole. R G1 , R G2 , R G3 , and R G4 However, each is independently selected from the group consisting of H, F, Cl, OH, and OCF2H, and is a compound according to exemplary embodiment 7, or a pharmaceutically acceptable salt or tautomer thereof.

[0467] Exemplary Embodiment 9. Ring B is a ring system, in formula, R 2a and R 2b Each of these cases independently involved hydrogen or C 1-6 It is alkyl, Two R's 3 The groups are linked together, and between the two atoms they bond, there is C 1-3 Can form alkylene crosslinking groups, R 4 However, C 1-3 Alkyl, C3-C4 carbocyrill, or C3-C4 carbocyrill-C 1-3 A compound according to any one of the exemplary embodiments 1 to 6, wherein the alkyl and the carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos, or a pharmaceutically acceptable salt or tautomer thereof.

[0468] Exemplary Embodiment 10. Ring B is a ring system, in formula, R 2a and R 2b Each of these cases is independently hydrogen or methyl, Two R's 3 The groups can be linked together to form an ethylene crosslinking group between the two atoms to which they are bonded. R 4 The compound described in Exemplary Embodiment 9, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is methyl, ethyl, cyclopropyl, or cyclopropyl-methyl.

[0469] Exemplary embodiment 11.G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is CR G4 The compound described in any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof.

[0470] Exemplary Embodiment 12. The compound described in Exemplary Embodiment 11, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is CH, G2 is CH, G3 is CH, and G4 is CH.

[0471] Exemplary embodiment 13.G1 is CR G1 The compound described in Exemplary Embodiment 11, wherein G2 is CH, G3 is CH, and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0472] Exemplary Embodiment 14. G1 is CH, and G2 is CR G2 The compound described in Exemplary Embodiment 11, wherein G3 is CH and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0473] Exemplary embodiment 15.G1 is CR G1 And G2 is CR G2 The compound described in Exemplary Embodiment 11, wherein G3 is CH and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0474] Exemplary embodiment 16.G1 is CR G1 G2 is CH, G3 is CH, and G4 is CR G4 The compound described in Exemplary Embodiment 11, or a pharmaceutically acceptable salt or tautomer thereof.

[0475] Exemplary Embodiment 17. G1 is N, and G2 is CR G2 And G3 is CR G3 And G4 is CR G4 The compound described in any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof.

[0476] Exemplary Embodiment 18. The compound described in Exemplary Embodiment 17, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is N, G2 is CH, G3 is CH, and G4 is CH.

[0477] Exemplary embodiment 19.G1 is CR G1 G2 is N, and G3 is CR G3 And G4 is CR G4 The compound described in any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof.

[0478] Exemplary Embodiment 20. The compound described in Exemplary Embodiment 19, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is CH, G2 is N, G3 is CH, and G4 is CH.

[0479] Exemplary embodiment 21.G1 is CR G1 The compound described in Exemplary Embodiment 19, wherein G2 is N, G3 is CH, and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0480] Exemplary embodiment 22.G1 is CR G1 And G2 is CR G2 G3 is N, and G4 is CR G4 The compound described in any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof.

[0481] Exemplary embodiment 23.G1 is CR G1 The compound described in Exemplary Embodiment 22, wherein G2 is CH, G3 is N, and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0482] Exemplary embodiment 24.G1 is CR G1 And G2 is CR G2 And G3 is CR G3 The compound according to any one of the exemplary embodiments 1 to 10, wherein G4 is N, or a pharmaceutically acceptable salt or tautomer thereof.

[0483] Exemplary embodiment 25.G1 is CRG1 The compound described in Exemplary Embodiment 24, wherein G2 is CH, G3 is CH, and G4 is N, or a pharmaceutically acceptable salt or tautomer thereof.

[0484] Exemplary Embodiment 26. G1 is N, and G2 is CR G2 And G3 is CR G3 The compound according to any one of the exemplary embodiments 1 to 10, wherein G4 is N, or a pharmaceutically acceptable salt or tautomer thereof.

[0485] Exemplary Embodiment 27. The compound described in Exemplary Embodiment 26, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is N, G2 is CH, G3 is CH, and G4 is N.

[0486] Exemplary Embodiment 28. G1 is N, and G2 is CR G2 G3 is N, and G4 is CR G4 The compound described in any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof.

[0487] Exemplary Embodiment 29. The compound according to Exemplary Embodiment 28, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is N, G2 is CH, G3 is N, and G4 is CH.

[0488] Exemplary embodiment 30.G1 is CR G1 G2 is N, G3 is N, and G4 is CR G4 The compound described in any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof.

[0489] Exemplary Embodiment 31. The compound according to Exemplary Embodiment 30, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is CH, G2 is N, G3 is N, and G4 is CH.

[0490] Exemplary embodiment 32.G1 is CR G1 And G2 is CR G2 The compound according to any one of the exemplary embodiments 1 to 10, wherein G3 is N and G4 is N, or a pharmaceutically acceptable salt or tautomer thereof.

[0491] Exemplary Embodiment 33. The compound described in Exemplary Embodiment 32, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is CH, G2 is CH, G3 is N, and G4 is N.

[0492] Exemplary embodiment 34.G1 is CR G1 And G4 is CR G4 And R 1 And G2 are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R G7 A compound according to any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof, forming a 5-membered heteroaryl ring independently substituted by .

[0493] Exemplary Embodiment 35. The compound described in Exemplary Embodiment 34, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1 is CH and G4 is CH.

[0494] Exemplary Embodiment 36.R 1 But, hello, C 1-6 Haloalkyl, -OR G5 , or C3-C4 carbocyclyl, wherein the carbocyclyl independently contains 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 A compound according to any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof, substituted with )2.

[0495] Exemplary Embodiment 37.R 1The compound described in Exemplary Embodiment 36, wherein the compound is -Cl, cyclopropyl, -CF3, -CF2H, -OCF3, or -OCF2H, or a pharmaceutically acceptable salt or tautomer thereof.

[0496] Exemplary Embodiment 38.R 1 And G2 are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R G7 A compound according to any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof, forming a 5-membered heteroaryl ring independently substituted by .

[0497] Exemplary Embodiment 39.R 1 The compound according to exemplary embodiment 38, or a pharmaceutically acceptable salt or tautomer thereof, wherein G2 and G2 are linked together with the atoms to which they are bonded to form an oxazole, isoxazole, pyrazole, or imidazole.

[0498] Exemplary Embodiment 40.R G1 , R G2 , R G3 , and R G4 However, each independently produces hydrogen, halo, and -OR. G6 A compound according to any one of the exemplary embodiments 1 to 10, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

[0499] Exemplary Embodiment 41.R G1 , R G2 , R G3 , and R G4 However, each is independently selected from the group consisting of hydrogen, F, Cl, OH, and OCF2H, and is a compound according to exemplary embodiment 40, or a pharmaceutically acceptable salt or tautomer thereof.

[0500] Exemplary Embodiment 42.R G5 and R G6 However, each independently, hydrogen or C 1-6A compound described in any one of the exemplary embodiments 1 to 10, which is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0501] Exemplary Embodiment 43.R G5 However, the compound described in Exemplary Embodiment 42, which is CF3 or CF2H, or a pharmaceutically acceptable salt or tautomer thereof.

[0502] Exemplary Embodiment 44.R G6 The compound described in Exemplary Embodiment 42, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is hydrogen or CF2H.

[0503] Exemplary Embodiment 45.R 2a and R 2b Each of these cases independently involved hydrogen or C 1-6 A compound described in any one of the exemplary embodiments 1 to 44, which is alkyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0504] Exemplary Embodiment 46.R 2a and R 2b Each of these instances is independently hydrogen or methyl, the compound according to exemplary embodiment 45, or a pharmaceutically acceptable salt or tautomer thereof.

[0505] Exemplary Embodiment 47.R 4 However, hydrogen, C 1-3 Alkyl, C3-C4 carbocyrill, or C3-C4 carbocyrill-C 1-3 A compound according to any one of the exemplary embodiments 1 to 46, wherein the alkyl and the carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos, if their valencies are acceptable, or a pharmaceutically acceptable salt or tautomer thereof.

[0506] Exemplary Embodiment 48.R 4 The compound described in Exemplary Embodiment 47, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is methyl, ethyl, cyclopropyl, or cyclopropyl-methyl.

[0507] Exemplary Embodiment 49. Two R 3 The groups are linked together, and between the two atoms they bond, there is C 1-3 A compound according to any one of the exemplary embodiments 1 to 48, or a pharmaceutically acceptable salt or tautomer thereof, that can form an alkylene crosslinking group.

[0508] Exemplary Embodiment 50. Two R 3 A compound according to exemplary embodiment 49, or a pharmaceutically acceptable salt or tautomer thereof, wherein the groups can be linked to form an ethylene crosslinking group between the two atoms to which they are linked.

[0509] Exemplary Embodiment 51.n is 1, a compound according to any one of Exemplary Embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0510] A compound according to any one of the exemplary embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof, wherein exemplary embodiment 52.n is 0.

[0511] Exemplary Embodiment 53.p is a compound according to any one of Exemplary Embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0512] Exemplary Embodiment 54. A compound according to any one of Exemplary Embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof, wherein m is 0.

[0513] Exemplary Embodiment 55.m is a compound according to any one of Exemplary Embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0514] Exemplary Embodiment 56.m is a compound according to any one of Exemplary Embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0515] Exemplary Embodiment 57. Ring A of the formula: [ka] However, the basis of the following equation: [ka] And, In the formula, R G1 , R G2 , R G3 , and R G4 However, each operates independently, Haro, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 A compound according to any one of the exemplary embodiments 1 to 50, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

[0516] Exemplary Embodiment 58. The rings A(a-2), (a-4), (a-5), (a-6) of the formula are based on the following formula: [ka] The compound described in Exemplary Embodiment 57, or a pharmaceutically acceptable salt or tautomer thereof.

[0517] Exemplary Embodiment 59. Ring A of the formula: [ka] However, the basis of the following equation: [ka] And, In the formula, R G1 But, hello, C 1-6 Alkyl, C 1-6 Haloalkyl or -OR G6 The compound described in any one of the exemplary embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0518] Exemplary Embodiment 60. The ring A(a-7N), (a-8N), or (a-9N) of formula A is of the following formula: [ka] The compound described in Exemplary Embodiment 59, or a pharmaceutically acceptable salt or tautomer thereof.

[0519] Exemplary Embodiment 61. Ring A of the formula: [ka] Furthermore, R 1 And G2 are linked together with the atoms to which they are bonded to form a 5-membered heteroaryl ring, in the formula, the ring A, the R 1 , and G 2 However, the basis of the following equation: [ka] Obtained, During the ceremony, X is O, S, NH, or NR G7 And, Y is N, CH, or CR G7 And, z is either 0 or 1, However, R G7 However, if it is a group bonded to a nitrogen (N) atom, R G7 However, C 1-6 Alkyl or C 1-6 A compound according to any one of the exemplary embodiments 1 to 50, provided that it is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0520] Exemplary Embodiment 62. Ring A, R 1 , and G2 are linked together with the atoms to which they are bonded to form a 5-membered heteroaryl ring, wherein the group has the following formula: [ka] The compound described in Exemplary Embodiment 61, or a pharmaceutically acceptable salt or tautomer thereof.

[0521] Exemplary Embodiment 63. Ring A is based on the following formula: [ka] The compound described in any one of the exemplary embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0522] Exemplary Embodiment 64. Ring A is based on the following formula: [ka] [ka] The compound described in any one of the exemplary embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0523] Exemplary embodiment 65. Ring B of formula: [ka] However, the basis of the following equation: [ka] The compound described in any one of the exemplary embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0524] Exemplary Embodiment 66. Ring B is based on the following formula: [ka] And, In the formula, R 2a and R 2b Each case is independent of Halo, C 1-6 Alkyl, C 1-6 A compound according to exemplary embodiment 65, which is a haloalkyl, a C3-C4 carbocykrill, or a 3-4 membered heterocycline, or a pharmaceutically acceptable salt or tautomer thereof.

[0525] Exemplary Embodiment 67. The rings B(b-1), (b-2), (b-3), or (b-4) of the formula are two R 3 The bases are linked together, C 1-3 Alkylene crosslinking group or C 1-3 When forming a haloalkylene crosslinking group, the group is based on the following formula: [ka] And, In the formula, L is C 1-3 Alkylene crosslinking group or C 1-3 A compound described in exemplary embodiment 65, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

[0526] Exemplary Embodiment 68. Ring B is based on the following formula: [ka] And, In the formula, R 2a and R 2b Each case is independent of Halo, C 1-6 Alkyl, C 1-6 A compound according to exemplary embodiment 67, which is a haloalkyl, a C3-C4 carbocykrill, or a 3-4 membered heterocycline, or a pharmaceutically acceptable salt or tautomer thereof.

[0527] Exemplary Embodiment 69. Ring B is based on the following formula: [ka] The compound described in any one of the exemplary embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0528] Exemplary Embodiment 70. Ring B is based on the following formula: [ka] [ka] [ka] The compound described in any one of the exemplary embodiments 1 to 50, or a pharmaceutically acceptable salt or tautomer thereof.

[0529] Exemplary Embodiment 71. The compound according to any one of the prior claims, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is selected from the compounds listed in Table 1 or Table 2.

[0530] Exemplary Embodiment 72. A pharmaceutical composition comprising a compound described in any one of Exemplary Embodiments 1 to 71, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.

[0531] Exemplary Embodiment 73. A method for modulating NLRP3 activity, comprising administering to a subject a compound described in any one of Exemplary Embodiments 1 to 71, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition described in Exemplary Embodiment 72.

[0532] Exemplary Embodiment 74. A method for treating or preventing a disease or disorder, comprising administering to a subject a compound described in any one of Exemplary Embodiments 1 to 71, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition described in Exemplary Embodiment 72.

[0533] Exemplary Embodiment 75. A compound according to any one of Exemplary Embodiments 1 to 71, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to Exemplary Embodiment 72, for use in treating or preventing a disease or disorder.

[0534] Exemplary Embodiment 76. Use of a compound described in any one of Exemplary Embodiments 1 to 71, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for the treatment or prevention of a disease or disorder.

[0535] Exemplary Embodiment 77. Use of any one of the exemplary embodiments 1 to 71, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment or prevention of a disease or disorder.

[0536] Exemplary Embodiment 78. The method, compound, or use according to any one of the Exemplary Embodiments 73 to 77, wherein the disease or disorder is an NLRP3-related disease or disorder.

[0537] Exemplary Embodiment 79. The method, compound, or use according to any one of the Exemplary Embodiments 73 to 78, wherein the subject is a human.

[0538] Exemplary Embodiment 80. The method, compound, or use according to any one of Exemplary Embodiments 73 to 79, wherein the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disorder of the muscle, an inflammatory disorder, an autoimmune disorder, cancer, an infectious disease, a metabolic disorder, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disorder, a rheumatic disease, a psychological disorder, a graft-versus-host disease, pain (including disorders related to pain management), or an NLRP3-related disorder in a subject determined to have germline or somatic nonsilent mutations in NLRP3.

[0539] Exemplary Embodiment 81. The method, compound, or use according to Exemplary Embodiment 80, wherein the central nervous system disorder or disability is dementia, Alzheimer's disease ("AD"), epilepsy, traumatic brain injury ("TBI"), multiple sclerosis ("MS"), developmental disorder, acute disseminated encephalomyelitis, transverse myelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), Huntington's disease ("HD"), or spinal cord injury.

[0540] Exemplary Embodiment 82. The method, compound, or use according to Exemplary Embodiment 80, wherein the primary neurological disorder of the muscle is dystrophy or spinal muscular atrophy.

[0541] Exemplary Embodiment 83. The method, compound, or use according to Exemplary Embodiment 80, wherein the inflammatory disorder is gout or inflammatory anemia.

[0542] Exemplary Embodiment 84. The method, compound, or use according to Exemplary Embodiment 80, wherein the autoimmune disease is ulcerative colitis.

[0543] Exemplary Embodiment 85. The method, compound, or use according to Exemplary Embodiment 80, wherein the cancer is skin cancer or colon cancer.

[0544] Exemplary Embodiment 86. The method, compound, or use of Exemplary Embodiment 80, wherein the infection is a neurological infection.

[0545] Exemplary Embodiment 87. The method, compound, or use according to Exemplary Embodiment 80, wherein the metabolic disorder is diabetes mellitus.

[0546] Exemplary Embodiment 88. The method, compound, or use according to Exemplary Embodiment 80, wherein the cardiovascular disease is stroke.

[0547] Exemplary Embodiment 89. The method, compound, or use according to Exemplary Embodiment 80, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.

[0548] Exemplary Embodiment 90. The method, compound, or use according to Exemplary Embodiment 80, wherein the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease.

[0549] Exemplary Embodiment 91. The method, compound, or use according to Exemplary Embodiment 80, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0550] Exemplary Embodiment 92. The method, compound, or use according to Exemplary Embodiment 80, wherein the eye disease is optic neuritis or macular degeneration.

[0551] Exemplary Embodiment 93. The method, compound, or use according to Exemplary Embodiment 80, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0552] Exemplary Embodiment 94. The method, compound, or use according to Exemplary Embodiment 80, wherein the rheumatic disease is osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0553] Exemplary Embodiment 95. The method, compound, or use according to Exemplary Embodiment 80, wherein the psychological disorder is a neuropsychiatric condition selected from the group consisting of depression, major depressive disorder, and treatment-resistant depression.

[0554] Exemplary Embodiment 96. The method, compound, or use according to Exemplary Embodiment 80, wherein the pain is pain management dependence, osteoarthritis pain, or allegorrhea.

[0555] Exemplary Embodiment 97. The method, compound, or use according to Exemplary Embodiment 80, wherein the NLRP3-related disease in a subject determined to have germline or somatic nonsilent mutations in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0556] Exemplary Embodiment 98. The method, compound, or use according to Exemplary Embodiment 80, wherein the disease or disorder is dementia, Alzheimer's disease ("AD"), epilepsy, traumatic brain injury ("TBI"), multiple sclerosis ("MS"), developmental disorder, acute disseminated encephalomyelitis, transverse osteomyelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), spinal muscular atrophy, Huntington's disease ("HD"), spinal cord injury, dystrophy, neuroinfection, pain management dependence, neuropsychiatric disorders (e.g., depression, major depressive disorder, treatment-resistant depression), neonatal onset multi-organ inflammatory disease ("NOMID"), asthma, osteoarthritis, ulcerative colitis, gout, inflammatory anemia, Still's disease, chronic obstructive pulmonary disease ("COPD"), osteoarthritis pain, or hidradenitis suppurativa.

[0557] Exemplary Embodiment 99. A process for preparing a compound of formula (IB) described in any one of the prior exemplary embodiments, or a salt or tautomer thereof, wherein the compound is synthesized according to general scheme A or B. [Examples]

[0558] Examples are provided below to allow for a more complete understanding of this disclosure. These examples are for illustrative purposes only and should not be construed as limiting this disclosure in any way.

[0559] Analysis method Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as described, and at 300.3 K unless otherwise specified, with chemical shifts (δ) reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16, or 32 scans. Typical NMR solvents include deuterated dimethyl sulfoxide (DMSO-d6) and deuterated methanol (CD3OD).

[0560] Liquid chromatography-mass spectrometry (LCMS) and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7–8.0 μl, and flow rates were typically 0.8 or 1.2 mL / min. Detection methods included diode array (DAD) or evaporative light scattering (ELSD), as well as positive ion electrospray ionization. The MS range was 100–1000 Da. The mobile phase of water and / or acetonitrile (MeCN) may contain modifiers such as trifluoroacetic acid (TFA), formic acid (FA), or ammonium carbonate (typically 0.01–0.04%). ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (min).

[0561] Purification / Separation Methods. The purification and / or separation chromatography methods used for the purification and / or isolation of exemplary compounds, depending on the synthesis method, are described. RT = Retention time (minutes); Preparative = Preparative high-performance liquid chromatography.

[0562] The compounds are numbered according to the following numbering system, where R 2a and R 2b It is not hydrogen. [Table 3-1] [Table 3-2]

[0563] An asterisk (*) next to the compound number (#) indicates that any stereochemistry has been assigned. Future tense language ("may be prepared" / "may be synthesized") indicates examples that will be implemented.

[0564] Synthesis example Example 1. (R)-3-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chlorophenyl)-1-methylurea (compound 2A) and (S)-3-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chlorophenyl)-1-methylurea (compound 2B) Scheme 1A. [ka] Scheme 1B. [ka]

[0565] Example 1 follows Protocol B. Step 1: To a stirred solution of 4-chloro-N-methylaniline ("Aniline(iv) Reagent") (250 mg, 1.76 mmol, 1 equivalent) and pyridine (419 mg, 5.29 mmol, 3 equivalents) in dichloromethane (DCM) (5 mL), 4-nitrophenylcarbonochloride (427 mg, 2.11 mmol, 1.2 equivalents) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LC-MS. Upon completion, the reaction was quenched by adding water (5 mL) at room temperature, and the resulting mixture was extracted with ethyl acetate (SiO) (2 × 15 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to obtain 4-nitrophenyl N-(4-chlorophenyl)-N-methylcarbamate (400 mg, yield 74%). LCMS: (ES, m / z): RT=1.00 min, m / z=307.5 [M+H] + .

[0566] Step 2: 4-nitrophenyl N-(4-chlorophenyl)-N-methylcarbamate (200 mg, 0.65 mmol, 1 equivalent), potassium methaneperoxoate (454 mg, 3.26 mmol, 5 equivalents), (3R)-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine ("Amine(i) Reagent") (329 mg, 1.95 mmol, 3 equivalents), and dimethylformamide (DMF) (4 mL) were added to a 20 mL vial at 130 °C. The reaction mixture was irradiated with microwave radiation at 130 °C for 1 hour, and the reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel; mobile phase: acetonitrile in water, gradient from 0% to 100% over 20 minutes; detector: UV 254 nm) to obtain the crude product (40 mg). This was then purified by preparative HPLC (YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L (NH4)HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 25% B, 25% B over 10 minutes; wavelength: 254 nm; RT (min): 9.0) to obtain compound 2A (5.9 mg). LCMS: (ES, m / z): RT = 1.33 min, m / z = 336.0 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.34 (m, 2H), 7.34 - 7.22 (m, 2H), 6.09 (d, J = 7.8 Hz, 1H), 3.80 - 3.57 (m, 3H), 3.15 (s, 3H), 2.84 - 2.64 (m, 2H), 1.83 - 1.62 (m, 2H), 1.61 - 1.34 (m, 2H).

[0567] Compound 2B can be prepared according to this example using 4-chloro-N-methylaniline as the aniline(iv) reagent and (3S)-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine as the amine(i) reagent. Example 2. 1-(4-chlorophenyl)-1-methyl-3-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)urea (compound 4, Rac-4), 1-(4-chlorophenyl)-1-methyl-3-((3R,5R)-5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)urea (compound 4A*), 1-(4-chlorophenyl)-1-methyl-3-((3S,5R)-5-methyl- 1-(1H-tetrazol-5-yl)azepan-3-yl)urea (compound 4B*), 1-(4-chlorophenyl)-1-methyl-3-(3R,5S)-5-methyl-1-(1H-tetrazol-5-yl)azepan-3-yl)urea (compound 4C*), and 1-(4-chlorophenyl)-1-methyl-3-((3S,5S)-5-methyl-1-(1H-tetrazol-5-yl)azepan-3-yl)urea (compound 4D*) Scheme 2A. [ka]

[0568] Scheme 2B. [ka] Scheme 2C. [ka] Example 2 follows Protocol B. Step 1: Allylamine hydrochloride (25.0 g, 267 mmol, 1 equivalent), ethanol (EtOH) (400 mL), ethyl acrylate (32.1 g, 320 mmol, 1.2 equivalents), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (81.4 g, 534 mmol, 2 equivalents) were added to a 1000 mL round-bottom flask at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours, quenched by adding water at room temperature (100 mL), and then concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate (siRNA) (3 × 500 mL), the organic layer was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, ethyl 3-(propa-2-en-1-ylamino)propanoate (26.0 g, yield 62%). LCMS:(ES,m / z):RT=0.236 min, m / z=158[M+1] + .

[0569] Step 2: Ethyl 3-(propa-2-en-1-ylamino)propanoate (25.0 g, 159 mmol, 1 equivalent), di-tert-butyl dicarbonate (69.4 g, 318 mmol, 2 equivalents), and dichloromethane (DCM) (300 mL) were added to a 500 mL three-necked round-bottom flask at 0°C. The resulting mixture was stirred at room temperature for 2 hours, and the reaction was then quenched by adding 200 mL of water / ice at 0°C. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 500 mL), the organic layer was dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (12:1) to obtain ethyl 3-[(tert-butoxycarbonyl)(propa-2-en-1-yl)amino]propanoate (23.0 g, yield 56%). LCMS: (ES, m / z): RT=0.993 min, m / z=258[M+1]+.

[0570] Step 3: To a stirred solution of ethyl 3-[(tert-butoxycarbonyl)(propa-2-en-1-yl)amino]propanoate (20.0 g, 77.7 mmol, 1 equivalent) in tetrahydrofuran (THF) (300 mL), lithium hexamethyldisilazide (LiHMDS) (15.6 g, 93.3 mmol, 1.2 equivalents) was added dropwise under a nitrogen atmosphere at -78 °C, and the resulting mixture was stirred for 30 minutes under a nitrogen atmosphere at -78 °C. Then, 3-bromo-2-methylprop-1-ene (20.8 g, 155 mmol, 2 equivalents) was added dropwise under a nitrogen atmosphere at -78 °C, and the resulting mixture was stirred for 1 hour under a nitrogen atmosphere at 0 °C. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (500 mL) at 0°C. The aqueous layer was then extracted with ethyl acetate ( Depositphotos) (3 × 500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (12:1) to obtain ethyl 2-{[(tert-butoxycarbonyl)(propa-2-en-1-yl)amino]methyl}penta-4-enoate (15.0 g, yield 65%). LCMS: (ES, m / z): RT = 1.097 min, m / z = 312 [M+1] + .

[0571] Step 4: Ethyl 2-{[(tert-butoxycarbonyl)(propa-2-en-1-yl)amino]methyl}-4-methylpenta-4-enoate (40.0 g, 128 mmol, 1 equivalent), tetrahydrofuran (THF) (4000 mL), and dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II) (Grubbs second-generation catalyst) (16.4 g, 19.3 mmol, 0.15 equivalents) were added to a 5000 mL three-necked round-bottom flask at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 55 °C for 2 hours, and then quenched by adding water (500 mL). Next, the aqueous layer was extracted with ethyl acetate (RINKAN) (3 × 300 mL), the organic layer was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (12:1) to obtain 1-tert-butyl 3-ethyl 5-methyl-2,3,4,7-tetrahydroazepine-1,3-dicarboxylate) (30.0 g, yield 82%).

[0572] Step 5: 1-tert-butyl 3-ethyl 5-methyl-2,3,4,7-tetrahydroazepine-1,3-dicarboxylate (20.0 g, 70.6 mmol, 1 equivalent), methanol (MeOH) (100 mL), NaOH (14.1 g, 353 mmol, 5 equivalents), and water (100 mL) were added to a 500 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then acidified to pH 6 at 0°C with HCl (aqueous solution) (2 M), the aqueous layer was extracted with ethyl acetate (siRNA) (3 × 200 mL), the organic layer was dried over anhydrous Na₂SO₄, and filtered. The filtrate was then concentrated under reduced pressure to obtain crude 1-tert-butyl 3-ethyl 5-methyl-2,3,4,7-tetrahydroazepine-1,3-dicarboxylate.

[0573] Step 6: 1-(tert-butoxycarbonyl)-5-methyl-2,3,4,7-tetrahydroazepine-3-carboxylic acid (20.0 g, 78.3 mmol, 1 equivalent), toluene (250 mL), benzyl alcohol (25.4 g, 235 mmol, 3 equivalents), diphenyl phosphoryl azide (DPPA) (64.7 g, 235 mmol, 3 equivalents), and triethylamine (23.8 g, 235 mmol, 3 equivalents) were added to a 500 mL three-necked round-bottom flask at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 100°C for 3 hours, concentrated under reduced pressure, water (500 mL) was added, the aqueous layer was extracted with ethyl acetate (3 × 500 mL), the organic layer was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by reverse flash chromatography (C18 silica column; mobile phase: acetonitrile in water, 50% to 60% gradient over 10 minutes; detector: UV 254 nm) to obtain tert-butyl 3-{[(benzyloxy)carbonyl]amino}-5-methyl-2,3,4,7-tetrahydroazepine-1-carboxylate (12 g, yield 43%). LCMS: (ES, m / z): RT = 1.065 min, m / z = 361 [M+1] + .

[0574] Step 7: In a 100 mL round-bottom flask, tert-butyl 3-{[(benzyloxy)carbonyl]amino}-5-methyl-2,3,4,7-tetrahydroazepine-1-carboxylate (10.0 g, 27.8 mmol, 1 equivalent), dichloromethane (DCM) (25 mL), and trifluoroacetic acid (TFA) (5 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure to obtain crude benzyl N-(5-methyl-2,3,4,7-tetrahydro-1H-azepine-3-yl)carbamate (8.0 g). LCMS: (ES, m / z): RT = 0.563 min, m / z = 261 [M+1] + .

[0575] Step 8: Benzyl N-(5-methyl-2,3,4,7-tetrahydro-1H-azepin-3-yl)carbamate (8.0 g, 30.7 mmol, 1 equivalent), acetonitrile (50 mL), K2CO3 (12.8 g, 92.2 mmol, 3 equivalents), and BrCN (3.91 g, 36.9 mmol, 1.2 equivalents) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour, and then water (100 mL) was added. Next, the aqueous layer was extracted with ethyl acetate (RINKAN) (3 × 200 mL), and the organic layer was concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (10:1) to obtain benzyl N-(1-cyano-5-methyl-2,3,4,7-tetrahydroazepine-3-yl)carbamate (7.0 g, yield 80%). LCMS: (ES, m / z): RT = 0.837 min, m / z = 286 [M+1] + .

[0576] Step 9: Benzyl N-(1-cyano-5-methyl-2,3,4,7-tetrahydroazepin-3-yl)carbamate (5.0 g, 17.5 mmol, 1 equivalent), NH4Cl (2.81 g, 52.6 mmol, 3 equivalents), and azidotrimethylsilane (6.06 g, 52.6 mmol, 3 equivalents) were added to a 50 mL round-bottom flask at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature and concentrated to obtain a residue, which was purified by reverse flash chromatography (C18 silica column; mobile phase: acetonitrile in water, 40% to 60% gradient over 10 minutes; detector: UV 254 nm) to obtain N-[5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)-2,3,4,7-tetrahydroazepine-3-yl]carbamate (4 g, yield 70%). LCMS: (ES, m / z): RT=0.773 min, m / z=329 [M+1] + .

[0577] Step 10: N-[5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)-2,3,4,7-tetrahydroazepine-3-yl]carbamate (4.0 g, 12.2 mmol, 1 equivalent), methanol (MeOH) (100 mL), and Pd / C (1.30 g, 12.2 mmol) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred overnight under a hydrogen atmosphere at 70°C. The resulting mixture was then filtered, the filter cake was washed with methanol (MeOH) (3 × 20 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepan-3-amine ("Amine(i) Reagent") (2.5 g). LCMS:(ES,m / z):RT=0.101 min, 0.289,m / z=197[M+1] + .

[0578] Step 11: 4-chloro-N-methylaniline ("Aniline(iv) Reagent") (250 mg, 1.76 mmol, 1 equivalent), triethylamine (TEA) (536 mg, 5.29 mmol, 3 equivalents), and dichloromethane (DCM) (3 mL) were added to an 8 mL vial. Diphosgene (419 mg, 2.11 mmol, 1.2 equivalents) was added to the mixture at 0°C. The resulting mixture was stirred for a further 1 hour at 25°C, and the reaction was monitored by LC-MS. Upon completion of the reaction, the resulting mixture was filtered, the filter cake was washed with ethyl acetate (RINKAN) (3 × 10 mL), and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by preparative TLC (petroleum ether / ethyl acetate 3:1) to obtain trichloromethyl N-(4-chlorophenyl)-N-methylcarbamate (400 mg, yield 75%). LCMS: (ES, m / z): RT = 1.09 mins.

[0579] Step 12: 4-nitrophenyl N-(4-chlorophenyl)-N-methylcarbamate (200 mg, 0.652 mmol, 1 equivalent), potassium methaneperoxoate (272 mg, 1.96 mmol, 3 equivalents), 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepan-3-amine (154 mg, 0.782 mmol, 1.2 equivalents), and acetonitrile (6 mL) were added to a 40 mL vial. The resulting mixture was stirred at 80°C for 12 hours, and the reaction was monitored by LC-MS. Upon completion, the resulting mixture was filtered, the filtered cake was washed with methanol (MeOH) (3 × 10 mL), and the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by reverse flash chromatography (C18 silica gel; mobile phase: acetonitrile (MeCN) in water (0.1% NH3.H2O), gradient from 0% to 100% over 20 minutes; detector: UV 254 nm) to obtain the crude product 1-(4-chlorophenyl)-1-methyl-3-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)urea (compound 4, Rac-4) (300 mg), which was then subjected to preparative HPLC (XSelect CSH C18 OBD column 30 × 150 mm 5 μm; mobile phase A: acetonitrile, mobile phase B: water (0.05% trifluoroacetic acid); flow rate: 60 mL / min; gradient: 34% B to 44% B, 44% over 10 minutes) Further purification by (B; wavelength: 254 nm; RT (min): 6.32~8.77) yielded a mixture of two trans isomers of 1-(4-chlorophenyl)-1-methyl-3-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)urea (79 mg, purity = 99.00%) and two cis isomers of 1-(4-chlorophenyl)-1-methyl-3-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)urea (13 mg, purity = 98.00%), and the designation of trans and cis isomers was arbitrarily assigned. Trans isomer: LCMS: (ES, m / z): RT = 0.63 min, m / z = 364.0 [M + H] + . Cis isomer: LCMS: (ES, m / z): RT=0.61 min, m / z=364.0[M+H] + .

[0580] Step 13: A mixture of trans isomers of 1-(4-chlorophenyl)-1-methyl-3-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)urea (79 mg) was purified by preparative chiral HPLC (CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: 15% B~15% B at 21 min; wavelength: 254 / 220 nm) to obtain compound 4B* (RT(min): 17.35, 26.0 mg) and compound 4C* (RT(min): 19.44, 23.0 mg). Stereochemistry was arbitrarily assigned.

[0581] Compound 4B*:LCMS:(ES,m / z):RT=0.65 min, m / z=364.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.32 (m, 2H), 7.28 - 7.20 (m, 2H), 5.93 (s, J = 7.8 Hz, 1H), 4.11 (s, J = 8.0, 4.3 Hz, 1H), 3.62 (s, J = 18.7, 10.1, 4.8 Hz, 3H), 3.22 (s, J = 13.9, 9.8, 4.3 Hz, 1H), 3.14 (s, 3H), 1.91 - 1.81 (m, 1H), 1.70 (s, J = 15.4 Hz, 1H), 1.61 (s, J = 14.2, 5.7, 2.2 Hz, 1H), 1.49 (s, J = 14.4, 9.7, 4.7 Hz, 1H), 1.34 (s, J = 13.9, 9.2, 4.6 Hz, 1H), 0.89 (s, J = 6.8 Hz, 3H).

[0582] Compound 4C*:LCMS:(ES,m / z):RT=0.64 min, m / z=364.0[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.39 - 7.31 (m, 2H), 7.21 - 7.13 (m, 2H), 4.11 (s, J = 4.1 Hz, 1H), 3.73 (s, J = 15.0, 6.6 Hz, 1H), 3.68 - 3.50 (m, 2H), 3.26 (s, J = 8.4, 4.6 Hz, 1H), 3.22 (s, 3H), 1.88 - 1.59 (m, 4H), 1.48 (s, J = 13.7, 9.3, 4.2 Hz, 1H), 0.99 (s, J = 6.4 Hz, 3H).

[0583] Step 14: A mixture of cis isomers (13 mg) of 1-(4-chlorophenyl)-1-methyl-3-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)urea was purified by preparative chiral HPLC (CHIRALPAK IG, 2*25cm, 5μm; mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: 20% B~20% B at 14 min; wavelength: 254 / 220 nm) to obtain compound 4A* (RT(min): 12.72, 4.3 mg) and compound 4D* (RT(min): 9.84, 5.4 mg). Stereochemistry was arbitrarily assigned.

[0584] Compound 4A*:LCMS:(ES,m / z):RT=1.15 min, m / z=364.0[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 7.47 - 7.38 (m, 2H), 7.35 - 7.26 (m, 2H), 6.41 (s, J = 7.8 Hz, 1H), 3.83 (s, J = 12.9 Hz, 1H), 3.62 (s, J = 14.2, 4.9 Hz, 1H), 3.56 (m, 2H), 3.48- 3.37 (m, 2H), 3.17 (s, 2H), 1.76 (s, J = 13.7 Hz, 1H), 1.65 (s, J = 13.3 Hz, 1H), 1.52 (s, 1H), 1.45 - 1.31 (m, 1H), 1.24 (s, J = 11.4 Hz, 1H), 0.91 (s, J = 6.7 Hz, 3H).

[0585] Compound 4D*:LCMS:(ES,m / z):RT=0.73 min,m / z=364.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 7.46 - 7.38 (m, 2H), 7.35 - 7.26 (m, 2H), 6.42 (s, J = 8.0 Hz, 1H), 3.87 - 3.79 (m, 1H), 3.62 (s, J = 14.1, 4.9 Hz, 1H), 3.59 (m, 1H), 3.56 - 3.36 (m, 2H), 3.17 (s, 3H), 1.76 (s, J = 14.1 Hz, 1H), 1.69 - 1.61 (m, 1H), 1.53 (s, 1H), 1.38 (s, J = 15.4, 5.2 Hz, 1H), 1.30 - 1.17 (m, 1H), 0.91 (s, J = 6.6 Hz, 3H).

[0586] Example 3.1-(4-クロロフェニル)-1-エチル-3-((3R,5S)-5-メチル-1-( 1H-Torotron-5-イル)Torotron-3-イル)urea (compound 6A), and compounds 6B~6D スキーム3A.

change

[0587] Step 1: In a 50 mL round-bottom flask, tert-butyl N-[(3R,5S)-5-methylpiperidine-3-yl]carbamate (1.5 g, 6.99 mmol, 1 equivalent), BrCN (1110 mg, 10.5 mmol, 1.5 equivalents), acetonitrile (20 mL), and K2CO3 (2.9 g, 21 mmol, 3 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours, and the reaction progress was monitored by LC-MS. Upon completion of the reaction, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl-N-[(3R,5S)-1-cyano-5-methylpiperidine-3-yl]carbamate (1.6 g, purity = 80%). LC-MS: (ES, m / z): RT = 0.603 min, m / z = 240 [M+1] + .

[0588] Step 2: In a 50 mL round-bottom flask, tert-butyl N-[(3R,5S)-1-cyano-5-methylpiperidine-3-yl]carbamate (1.6 g, 6.68 mmol, 1 equivalent), NH4Cl (1.08 g, 20.0 mmol, 3 equivalents), trimethylsilyl azide (TMSN3) (3120 mg, 13.4 mmol, 2 equivalents), and dimethylformamide (DMF) (3 mL) were added at room temperature. The resulting mixture was stirred at 100 °C for 16 hours, and the reaction progress was monitored by LC-MS. Upon completion of the reaction, the residue was purified by reverse flash chromatography (C18 silica gel column; mobile phase: acetonitrile in water, gradient from 10% to 50% over 10 minutes; detector: UV 254 nm) to obtain tert-butyl N-[(3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-yl]carbamate (1.50 g, yield 80%). LCMS: (ES, m / z): RT=0.499 min, m / z=283 [M+1] + .

[0589] Step 3: In a 250 mL round-bottom flask, tert-butyl N-[(3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-yl]carbamate (1.5 g, 5.313 mmol, 1 equivalent) and dichloromethane (5 mL) were added at room temperature. The resulting mixture was stirred under an HCl (g) atmosphere at room temperature for 1 hour, and then concentrated under reduced pressure to obtain (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine ("Amine(i) Reagent") (1 g, HCl salt). LCMS: (ES, m / z): RT = 0.151 min, m / z = 183 [M+1] + .

[0590] Step 4: A solution of 4-chloro-N-ethylaniline ("Aniline(iv) Reagent") (1.00 g, 6.42 mmol, 1 equivalent) in dichloromethane was treated with triethylamine (1.95 g, 19.3 mmol, 3 equivalents) at 0°C, followed by the dropwise addition of diphosgene (1.40 g, 7.06 mmol, 1.1 equivalents) at 0°C. The resulting mixture was stirred at room temperature for 2 hours, and the reaction progress was monitored by LC-MS. Upon completion of the reaction, the reaction mixture was concentrated to obtain the crude residue, which was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (5:1) to obtain trichloromethyl N-(4-chlorophenyl)-N-ethylcarbamate (1.00 g, 49.1%). LC-MS: (ES, m / z) RT = 0.76 min, m / z = 276 [M + H] + .

[0591] Step 5: Trichloromethyl N-(4-chlorophenyl)-N-ethyl carbamate (10.0 mg, 0.03 mmol, 1 equivalent), (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine (HCl salt, 5.75 mg, 0.03 mmol, 1 equivalent), K2CO3 (13.1 mg, 0.09 mmol, 3 equivalents), and dimethylformamide (1 mL) were added to a 25 mL round-bottom flask at room temperature, and the reaction progress was monitored by LC-MS. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse flash chromatography (C18 silica gel column; mobile phase: acetonitrile in water, gradient of 10% to 50% over 400 minutes; detector: UV 254 nm) to obtain the crude product (30 mg). This was further purified by preparative HPLC (YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L (NH4)HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 15% B to 25% B, 25% B over 12 minutes; wavelength: 254 nm; RT (min): 11.2) to obtain compound 6A (15.0 mg). LCMS: (ES, m / z) RT=0.87 min, m / z=364 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.42 (m, 2H), 7.28 - 7.20 (m, 2H), 5.77 (d, J = 8.2 Hz, 1H), 3.85 (m, J = 11.7 Hz, 1H), 3.79 - 3.54 (m, 4H), 2.46 (s, 1H), 2.26 (t, J = 11.9 Hz, 1H), 1.78 (d, J = 12.6 Hz, 1H), 1.71 - 1.63 (m, 1H), 1.10 - 0.96 (m, 4H), 0.87 (d, J = 6.5 Hz, 3H).

[0592] Compound 6B can be prepared according to this Example 3, using 4-chloro-N-ethylaniline as the aniline(iv) reagent and (3S,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine as the amine(i) reagent.

[0593] Compound 6C can be prepared according to Example 3, using 4-chloro-N-ethylaniline as the aniline(iv) reagent and (3R,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine as the amine(i) reagent.

[0594] Compound 6D can be prepared according to Example 3, using 4-chloro-N-ethylaniline as the aniline(iv) reagent and (3S,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine as the amine(i) reagent. Examples 4.1-(4-(difluoromethoxy)phenyl)-1-methyl-3-((1R,4R,5S)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 42'*), 1-(4-(difluoromethoxy)phenyl)-1-methyl-3-((1S,4S,5R)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 42''*), and compounds 42A*, 42B*, 42C*, and 42D* Scheme 4A. [ka] Scheme 4B. [ka] Scheme 4C. [ka] Scheme 4D. [ka]

[0595] Example 4 follows Protocol B. Step 1: In a 20 mL vial, tert-butyl 2-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 2.66 mmol, 1 equivalent) and 2-iodooxybenzoic acid (IBX) (2240 ​​mg, 7.98 mmol, 3 equivalents) were added in dimethyl sulfoxide (DMSO) (7 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 hours. The reaction was monitored by LC-MS until completion. The reaction was repeated 24 times, the batches were combined, and volatiles were removed under reduced pressure. Next, the residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, acetonitrile (MeCN) in water, 30%-40% gradient over 10 minutes, detector, UV 254 nm) to obtain tert-butyl 4-oxo-8-azabicyclo[3.2.1]octo-2-ene-8-carboxylate (6 g, yield 41%). LCMS: (ES, m / z) RT=0.77 min, m / z=168.1 [M+H] + .

[0596] Step 2: To a stirred solution of tert-butyl 4-oxo-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate (1000 mg, 4.47 mmol, 1 equivalent) in tetrahydrofuran (15 mL), lithium dimethylcuprete (Me2CuLi) (0.5 M in Et2O, 18 mL, 9 mmol, 2 equivalents) was added dropwise under a nitrogen atmosphere at -78°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water at room temperature (10 mL). The resulting mixture was extracted with ethyl acetate (siRNA) (2 × 50 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous sodium SiO4. After filtration, the filtrate was concentrated under reduced pressure. The reaction was repeated five times, and the batches were combined for purification by reverse-phase flash chromatography (C18 silica gel; mobile phase, acetonitrile (MeCN) in water, 45%–55% gradient over 10 minutes; detector, UV 254 nm) to obtain an isomer mixture of tert-butyl 2-methyl-4-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (4.0 g, yield 63%) (cis-4-Me / N-bridged head, assumed). LCMS: (ES, m / z) RT = 0.87 min, m / z = 184.2 [M + H] + .

[0597] Step 3: A solution of isomers of tert-butyl 2-methyl-4-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (trans Me-bridged head, assumed) (1 g, 4.18 mmol, 1 equivalent) and benzylamine (900 mg, 8.37 mmol, 2 equivalents) in methanol (7 mL) was stirred at 60°C for 16 hours. NaBH3CN (790 mg, 12.5 mmol, 3 equivalents) was added to the mixture at 0°C. The resulting mixture was stirred for a further 1 hour at 60°C. The reaction was monitored by LC-MS. The reaction was quenched with water at room temperature (3 mL). The resulting mixture was extracted with ELISA (2 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The reaction was repeated three times, and the batches were combined for purification by silica gel column chromatography elution with dichloromethane / petroleum ether (1:1) to obtain a mixture of isomers of tert-butyl 2-(benzylamino)-4-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (cis-4-Me / N-bridged head, assumed) (3g, yield 55%). LCMS: (ES, m / z) RT=0.71 min, m / z=331.2 [M+H] + .

[0598] Step 4: Benzyl bromide (2330 mg, 13.61 mmol, 1.50 equivalents) was added at room temperature to a stirred solution of isomers of tert-butyl(2-(benzylamino)-4-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (cis-4-Me / N-crosslinked head, assumed)) (3 g, 9.07 mmol, 1 equivalent) and K2CO3 (3160 mg, 22.7 mmol, 2.5 equivalents) in acetonitrile (30 mL). The resulting mixture was stirred at 80 °C for 5 hours. The reaction was monitored by LC-MS. The reaction was quenched with water at room temperature (10 mL). The resulting mixture was then acetic acid Extraction was performed with ethyl(siRNA) (2 × 50 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with dichloromethane / petroleum ether (1:2) to obtain a mixture of isomers of tert-butyl(2-(dibenzylamino)-4-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (cis-4-Me / N-bridged head, assumed)) (3.5 g, yield 92%). LCMS: (ES, m / z) RT = 0.80 min, m / z = 421.2 [M + H] + .

[0599] Step 5: In a 100 mL round-bottom flask, tert-butyl(2-(dibenzylamino)-4-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (cis-4-Me / N-bridged head, assumed)) (3.5 g, 8.32 mmol, 1 equivalent) and an isomer mixture of HCl (gas) (4M) in 1,4-dioxane (30 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure to obtain a crude isomer mixture of N,N-dibenzyl-4-methyl-8-azabicyclo[3.2.1]octane-2-amine (cis-4-Me / N-bridged head, assumed), which was used directly in the next step without purification. LC-MS: (ES, m / z) RT = 0.52 min, m / z = 321.0 [M + H] + .

[0600] Step 6: N,N-dibenzyl-4-methyl-8-azabicyclo[3.2.1]octane-2-amine (3 g, 9.36 mmol, 1 equivalent), cyanogen bromide (1.98 g, 18.7 mmol, 2 equivalents), K2CO3 (3.91 g, 28.1 mmol, 3 equivalents), and acetonitrile (30 mL) were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at 80°C for 2 hours. The reaction was monitored by LC-MS. The reaction was quenched with water at room temperature (10 mL). The resulting mixture was extracted with ethyl acetate (RINKAN) (3 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude isomer mixture of 2-(dibenzylamino)-4-methyl-8-azabicyclo[3.2.1]octane-8-carbonitrile (with a assumed cis-4-Me / N crosslinked head), which was used directly in the next step without purification. LCMS: (ES, m / z) RT = 0.78 min, m / z = 346.0 [M + H] + .

[0601] Step 7: A mixture of isomers of 2-(dibenzylamino)-4-methyl-8-azabicyclo[3.2.1]octane-8-carbonitrile (cis-4-Me / N-bridged head, assumed) (2.30 g, 6.65 mmol, 1 equivalent), dibutyltin oxide (1.66 g, 6.65 mmol, 1 equivalent), trimethylsilyl azide (2.30 g, 20.0 mmol, 3 equivalents), and dimethylformamide (DMF) (20 mL) was added to a 40 mL vial at room temperature. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LC-MS. The residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, acetonitrile in water (0.1% trifluoroacetic acid), gradient of 30% to 50% over 10 min; detector, UV 254 nm) to obtain a mixture of isomers of N,N-dibenzyl-4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-amine (cis-4-Me / N-bridged head, assumed) (2.10 g, yield 72%). LCMS: (ES, m / z) RT = 0.74 min, m / z = 389.0 [M + H]+ .

[0602] Step 8: In a 100 mL round-bottom flask, an isomer mixture of N,N-dibenzyl-4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-amine (cis-4-Me / N-bridged head, assumed) (2 g, 5.14 mmol, 1 equivalent) was added in methanol (MeOH) (20 mL), and Pd / C (1.36 g, 10.28 mmol, 2 equivalents) and HCl (12 M) (0.5 mL) were added at room temperature. The resulting mixture was stirred for 6 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 × 25 mL). The filtrate was concentrated under reduced pressure to obtain a mixture of isomers of 4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo[3.2.1]octane-2-amine, HCl salt (cis-4-Me / N-bridged head, assumed) (1.20 g, 96% yield). LCMS: (ES, m / z) RT = 0.25 min, m / z = 209.0 [M + H] + .

[0603] Step 9: 4-(difluoromethoxy)aniline (1 g, 6.28 mmol, 1 equivalent), sodium methoxide (NaOMe) (1.02 g, 18.9 mmol, 3 equivalents), formaldehyde (HCHO) (40% in water, 1.26 g, 12.6 mmol, 2 equivalents), and methanol (MeOH) (20 mL) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 16 hours, and then NaBH4 (0.36 g, 9.43 mmol, 1.5 equivalents) was partially added at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. The reaction was quenched by adding water (20 mL) at 0°C. The aqueous layer was extracted with ethyl acetate (SiO) (3 × 10 mL). The resulting mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (6:1) to obtain 4-(difluoromethoxy)-N-methylaniline ("Aniline(iv) Reagent") (1 g, 92% yield). LCMS: (ES, m / z) RT=0.422 min, m / z=174 [M+H] + .

[0604] Step 10: 4-(difluoromethoxy)-N-methylaniline (1 g, 5.77 mmol, 1 equivalent), triethylamine (1.75 g, 17.32 mmol, 3 equivalents), and dichloromethane (DCM) (20 mL) were added to a 250 mL round-bottom flask at room temperature, followed by the dropwise addition of ClC(=O)OCCl3 (diphosgene) (1.71 g, 8.66 mmol, 1.5 equivalents) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (10:1) to obtain trichloromethyl N-[4-(difluoromethoxy)phenyl]-N-methylcarbamate (1 g, 52% yield).

[0605] Step 11: In a 25 mL round-bottom flask, a mixture of isomers of 4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo[3.2.1]octane-2-amine hydrochloride ("Amine(i) Reagent") (cis-4-Me / N-bridged head, assumed) (80 mg, 0.32 mmol, 1 equivalent), K2CO3 (135.53 mg, 0.98 mmol, 3 equivalents), and dimethylformamide (DMF) (2 mL) was added at room temperature. Then, trichloromethyl N-[4-(difluoromethoxy)phenyl]-N-methylcarbamate (164 mg, 0.49 mmol, 1.5 equivalents) in dimethylformamide (DMF) (1 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. The volatile components were removed under reduced pressure, and the residue was directly purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, acetonitrile in water (0.1% trifluoroacetic acid), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to obtain a mixture of isomers of compound 42'* and compound 42''* (cis-4-Me / N-bridged head, assumed) (50 mg, yield 38%). LCMS: (ES, m / z) RT = 0.622 min, m / z = 408 [M + H] + The stereochemistry was assigned arbitrarily.

[0606] Step 12: The crude product, a mixture of compound 42'* and compound 42''*, was purified by preparative HPLC (column: XBridge preparative OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile (MeCN); flow rate: 60 mL / min; gradient: 15% B to 25% B at 10 min; wavelength: 254 nm / 220 nm) to obtain a first eluted isomer mixture (cis at positions 2 and 4, assumed, RT(min): 9.5, 35 mg, yield 43%) and a second eluted isomer mixture (trans at positions 2 and 4, assumed, RT(min): 13.5, 15 mg, yield 19%). LCMS: (ES, m / z) RT=0.624 min, m / z=408 [M+H] + .

[0607] Step 13: The second eluted isomer mixture (assumed to be trans at positions 2 and 4) (15 mg) was purified by chiral preparative HPLC (column: CHIRAL ART cellulose-SC, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: ethanol (EtOH):dichloromethane (DCM) = 1:1; flow rate: 20 mL / min; gradient: 30%B~30%B in 10 mins; wavelength: 220 / 254 nm) to obtain compound 42A* (RT(min) = 7.54, 3.9 mg) and compound 42D* (RT(min) = 9.26, 5 mg), and their stereochemistry was arbitrarily assigned.

[0608] Compound 42A*:LCMS:(ES,m / z) RT=0.813 min, m / z=408[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.38 - 7.30 (m, 2H), 7.24 (d, J = 8.8 Hz, 2H), 6.87 (t, J = 73.9 Hz, 1H), 4.24 (d, J = 5.4 Hz, 1H), 4.13 - 4.03 (m, 2H), 3.26 (s, 3H), 2.00 - 1.86 (m, 2H), 1.83 - 1.74 (m, 1H), 1.74- 1.62 (m, 3H), 1.45 (dd, J = 13.6, 5.4 Hz, 1H), 1.12 (d, J = 7.0Hz, 3H).

[0609] Compound 42D*:LCMS:(ES,m / z) RT=0.808 min, m / z=408[M+H] + . 1H NMR (400 MHz,methanol-d4) δ 7.38 - 7.30 (m, 2H), 7.27 - 7.20 (m, 2H), 6.87 (t, J = 73.9 Hz, 1H), 4.24 (s, 1H), 4.09 (t, J = 8.9 Hz, 2H), 3.26 (d, J = 1.0 Hz, 3H), 2.01 - 1.86 (m, 2H), 1.85 - 1.76 (m, 1H), 1.74 - 1.62 (m, 3H), 1.45 (d, J = 13.6 Hz, 1H), 1.12 (d, J = 7.0 Hz, 3H).

[0610] Step 14: The first eluted isomer mixture (assumed to be cis at positions 2 and 4) (35 mg) was purified by chiral preparative HPLC (column: CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: ethanol (EtOH):dichloromethane (DCM) = 1:1; flow rate: 20 mL / min; gradient: 30% B to 30% B at 7.5 min; wavelength: 220 / 254 nm) to obtain compound 42B* (RT(min) = 4.73, 9.3 mg) and compound 42C* (RT(min) = 5.96, 11.6 mg), and their stereochemistry was arbitrarily assigned.

[0611] Compound 42B*:LCMS:(ES,m / z)RT=0.733 min, m / z=408[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.28 - 7.19 (m, 2H), 7.12 - 7.03 (m, 2H), 6.79 (t, J = 73.7 Hz, 1H), 4.26 (d, J = 4.5 Hz, 1H), 3.96 (s, 1H), 3.79 (t, J = 4.4 Hz, 1H), 3.23 (s, 3H), 2.13 (t, J = 6.2 Hz, 1H), 1.97 (d, J = 9.8 Hz, 2H), 1.82 (d, J = 12.3 Hz, 3H), 1.38 - 1.32 (m, 1H), 0.81 (d, J = 7.2 Hz, 3H).

[0612] Compound 42C*:LCMS:(ES,m / z) RT=0.730 min, m / z=408[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.28 - 7.19 (m, 2H), 7.12 - 7.03 (m, 2H), 6.79 (t, J = 73.7 Hz, 1H), 4.26 (s, 1H), 3.96 (s, 1H), 3.79 (s, 1H), 3.23 (d, J = 0.9 Hz, 3H), 2.13 (d, J = 15.1 Hz, 1H), 2.00 - 1.93 (m, 2H), 1.87 - 1.74 (m, 3H), 1.32 (d, J = 15.0 Hz, 1H), 0.81 (d, J = 7.3 Hz, 3H). Example 5.1-(4-(difluoromethoxy)-2-fluorophenyl)-1-ethyl-3-((1R,2R,4R,5S)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 65A*) and 1-(4-(difluoromethoxy)-2-fluorophenyl)-1-ethyl-3-((1S,2S,4S,5R)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 65D*) Scheme 6A. [ka] Scheme 6B. [ka]

[0613] Example 5 follows Protocol B. Step 1: 3-hydroxypyridine (50.0 g, 526 mmol, 1 equivalent), isopropanol (IPA) (500 mL), and benzyl bromide (BnBr) (96.2 g, 562 mmol, 1.07 equivalents) were added to a 1 L three-necked round-bottom flask at room temperature. The resulting mixture was stirred overnight at 80°C, and then concentrated under reduced pressure. The residue was purified by washing with ethyl acetate ( Depositphotos) (200 mL). The solid was collected and dried under vacuum. This yielded 1-benzyl-3-hydroxypyridine-1-ium bromide (135 g, 97% yield). LCMS: (ES, m / z): RT = 0.47 min, m / z = 186.1 [M + H] + .

[0614] Step 2: Triethylamine (NEt3) (14.2 g, 141 mmol, 1.50 equivalents) was added dropwise to a stirred solution of 1-benzyl-3-hydroxypyridine-1-bromide (25.0 g, 93.9 mmol, 1 equivalent), (ethensulfonyl)benzene (21.0 g, 125 mmol, 1.33 equivalents), and hydroquinone (207 mg, 1.88 mmol, 0.02 equivalents) in tetrahydrofuran (THF) (200 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight under a nitrogen atmosphere at 65 °C. The reaction was quenched by adding water at room temperature (300 mL). The aqueous layer was extracted with ethyl acetate (RINKAN) (3 × 200 mL). The organic phase was concentrated under reduced pressure, and the solid was precipitated. The precipitated solid was collected and washed with RINKAN (3 × 50 mL). This yielded a mixture of the expected (1R,5R,6S)-8-benzyl-6-(phenylsulfonyl)-8-azabicyclo[3.2.1]octa-3-en-2-one and the corresponding enantiomer (20 g, 60% yield). LCMS: (ES, m / z): RT=0.91 min, m / z=354.1 [M+H] + .

[0615] Step 3: To a stirred solution of the mixture from Step 2 (20 g, 56.6 mmol, 1 equivalent) in 200 mL of tetrahydrofuran (THF), lithium dimethylcopper (Me2CuLi) (0.5 M in diethyl ether (Et2O)) (169.8 mL, 84.88 mmol, 1.50 equivalents) was added dropwise under a nitrogen atmosphere at -78°C. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The reaction was quenched by adding water at 0°C (500 mL). The resulting mixture was extracted with ethyl acetate (RINKAN) (3 × 500 mL). The combined organic layers were washed with water (2 × 300 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of the assumed (1R,4R,5R,6S)-8-benzyl-4-methyl-6-(phenylsulfonyl)-8-azabicyclo[3.2.1]octan-2-one and the corresponding enantiomer (18.0 g, yield 86%). LCMS: (ES, m / z): RT = 1.01 min, m / z = 370.1 [M + H] + .

[0616] Step 4: In a 100 mL three-necked round-bottom flask, the mixture from Step 3 (2.58 g, 6.98 mmol, 1 equivalent), hydroxylamine hydrochloride (534 mg, 7.68 mmol, 1.1 equivalents), pyridine (1104 mg, 13.96 mmol, 2 equivalents), and ethanol (EtOH) (25.8 mL) was added at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (HCl) (3 × 100 mL). The combined organic layers were washed with water (2 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The solid was precipitated, and the precipitated solid was collected to obtain a mixture of the expected N-[(1R,4R,5R,6S)-6-(benzenesulfonyl)-8-benzyl-4-methyl-8-azabicyclo[3.2.1]octane-2-ylidene]hydroxylamine and the corresponding enantiomer (2.5 g, 93% yield). LCMS: (ES, m / z): RT = 0.78 min, m / z = 385.1 [M + H] + .

[0617] Step 5: A solution of the mixture from Step 4 (2.50 g, 6.50 mmol, 1 equivalent) in dimethylformamide (DMF) was treated with NaBH3CN (1.63 g, 26.0 mmol, 4 equivalents) and sodium bisulfate (2.34 g, 19.5 mmol, 3.00 equivalents) at room temperature for 5 minutes, followed by the partial addition of molybdenum pentachloride (0.89 g, 3.25 mmol, 0.5 equivalents) at room temperature. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The reaction was quenched by the addition of saturated NaHCO3 (aqueous solution) (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (SiO) (3 × 100 mL). The combined organic layers were washed with water (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a mixture of the expected (1R,2R,4R,5R,6S)-8-benzyl-4-methyl-6-(phenylsulfonyl)-8-azabicyclo[3.2.1]octane-2-amine and the corresponding enantiomer (1.80 g, 75% yield). LCMS: (ES, m / z): RT=0.65 min, m / z=371.1 [M+H] + .

[0618] Step 6: The mixture from Step 5 (1 g, 2.69 mmol, 1 equivalent) and magnesium chips (treated with 0.5% HCl) (0.52 g, 22 mmol, 7.9 equivalents) were mixed in methanol (MeOH) (15 mL) and stirred overnight at room temperature. Acetic acid (AcOH) (0.66 mL) and H2O (10 mL) were added to the mixture at room temperature. The resulting mixture was stirred for a further 1 hour at room temperature. The reaction was quenched by adding saturated NaOH (aqueous solution) (5 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (SiO) (3 × 10 mL), the combined organic layer was washed with water (3 × 10 mL), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of the assumed (1R,2R,4R,5S)-8-benzyl-4-methyl-8-azabicyclo[3.2.1]octane-2-amine and the corresponding enantiomer (700 mg, yield 84%). LCMS: (ES, m / z): RT = 0.34 min, m / z = 231.1 [M + H] + .

[0619] Step 7: The mixture from Step 6 (700 mg, 3.03 mmol, 1.00 equivalent), methanol (MeOH) (3 mL), and ditert-butyl dicarbonate (Boc2O) (796 mg, 3.64 mmol, 1.20 equivalent) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (5:1) to obtain a mixture of the expected tert-butyl ((1R,2R,4R,5S)-8-benzyl-4-methyl-8-azabicyclo[3.2.1]octan-2-yl) carbamate and the corresponding enantiomer (800 mg, yield 80%). LCMS: (ES, m / z): RT = 0.62 min, m / z = 331.1 [M + H] + .

[0620] Step 8: To a stirred solution of the mixture from Step 7 (4.30 g, 13.0 mmol, 1 equivalent) in isopropanol (i-PrOH) (50 mL), Pd / C (wet, 10% carbon, 2.76 g) was added at room temperature. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The resulting mixture was filtered, and the filtrate cake was washed with methanol MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure to obtain a mixture of the expected tert-butyl ((1R,2R,4R,5S)-4-methyl-8-azabicyclo[3.2.1]octan-2-yl) carbamate and the corresponding enantiomer (2.7 g, 86% yield). LCMS: (ES, m / z): RT = 0.50 min, m / z = 241.2 [M + H] + .

[0621] Step 9: To a stirred solution of the mixture from Step 8 (2.70 g, 11.2 mmol, 1 equivalent) and K2CO3 (4.69 g, 33.7 mmol, 3.00 equivalent) in acetonitrile (30 mL), cyanogen bromide (4.76 g, 44.9 mmol, 4.00 equivalent) was added at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. The reaction was quenched with water at room temperature (50 mL). The resulting mixture was extracted with ethyl acetate (SiO) (2 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of the expected tert-butyl((1R,2R,4R,5S)-8-cyano-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (2.7 g, 91% yield). LCMS: (ES, m / z): RT = 0.66 min, m / z = 266.2 [M + H] + .

[0622] Step 10: Trimethylsilyl azide (1.12 g, 9.79 mmol, 2 equivalents) was added at room temperature to a stirred solution of the mixture from Step 9 (1.30 g, 4.89 mmol, 1 equivalent) and dibutyltin oxide (Bu2SnO) (2.43 g, 9.79 mmol, 2 equivalents) in dimethylformamide (DMF) (13 mL). The resulting mixture was stirred at 120 °C for 2 hours. The residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 30%-50% gradient over 10 min; detector, UV254 / 220 nm) to obtain a mixture of the assumed tert-butyl((1R,2R,4R,5S)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl) carbamate and the corresponding enantiomer (0.90 g, yield 60%). LCMS: (ES, m / z): RT=0.67 min, m / z=309.1 [M+H] + .

[0623] Step 11: The mixture from Step 10 (0.90 g, 2.9 mmol, 1.0 equivalent) and HCl (gas) in 1,4-dioxane (4 M, 10.0 mL) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain a mixture of the expected (1R,2R,4R,5S)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octane-2-amine hydrochloride (RRRS-isomer) and (1S,2S,4S,5R)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octane-2-amine hydrochloride (SSSR-isomer) (0.80 g, 95% yield), which are collectively referred to as "amine(i) reagent". LCMS:(ES,m / z):RT=0.15 min, m / z=209.1[M+H] + .

[0624] Step 12: 1-Bromo-4-(difluoromethoxy)-2-fluorobenzene (1g, 4.15 mmol, 1 equivalent), tert-butylcarbamate (972 mg, 8.30 mmol, 2 equivalents), dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (XPhos) (396 mg, 0.830 mmol, 0.2 equivalents), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd A mixture of G3 (350 mg, 0.42 mmol, 0.10 equivalents) and Cs2CO3 (4.06 g, 12.5 mmol, 3.00 equivalents) in dioxane (10 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction was quenched by adding water at room temperature (50 mL). The resulting mixture was extracted with ethyl acetate ( Depositphotos) (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (5:1) to obtain tert-butyl N-[4-(difluoromethoxy)-2-fluorophenyl]carbamate (930 mg, yield 77%). LCMS: (ES, m / z): RT = 0.95 min, m / z = 276.0 [MH] - .

[0625] Step 13: In a 40 mL vial, tert-butyl N-[4-(difluoromethoxy)-2-fluorophenyl]carbamate (800 mg, 2.89 mmol, 1 equivalent) and tetrahydrofuran (THF) (9 mL) were added at room temperature. NaH (60% dispersion in mineral oil, 139 mg, 5.77 mmol, 2 equivalents) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 0°C for a further 30 minutes. Ethyl iodide (675 mg, 4.33 mmol, 1.5 equivalents) was added to the mixture at 0°C. The resulting mixture was stirred at room temperature for a further 1 hour. The reaction was quenched with saturated NH4Cl (aqueous solution) (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (RINKAN) (3 × 250 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to obtain tert-butyl N-[4-(difluoromethoxy)-2-fluorophenyl]-N-ethylcarbamate (700 mg, yield 76%). LCMS: (ES, m / z): RT=1.02 min, m / z=306.1 [M+H] + .

[0626] Step 14: In a 20 mL vial, tert-butyl N-[4-(difluoromethoxy)-2-fluorophenyl]-N-ethyl carbamate (600 mg, 1.97 mmol, 1 equivalent) and HCl (gas) in 1,4-dioxane (4 M, 7 mL) were added at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 4-(difluoromethoxy)-N-ethylaniline hydrochloride ("Aniline(iv) Reagent") (350 mg, yield 92%). LCMS: (ES, m / z): RT = 0.89 min, m / z = 206.1 [M + H] + .

[0627] Step 15: 4-(difluoromethoxy)-N-ethylaniline hydrochloride (300 mg, 1.60 mmol, 1 equivalent), triethylamine (TEA) (324 mg, 3.21 mmol, 2 equivalents), and dichloromethane (DCM) (3 mL) were added to a 20 mL vial at room temperature. Trichloromethylcarbonochloride (476 mg, 2.41 mmol, 1.5 equivalents) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at room temperature for a further 1 hour. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (RINKAN) (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to obtain trichloromethyl N-[4-(difluoromethoxy)-2-fluorophenyl]-N-ethylcarbamate (300 mg, 50% yield). LCMS: (ES, m / z): RT=0.99 min, m / z=366.1 [M+H] + .

[0628] Step 16: Trichloromethyl N-[4-(difluoromethoxy)-2-fluorophenyl]-N-ethyl carbamate (200 mg, 0.55 mmol, 1 equivalent), the "Amine(i) Reagent" from Step 11 (200 mg, 0.82 mmol, 1.50 equivalents), diisopropylethylamine (DIEA) (353 mg, 2.73 mmol, 5 equivalents), and acetonitrile (4 mL) were added to a 20 mL vial at room temperature for 1 hour. The reaction was monitored by LC-MS. The reaction was quenched by adding water at room temperature (30 mL). The resulting mixture was extracted with ethyl acetate ( Depositphotos) (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue (150 mg, 90% purity), which was then subjected to preparative HPLC (XBridge preparative OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min, gradient: 25% B to 35% over 10 minutes). Purified by (B; wavelength: 254 / 220 nm; RT (min): 7.28), a mixture (100 mg) of 1-(4-(difluoromethoxy)-2-fluorophenyl)-1-ethyl-3-((1R,2R,4R,5S)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 65A*) and 1-(4-(difluoromethoxy)-2-fluorophenyl)-1-ethyl-3-((1S,2S,4S,5R)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 65D*) was obtained. LCMS: (ES, m / z): RT = 0.71 min, m / z = 440.1 [M + H] + .

[0629] Step 17: The mixture from Step 16 (100 mg, 97% purity) was purified by chiral HPLC (CHIRALPAK IC, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% TFA), mobile phase B: ethanol:dichloromethane = 1:1; flow rate: 20 mL / min; gradient: 25% B~25% B in 15 min; wavelength: 220 / 254 nm) to obtain compound 65A* (31.7 mg, RT(min): 9.32) as the first elution peak and compound 65D* (33.1 mg, RT(min): 12.57) as the second elution peak. Stereochemistry was arbitrarily assigned.

[0630] Compound 65A*:LCMS:(ES,m / z):RT=0.83 min, m / z=440.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.12 (m, 3H), 7.10 - 7.02 (m, 1H), 5.82 (d, J = 7.6 Hz, 1H), 4.27 - 4.16 (m, 1H), 4.04 - 3.88 (m, 2H), 3.63 - 3.46 (m, 2H), 1.91 - 1.60 (m, 4H), 1.58 - 1.38 (m, 2H), 1.32 - 1.17 (m, 1H), 1.15 - 0.92 (m, 6H).

[0631] Compound 65D*:LCMS:(ES,m / z):RT=0.83 min, m / z=440.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.14 (m, 3H), 7.10 - 7.03 (m, 1H), 5.82 (d, J = 7.6 Hz, 1H), 4.28 - 4.17 (m, 1H), 4.03 - 3.88 (m, 2H), 3.61 - 3.45 (m, 2H), 1.88 - 1.60 (m, 4H), 1.59 - 1.41 (m, 2H), 1.32 - 1.18 (m, 1H), 1.11 - 0.92 (m, 6H). Example 6.1-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-methyl-3-((1R,2R,4R,5S)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 56A*) and 1-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-methyl-3-((1S,2S,4S,5R)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (compound 56D*) [ka]

[0632] Example 6 follows Protocol B. Step 1: In a 500 mL round-bottom flask, add 1,4-dioxane (100 mL), 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (10.0 g, 38.6 mmol, 1 equivalent), tert-butylcarbamate (6.78 g, 57.9 mmol, 1.5 equivalents), and dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl [L-2-yl]phosphane (XPhos) (3.68 g, 7.72 mmol, 0.2 equivalents), Cs2CO3 (37.74 g, 115.83 mmol, 3 equivalents), and (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) (3.27 g, 3.86 mmol, 0.1 equivalents) were added at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LC-MS, quenched by adding water (200 mL) at room temperature, and the resulting mixture was extracted with ethyl acetate (siRNA) (3 × 200 mL). The combined organic layers were washed with water (2 × 200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, CH₃CN in water, gradient from 0% to 100% over 30 minutes; detector, UV220 / 254 nm) to obtain tert-butyl N-[2-fluoro-4-(trifluoromethoxy)phenyl]carbamate (8 g, yield 70%). LCMS: (ES, m / z): RT = 0.965 min, m / z = 296.1 [M + H] + .

[0633] Step 2: To a solution of tert-butyl N-[2-fluoro-4-(trifluoromethoxy)phenyl]carbamate (8.00 g, 27.07 mmol, 1 equivalent) in tetrahydrofuran (THF) (80 mL), NaH (60% of mineral oil, 3.25 g, 81.21 mmol, 3 equivalents) was added in batch at 0°C. The resulting mixture was warmed to room temperature and stirred for 30 minutes, then methyl iodide (7.69 g, 54.1 mmol, 2 equivalents) was added. The resulting mixture was stirred at room temperature for 1 hour, and its progress was monitored by LC-MS. The reaction was quenched by adding water at room temperature (300 mL), and the resulting mixture was extracted with methylene chloride (3 × 300 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, CH3CN in water, gradient from 0% to 100% over 30 minutes; detector, UV254 / 220nm) to obtain tert-butyl N-[2-fluoro-4-(trifluoromethoxy)phenyl]-N-methylcarbamate (6.5 g, yield 74%). LCMS: (ES, m / z): RT=0.954 min, m / z=310.1 [M+H] + .

[0634] Step 3: In a 250 mL round-bottom flask, tert-butyl N-[2-fluoro-4-(trifluoromethoxy)phenyl]-N-methylcarbamate (6.50 g, 22.63 mmol, 1.00 equivalent) and an anhydrous solution of HCl (4 M, 70.00 mL) in 1,4-dioxane were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS, and the mixture was concentrated under reduced pressure to obtain 2-fluoro-N-methyl-4-(trifluoromethoxy)aniline hydrochloride (5.5 g, 80% yield). LC-MS: (ES, m / z): RT = 0.872 min, m / z = 210.1 [M + H] + .

[0635] Step 4: 2-Fluoro-N-methyl-4-(trifluoromethoxy)aniline hydrochloride (5.00 g, 23.90 mmol, 1 equivalent), dichloromethane (50 mL), and diisopropylethylamine (9.27 g, 71.70 mmol, 3 equivalents) were added to a 250 mL round-bottom flask at room temperature. Diphosgene (5.68 g, 28.68 mmol, 1.2 equivalents) was added at 0°C, and the resulting mixture was warmed and stirred for 1 hour under a nitrogen atmosphere at room temperature. The reaction was monitored by LC-MS, quenched by adding water (300 mL) at room temperature, and extracted with ethyl acetate (siRNA) (3 × 200 mL). The combined organic layers were washed with water (2 × 200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate = 1:1 to obtain trichloromethyl N-[2-fluoro-4-(trifluoromethoxy)phenyl]-N-methylcarbamate (3.5 g, yield 40%) ("Aniline(iv) Reagent"). LCMS: (ES, m / z): RT = 0.884 min, m / z = 367.1 [M + H] + .

[0636] Step 5: In a 250 mL round-bottom flask, add trichloromethyl N-[2-fluoro-4-(trifluoromethoxy)phenyl]-N-methylcarbamate ("Aniline (iv) Reagent") (4.80 g, 12.95 mmol, 1 equivalent), and the expected (1R,2R,4R,5S)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octane-2-amine hydrochloride (RRRS-Aniline). A mixture of (SSSR-isomer) and (1S,2S,4S,5R)-4-methyl-8-(1H-tetrazole-5-yl)-8-azabicyclo[3.2.1]octane-2-amine hydrochloride (SSSR-isomer) (product of Example 5, step 11) (5.40 g, 25.91 mmol, 2 equivalents), acetonitrile (50 mL), and diisopropylethylamine (5.02 g, 38.86 mmol, 3 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then quenched by adding water at room temperature (100 mL), and extracted with ethyl acetate (siRNA) (3 × 100 mL). The combined organic layers were washed with water (2 × 100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, CH3CN in water (0.1% trifluoroacetic acid), gradient from 0% to 100% over 30 minutes; detector, UV254 / 220nm) to obtain 1-[2-fluoro-4-(trifluoromethoxy)phenyl]-1-methyl-3-[(1R,2R,4R,5S)-4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo[3 A mixture of the expected compounds [2.1]octan-2-yl]urea trifluoroacetate (compound 56A*) and 1-[2-fluoro-4-(trifluoromethoxy)phenyl]-1-methyl-3-[(1S,2S,4S,5R)-4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl]urea trifluoroacetate (compound 56D*) (3.80 g, purity 80%) was obtained.This mixture was further purified by preparative HPLC (Xselect CSH C18 OBD column 30*150 mm; 5 μm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: methanol; flow rate: 25 mL / min; gradient: 56% B to 66% B at 10 min; wavelength: 254 / 220 nm; RT (min): 11) to obtain a purified mixture (2.20 g, yield 38%). LCMS: (ES, m / z): RT = 0.801 min, m / z = 444.1 [M + H]. + .

[0637] Step 6: The mixture from Step 5 (2.20 g, purity = 95%) is separated by preparative chiral HPLC (Chiral ART Cellulose-SC, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: ethanol:dichloromethane = 1:1; flow rate: 20 mL / min; gradient: isocratic 20; wavelength: 220 / 254 nm) and the first elution peak is assumed to be 1-[2-fluoro-4-(trifluoromethoxy)phenyl]-1-methyl-3-[(1R,2R,4R,5S)-4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo [3.2.1]octan-2-yl]urea (compound 56A*) (739.7 mg, yield 29%, RT(min) = 10.47) and 1-[2-fluoro-4-(trifluoromethoxy)phenyl]-1-methyl-3-[(1S,2S,4S,5R)-4-methyl-8-(1H-1,2,3,4-tetrazole-5-yl)-8-azabicyclo[3.2.1]octan-2-yl]urea (compound 56D*) (660.1 mg, yield 25%, RT(min) = 12.91), which is assumed to be the second elution peak. Stereochemistry was arbitrarily assigned.

[0638] Compound 56A*:LCMS:(ES,m / z):RT=1.629 min, m / z=444.1[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.52 (d, J = 8.8 Hz, 1H), 7.33 - 7.15 (m, 2H), 4.40 - 4.31 (m, 1H), 4.28 - 4.05 (m, 2H), 3.31 - 3.21 (m, 3H), 2.05 - 1.86 (m, 3H), 1.78 - 1.62 (m, 3H), 1.53 - 1.38 (m, 1H), 1.26- 1.07 (m, 3H).

[0639] Compound 56D*:LCMS:(ES,m / z):RT=1.629 min, m / z=444.1[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.52 (d, J = 8.8 Hz, 1H), 7.35 - 7.16 (m, 2H), 4.39 - 4.29 (m, 1H), 4.26- 4.08 (m, 2H), 3.31 - 3.23 (m, 3H), 2.03 - 1.82 (m, 3H), 1.77 - 1.61 (m, 3H), 1.52 - 1.43 (m, 1H), 1.21 - 1.05 (m, 3H).

[0640] The compounds provided in Table A below have been prepared, or may be prepared, according to the general procedures and examples described above. LC-MS data is provided for each compound prepared according to the procedures described. A dashed (--) row in Table A means that data was not obtained. "Rac-X" means a mixture of two or more stereoisomers, e.g., compounds X'X”, X”, X''”, XA, XB, XC, XD, XE, XF, XG, and / or XH, including the data provided in the assay methods section for the purposes of the examples. [Table 4-1] [Table 4-2] [Table 4-3] Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 Table 4-23 Table 4-24 Table 4-25 Table 4-26 Table 4-27 Table 4-28 Table 4-29 Table 4-30 Table 4-31 Table 4-32 Table 4-33 Table 4-34 Table 4-35 Table 4-36 Table 4-37 Table 4-38 Table 4-39 Table 4-40 Table 4-41 Table 4-42 Table 4-43 Table 4-44 Table 4-45 Table 4-46 Table 4-47 Table 4-48 Table 4-49 Table 4-50 Table 4-51 Table 4-52 Table 4-53 Table 4-54 Table 4-55 Table 4-56 Table 4-57 Table 4-58 Table 4-59 Table 4-60 Table 4-61 Table 4-62 Table 4-63 Table 4-64 Table 4-65 Table 4-66 Table 4-67 Table 4-68 Table 4-69 Table 4-70 Table 4-71 Table 4-72 Table 4-73 Table 4-74 Table 4-75 Table 4-76 Table 4-77 Table 4-78 Table 4-79 Table 4-80 Table 4-81 Table 4-82 Table 4-83 Table 4-84 Table 4-85 Table 4-86 Table 4-87 Table 4-88 Table 4-89 Table 4-90 Table 4-91 Table 4-92 Table 4-93 Table 4-94 Table 4-95 Table 4-96 Table 4-97 Table 4-98 Table 4-99 Table 4-100 Table 4-101 Table 4-102 Table 4-103 Table 4-104 Table 4-105 [Table 4-106] [Table 4-107] [Table 4-108] [Table 4-109] [Table 4-110] [Table 4-111]

[0641] Biological assay methods Scintillation proximity (SPA) NLRP3 assay The objective of this assay is to demonstrate that the test compound binds to the human NLRP3 protein by substituting 3H-MCC950, a selective inhibitor of NLRP3. Improved NLRP3 binding correlates with increased affinity for the NLRP3 protein, and consequently, with increased ability to inhibit its function.

[0642] The SPA experiment was performed using the total volume of 20 μL of assay buffer containing 20 mM HEPES pH 7.5, 150 mM NaCl, 5 mM MgCl2, 0.01% (v / v) Tween-20, 0.01% (w / v) bovine serum albumin (BSA), and 100 μM adenosine diphosphate (ADP). Human NLRP3 protein (350 nM) (see, e.g., Sharif et al., Nature (2019) 570:338-343, Hochheiser et al., Nature (2022) 604:184-189, Adreeva et al., Cell (2021) 184:6299-6312, Wang et al., J.Exp.Med. (2021) 219:e20211147) was incubated with various concentrations of the compound in a 5% dimethyl sulfoxide (DMSO) final solution in a white, half-area, 96-well OptiPlate (PerkinElmer No. 6002290) for 15 minutes at room temperature, after which a 125 nM final solution of 3H-MCC950 was added. After adding radiolabeled MCC950, the plate was incubated at room temperature for 60 minutes, and then 0.25 mg / ml of copper-coated polyvinyltoluene SPA beads (PerkinElmer number RPNQ0095) were added. The plate was then transferred to a microplate counter (PerkinElmer 2450 Microbeta) to collect binding data. The binding data was analyzed 6 hours after PVT bead addition, giving sufficient time to reach equilibrium. Specific binding was calculated from averaged overlaps by subtracting the signal from wells that did not contain the NLRP3 protein.

[0643] SPA NLRP3 IC 50 Assay results are provided in Table B. "A" activity = <1 μM, "B" activity = 1-10 μM, "C" activity => 10-50 μM, "D" activity => 50 μM-100 μM, and "E" activity => 100 μM. Human PBMC NLRP3 assay

[0644] The objective of this assay is to demonstrate whether the test compound can inhibit human NLRP3 function in cell lines.

[0645] Reagents: Human PBMC (normal): iX cell catalog number 10HU-003, RPMI 1640 medium containing GlutaMAX; ThermoFisher catalog number 61870127 (complete medium: 4.5 g / L D-glucose, 10% FBS, 100 mM NaPyr, 1% Pen / Strep, 10 mM HEPES, and 0.05 mM (registered trademark)-mercaptoethanol, assay medium: 4.5 g / L D-glucose, 100 mM NaPyr, 1% Pen / Strep, 10 mM HEPES, and 0.05 mM mercaptoethanol; 96-well V-bottom plate: Costar catalog number 3894, LPS (E. coli O26:B6): Prepared with Sigma catalog number L2654, 5 mg / mL preservative solution in PBS; ATP: Prepared with Sigma catalog number A6419, 250 mM preservative solution in 1 M HEPES (adjusted to pH 7.4).

[0646] Frozen PBMCs were rapidly thawed in a 37°C water bath for 2 minutes. The cells were then centrifuged at 1200 RPM for 5 minutes and resuspended in approximately 50 mL of fresh RPMI 1640 complete medium. Counting was performed using a hemocytometer, yielding 2.5 × 10⁶ cells. 5 The solution was adjusted to cells / mL. A V-shaped 96-well plate was prepared with 200 μL of PBMC (5 × 10¹⁶ cells per well). 4The cells were seeded in ) and incubated overnight at 37°C with 5% CO2. Next, assay medium containing 100 ng / ml LPS was prepared. The PBMCs were then centrifuged at 1,200 RPM for 5 minutes, the serum-containing medium was aspirated, and 150 μL / well of assay medium + LPS was immediately added. Assay medium without LPS was added to the untreated control wells. The cells were then primed with LPS at 37°C for 4 hours with 5% CO2. A 1000-fold concentration response curve (CRC) of the test compound in 100% DMSO was prepared. The CRC was then diluted 1:50 in assay medium, then further diluted 1:5-fold in assay medium, and finally obtained a 4-fold CRC in 0.4% DMSO / assay medium. Next, 50 μL / well of four times the amount of the test compound CRC or vehicle (0.4% DMSO / assay medium) was transferred to each well, and then incubated at 37°C for 30 minutes with 5% CO2. Cells were stimulated by adding 4 μL of 250 mM ATP at 37°C for 1 hour with 5% CO2, without further dilution (for a final concentration of 5 mM) using a 250 mM preservation solution prepared in 1 M Hepes. The plate was then centrifuged at 1200 RPM for 5 minutes, and 50 μL of medium was transferred to a clean 96-well preservation plate using a mesoscale platform for cytokine measurement and stored at -80°C until analysis. The compound was added 30 minutes before priming cells with LPS when it was necessary to quantify TNFα in a cytokine panel to confirm selectivity.

[0647] PBMC NLRP3 IC 50 Assay results are provided in Table B as measurements of cell potency. "A" activity = <0.01 μM, "B" activity = 0.01~0.1 μM, "C" activity => 0.1~0.5 μM, "D" activity => 0.5 μM. Human whole blood (hWB) NLRP3 assay

[0648] The objective of this assay is to demonstrate whether the test compound can inhibit human NLRP3 function in the whole blood system.

[0649] Human whole blood is collected from healthy volunteers after obtaining written informed consent. Blood is collected from volunteers using heparin lithium-coated tubes. The blood samples are distributed onto 96-well plates, using 90 μl per well.

[0650] Priming procedure: Priming was performed by adding 5 μl of LPS (O26:B6; Sigma L-2654) to a final concentration of 1 μg / ml in a humidified incubator with 5% CO2 at 37°C for 4.5 hours. Thirty minutes before NLRP3 activation, 5 μl of 20x compound solution or vehicle (2% dimethyl sulfoxide (DMSO)) was added to each well, and the plate was incubated on a shaker (450 rpm) in a humidified incubator with 5% CO2 at 37°C.

[0651] Alternative priming procedure: 30 minutes before LPS priming, 5 μl of 20x compound solution or vehicle (2% dimethyl sulfoxide (DMSO)) was added to each well, and the plate was incubated on a shaker (450 rpm) in a humidified incubator with 5% CO2 at 37°C. Priming was performed by adding 5 μl of LPS (O26:B6; Sigma L-2654) to a final concentration of 1 μg / ml in a humidified incubator with 5% CO2 at 37°C for 5 hours.

[0652] Next, activation is performed by adding 3.3 μl of 31X ATP solution per well. At the end of the 30-minute stimulation, the plate is centrifuged (800 g, 10 minutes, room temperature), and the plasma from each well is frozen at -80°C. The IL-1β levels in the supernatant are analyzed using a mesoscale detection assay (MSD K151TUK) according to the manufacturer's instructions.

[0653] There is no detectable difference between assay results using the priming procedure and assay results using the alternative priming procedure.

[0654] hWB NLRP3 IC 50 Assay results are provided in Table B as measurements of whole blood potency. "A" activity = <1 μM, "B" activity = 1-2 μM, "C" activity = >2-3 μM, "D" activity = >3 μM. Mouse whole blood (mWB) NLRP3 assay

[0655] The objective of this assay is to demonstrate whether the test compound can inhibit mouse NLRP3 function in the whole blood line.

[0656] Reagents: The following reagents were used: blood collection tubes (heparin); U-bottom 96-well tissue culture (Falcon 353077); LPS, ATP, and HBSS for compound dilution (Gibco 24020-117); and LPS, E. coli serotype O26:B6 (Sigma L-2654).

[0657] Mouse IL-1b MSD assay: Blood was collected from female CD1 mice (9-10 weeks old) by cardiac puncture. The blood was plated in 135 μL wells of a 96-well U-bottom plate. 7.5 μL of 20x LPS (20 μg / mL, final concentration 1 ug / mL) was added and mixed by gentle pipetting, and the mixture was incubated in a TC incubator for 5 hours. 20x compound or vehicle was added per 7.5 μL well and mixed by gentle pipetting. The compound was diluted 1 / 50 in HBSS and a 20x dilution curve was prepared in 2% DMSO. The mixture was incubated in a TC incubator for 30 minutes with shaking (450 rpm). 5 μl of 31x ATP (155 mM, final concentration 5 mM) was added and mixed by gentle pipetting. The mixture was incubated in a TC incubator for 30 minutes with shaking (450 rpm). The plate was centrifuged at 800 × g for 10 minutes to remove approximately 70 μL of plasma. Plasma was frozen if necessary. Mouse IL-1b was analyzed using the IL-1b MSD assay (K152TUK).

[0658] When it was necessary to quantify TNFα using a cytokine panel to confirm selectivity, the compound was added 30 minutes before priming the cells with LPS.

[0659] mWB NLRP3 IC 50 Assay results are provided in Table B as measurements of whole blood potency. "A" activity = <1 μM, "B" activity = 1-2 μM, "C" activity = >2-3 μM, "D" activity = >3 μM. Biological assay data

[0660] The various compounds described herein were tested according to the assays described above. Dashed lines (--) indicate that no data is available. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9]

[0661] Comparative Examples Compounds of formula (IB) containing the non-aromatic ring B described herein have been found to exhibit improved activity compared to compounds having a smaller (5-membered) ring at the corresponding ring B position. For example, PBMC ICs moving from Comparative Example A* (5-membered ring at the corresponding ring B position) to compound 2A (6-membered ring B) 50 See the data in Table C, which shows a >350-fold increase in titer, as measured by [method / function]. Larger rings, e.g., 7-membered ring B systems, are also well acceptable, for example, the binding activity (SPA IC) to move from compound 39A (6-membered ring B) to compound 11A* (7-membered ring B). 50 This compares a 5.9-fold increase to the previous figure.

[0662] Compounds of formula (IB) containing the non-aromatic ring B described herein have been found to exhibit improved activity compared to compounds having a phenyl ring at the corresponding ring B position. For example, PBMC IC2, which moves from Comparative Example B2 to Compound 2A. 50 When measured by [method], please refer to the data in Table C, which shows a >15-fold increase in potency.

[0663] For example, G1 is CR G1 And R G1 However, it is also perfectly acceptable to include an ortho substituent on ring A of a compound of formula (IB) that is a halo (e.g., fluoro or chloro). For example, compare the relatively similar efficacy of compound 2A without an ortho substituent with compound 66 containing an orthofluoro substituent, and also compare the relatively similar efficacy of compound 42A* without an ortho substituent with compound 57A* containing an orthofluoro substituent. Also, for example, compare the relatively similar efficacy of compound 5A* containing an ortho-fluoro substituent with compound 7A* containing an ortho-chloro substituent.

[0664] Various other permutations of equation (IB) on ring A, for example, R of ring A 1 However, if it is a halo, C1-haloalkyl, or -O(C1-haloalkyl), it is perfectly acceptable. For example, para-chloroR 1 Compound 5A* containing substituents and p-trifluoromethyl R 1Compound 13A* containing substituents and p-trifluoromethoxy R 1 We will compare its relatively similar efficacy with compound 24A* containing substituents. Also, for example, para-chloroR 1 Compound 4A* containing substituents and para-trifluoromethoxy R 1 We will also compare the relatively similar efficacy with compound 10A* containing substituents. Furthermore, for example, para-difluoromethoxy R 1 Compound 42A* containing substituents and para-trifluoromethoxy R 1 We will also compare its efficacy with that of compound 45A*, which contains substituents, as it is relatively similar.

[0665] Ethylene crosslinking groups on ring B have also been found to be sufficiently tolerable, for example, resulting in a more than 12-fold improvement in binding activity when transferring from compound 39A (without crosslinking group) to compound 45A* (SPA IC). 50 Compare them.

[0666] Additional structural motifs found in compounds of formula (IB) that improve activity include: (i) Free amino(NH) moiety directly bonded to ring B a. For example, the PBMC IC of comparative example C1 50 Data (The amino portion bonded to ring B is N-methyl, and the corresponding R 4 The position is H) and compound 2A (contains a free NH moiety directly bonded to ring B, R 4 Compared to (where the position is methyl), it showed a 40-fold improvement in potency. b. For example, the PBMC IC of comparative example C2 50 Data (The amino portion bonded to ring B is N-methyl, and the corresponding R 4 The position is also methyl) and compound 2A (contains a free NH moiety directly bonded to ring B, R 4 The position (methyl) also shows an improvement of more than 200 times in potency compared to, (ii)R 4 A substituted amino directly bonded to ring A at position a. For example, comparative example B1 (corresponding ring B is phenyl, and corresponding R 4Comparative Example B2 (where the substituent is H) (where the corresponding ring B is phenyl and the corresponding R) 4 The substituent is methyl) and the binding activity (SPA IC) moves to it. 50 ) compared to an improvement of more than 15 times, b. For example, compound 27A*(R 4 (is H) from compound 5A*(R 4 The binding activity (SPA IC) moves to methyl (SPA IC) 50 ) compared to an improvement of more than 19 times, c. Also, for example, R 4 Comparative Examples G, J1, and J2, which do not contain an amino group directly bonded to ring A at that position, are PBMC ICs. 50 Data, N-methyl R 4 Compared to compound 2A containing the substituent, it showed an increase in potency of more than 350 times for each comparison. d. For example, the corresponding NR 4 Comparative Example H of PBMC IC containing unsubstituted benzyl carbon at the position 50 Data, N-methyl R 4 Compared to compound 2A containing the substituent, it shows a 39-fold increase in potency. (iii) Presence of an unsubstituted tetrazolyl substituent bonded to the nitrogen ring atom of ring B a. For example, PBMC ICs of Comparative Example D1 and Comparative Example D2, each containing a phenyl ring at the corresponding unsubstituted tetrazolyl position. 50 The data compared to compound 2A, which contains an unsubstituted tetrazolyl substituent, showed increases in potency of over 146 times and 350 times, respectively. b. For example, PBMC IC of Comparative Example F containing an N-methylated tetrazolyl ring 50 The data shows a 58-fold increase in potency compared to compound 2A, which contains an unsubstituted tetrazolyl substituent.

[0667] Furthermore, non-aromatic ring B and non-hydrogen R described herein 4 Compounds of formula (IB) containing the group include the phenyl ring corresponding to the B position of the ring, and the corresponding R 4Compared to compounds with hydrogen atoms at the position, this has been found to result in improved activity. For example, SPA and PBMC IC in Table C. 50 Comparing the data, we see an improvement of more than 19 times in binding activity and more than 18 times in potency from Comparative Example B1 to Compound 2A, as well as an improvement of more than 1950 times in binding activity and more than 700 times in potency from Comparative Example B1 to Compound 4A*. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12]

[0668] Other Embodiments A claim or statement containing “or” between one or more elements of a group is considered satisfied if one, two or more, or all of the group elements are present, used, or otherwise related in a given product or process, unless the opposite is shown or otherwise evident from the context. This disclosure includes embodiments in which exactly one member of the group is present, used, or otherwise related in a given product or process. This disclosure includes embodiments in which two or more, or all, of the group members are present, used, or otherwise related in a given product or process.

[0669] Furthermore, this disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims or embodiments are introduced into another claim or embodiment. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where this disclosure enumerates elements presented as a list, for example in Markush group format, each subgroup of elements is also disclosed, and any element(s) may be removed from a group. Any variable (e.g., R-base) may appear two or more times (e.g., two or more times) within a given Markush structure, and that variable may be selected from a given list of two or more elements, and it should be further understood that, unless otherwise stated or understood in the context of this disclosure, the variable (e.g., R-base) in each repeated occurrence (e.g., two or more times) is independent of each other and is selected independently from that given list.

[0670] Furthermore, where the Disclosure, or any aspect thereof, is generally referred to as including certain elements and / or features, it should be understood that certain embodiments of the Disclosure, or aspects thereof, also consist of, or essentially consist of, such elements and / or features. For the sake of simplicity, such embodiments are not specifically described herein. It should also be noted that the terms “comprising” and “containing” are intended to be open and allow for the inclusion of additional elements or processes. Where a range is given, endpoints are understood to be included. Moreover, unless otherwise indicated or otherwise evident from the context and understanding of those skilled in the art, values ​​expressed as a range may, in different embodiments of the Disclosure, assume any specific value or subrange within the described range, up to one-tenth of the lower limit unit of the range, unless the context otherwise explicitly indicates.

[0671] This application refers to various published patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any of the incorporated references and this disclosure, this disclosure shall prevail. Furthermore, any particular embodiment of this disclosure that constitutes prior art may be expressly excluded from any one or more claims. Such embodiments may be excluded even if no exception is expressly stated herein, as they are considered to be known to those skilled in the art. Any particular embodiment of this disclosure may be excluded from any claim for any reason, whether or not it relates to the existence of prior art.

[0672] The scope of these embodiments described herein is not intended to be limited to the above description, but also includes the claims set forth in the appended patent claims. Those skilled in the art will understand that various changes and modifications to this description can be made without departing from the spirit or scope of this disclosure, as defined in the following claims.

Claims

1. Compound of formula (I-B): 【Chemistry 1】 or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, Ring A is a ring system, G １ is CR Ｇ１ or N, and G ２ is CR Ｇ２ or N, and G ３ is CR Ｇ３ or N, and G ４ is CR Ｇ４ or N, provided that １ G ２ G ３ and G ４ no more than two of them are N R １ But, hello, C １－６ Alkyl, C １－６ Haloalkyl, -OR Ｇ５ ,-SR Ｇ５ , -N(R Ｇ５ ) ２ , C ３ -C ４ Carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl and the heterocyclyl independently have 0, 1, 2, or 3 halos, C １－６ Alkyl, C １－６ Haloalkyl, -OR Ｇ５ ,-SR Ｇ５ , or -N(R Ｇ５ ) ２ It is replaced by, or R １ and G ２ However, they are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R atoms. Ｇ７ They independently form a five-membered heteroaryl ring, R Ｇ１ , R Ｇ２ , R Ｇ３ , and R Ｇ４ However, each is independent of hydrogen, halo, and C. １－６ Alkyl, C １－６ Haloalkyl and -OR Ｇ６ Selected from the group consisting of, R Ｇ５ and R Ｇ６ However, each independently, hydrogen, C １－６ Alkyl, or C １－６ It is a haloalkyl, R Ｇ７ Each of these cases is independent of Halo, C １－６ Alkyl, C １－６ Haloalkyl, -OR Ｇ５ ,-SR Ｇ５ , and -N(R Ｇ５ ) ２ And, Ring B is a ring system, n is 0 or 1, p is 1 or 2, m is 0, 1, 2, or 3, R ２ａ and R ２ｂ Each of these cases independently involved hydrogen, halo, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３ -C ４ A carbocyclyl or a 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is independently substituted with 0, 1, 2, or 3 halos, or R ２ａ and R ２ｂ The following are linked together and C is independently replaced by 0, 1, 2, or 3 halos. ３ Forms carbocyclyl, R ３ Each of these cases is independent of Halo, C １－６ Alkyl or C １－６ It is either a haloalkyl or has two R's. ３ The bases are linked together, C １－３ Alkylene crosslinking group or C １－３ Forms a haloalkylene crosslinking group, R ４ However, hydrogen, C １－３ Alkyl, C ３ -C ４ Carbocyclyl, or C ３ -C ４ Carbocyclyl-C １－３ It is alkyl-, and the alkyl and the carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos, and the carbocyclyl is further independently substituted with 0, 1, or 2 C １－３ Alkyl or C １－３ The compound, or a pharmaceutically acceptable salt or tautomer thereof, that is substituted with a haloalkyl group.

2. The compound in question is one of the following formulas: 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt or tautomer thereof.

3. The compound in question is one of the following formulas: 【Transformation 3】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or tautomer thereof.

4. The compound in question is one of the following formulas: 【Chemistry 4】 And in the formula, L is C １－３ Alkylene crosslinking group or C １－３ A compound according to claim 1, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

5. The compound in question is one of the following formulas: 【Chemistry 5-1】 【Chemistry 5-2】 The compound according to claim 4, or a pharmaceutically acceptable salt or tautomer thereof.

6. R ４ However, the compound described in any one of claims 1-5, which is not hydrogen, or a pharmaceutically acceptable salt or tautomer thereof.

7. Ring A is a ring system, and in the formula, R １ But, hello, C １－６ Haloalkyl, -OR Ｇ５ , or C ３ -C ４ It is a carbocyclyl, and the carbocyclyl independently contains 0, 1, 2, or 3 halos, C １－６ Alkyl, C １－６ Haloalkyl, -OR Ｇ５ ,-SR Ｇ５ , or -N(R Ｇ５ ) ２ It is replaced by, or R １ and G ２ However, they are linked together with the atoms they bond to, resulting in 0, 1, 2, or 3 R atoms. Ｇ７ They independently form a five-membered heteroaryl ring, R Ｇ１ 、R Ｇ２ 、R Ｇ３ 、and R 又是R Ｇ４ is each independently selected from the group consisting of hydrogen, halo, and -OR Ｇ６ and R Ｇ５ and R Ｇ６ each independently is hydrogen or a C １－６ haloalkyl, R Ｇ７ Each of these cases is independent of Halo, C １－６ Alkyl, C １－６ Haloalkyl, -OR Ｇ５ ,-SR Ｇ５ , and -N(R Ｇ５ ) ２ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or tautomer thereof.

8. Ring A is a ring system, and in the formula, R １ However, Cl, cyclopropyl, CF ３ CF ２ H, OCF ３ , or OCF ２ Is it H? or R １ and G ２ However, they are linked together with the atoms they bond to to form oxazoles, isoxazoles, pyrazoles, or imidazoles. R Ｇ１ , R Ｇ２ , R Ｇ３ , and R Ｇ４ However, each independently, H, F, Cl, OH, and OCF ２ A compound according to claim 7, selected from the group consisting of H, or a pharmaceutically acceptable salt or tautomer thereof.

9. Ring B is a ring system, and in the formula, R ２ａ and R ２ｂ Each of these cases independently involved hydrogen or C １－６ It is alkyl, Two R's ３ The bases are connected, C １－３ Forms alkylene crosslinking groups, R ４ However, C １－３ Alkyl, C ３ -C ４ Carbocyclyl, or C ３ -C ４ Carbocyclyl-C １－３ A compound according to any one of claims 1 to 8, wherein the alkyl and the carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halos, or a pharmaceutically acceptable salt or tautomer thereof.

10. Ring B is a ring system, and in the formula, R ２ａ and R ２ｂ Each of these cases is independently hydrogen or methyl, Two R's ３ The groups are linked together to form an ethylene crosslinking group. R ４ The compound according to claim 9, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is methyl, ethyl, cyclopropyl, or cyclopropyl-methyl.

11. G １ However, CR Ｇ１ G ２ However, CR Ｇ２ G ３ However, CR Ｇ３ G ４ However, CR Ｇ４ Is it, G １ However, N is G ２ However, CR Ｇ２ G ３ However, CR Ｇ３ G ４ However, CR Ｇ４ Is it, G １ However, CR Ｇ１ G ２ However, N is G ３ However, CR Ｇ３ G ４ However, CR Ｇ４ Is it, G １ However, CR Ｇ１ G ２ However, CR Ｇ２ G ３ However, N is G ４ However, CR Ｇ４ Is it, G １ However, CR Ｇ１ G ２ However, CR Ｇ２ G ３ However, CR Ｇ３ G ４ But is it N? G １ However, N is G ２ However, CR Ｇ２ G ３ However, CR Ｇ３ G ４ But is it N? G １ However, N is G ２ However, CR Ｇ２ G ３ However, N is G ４ However, CR Ｇ４ Is it, G １ However, CR Ｇ１ G ２ However, N is G ３ However, N is G ４ However, CR Ｇ４ is or G １ However, CR Ｇ１ G ２ However, CR Ｇ２ G ３ However, N is G ４ The compound according to any one of claims 1 to 10, wherein N is present, or a pharmaceutically acceptable salt or tautomer thereof.

12. G １ However, it is CH, G ２ However, it is CH, G ３ However, it is CH, G ４ But is it CH? G １ However, N is G ２ However, it is CH, G ３ However, it is CH, G ４ But is it CH? G １ However, it is CH, G ２ However, N is G ３ However, it is CH, G ４ But is it CH? G １ However, N is G ２ However, it is CH, G ３ However, it is CH, G ４ But is it N? G １ However, N is G ２ However, it is CH, G ３ However, N is G ４ However, is it CH or G １ However, it is CH, G ２ However, it is CH, G ３ However, N is G ４ The compound according to claim 11, or a pharmaceutically acceptable salt or tautomer thereof, wherein N is present.

13. G １ However, CR Ｇ１ G ４ However, CR Ｇ４ And R １ and G ２ However, they are linked together with the atoms to which they bond, resulting in 0, 1, 2, or 3 R atoms. Ｇ７ A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof, which independently forms a five-membered heteroaryl ring.

14. G １ However, it is CH, G ４ The compound according to claim 13, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is CH.

15. R １ However, -Cl, cyclopropyl, -CF ３ , -CF ２ H, -OCF ３ , or -OCF ２ A compound according to any one of claims 1-14, wherein H is present, or a pharmaceutically acceptable salt or tautomer thereof.

16. R １ and G ２ However, they are linked together with the atoms to which they bond, resulting in 0, 1, 2, or 3 R atoms. Ｇ７ A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or tautomer thereof, which independently forms a five-membered heteroaryl ring.

17. R １ and G ２ The compound according to claim 16, or a pharmaceutically acceptable salt or tautomer thereof, wherein these atoms are linked together with the atoms to which they bind to form an oxazole, isoxazole, pyrazole, or imidazole.

18. R Ｇ１ , R Ｇ２ , R Ｇ３ , and R Ｇ４ However, each independently, hydrogen, F, Cl, OH, and OCF ２ A compound according to any one of claims 1-9 and 12, selected from the group consisting of H, or a pharmaceutically acceptable salt or tautomer thereof.

19. R Ｇ５ However, CF ３ or CF ２ H and R Ｇ６ However, hydrogen or CF ２ The compound according to claim 1, wherein H is present, or a pharmaceutically acceptable salt or tautomer thereof.

20. R ２ａ and R ２ｂ A compound according to any one of claims 1-19, or a pharmaceutically acceptable salt or tautomer thereof, wherein each instance is independently hydrogen or methyl.

21. R ４ The compound according to any one of claims 1 to 20, wherein the compound is methyl, ethyl, cyclopropyl, or cyclopropyl-methyl, or a pharmaceutically acceptable salt or tautomer thereof.

22. Two R's ３ A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or tautomer thereof, wherein the groups are linked to form an ethylene crosslinking group.

23. Ring A of the equation: 【Transformation 6】 However, the basis of the following equation: 【Transformation 7】 That is, In the formula, R Ｇ１ , R Ｇ２ , R Ｇ３ , and R Ｇ４ However, each operates independently, Haro, C １－６ Alkyl, C １－６ Haloalkyl and -OR Ｇ６ A compound according to any one of claims 1 to 22, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

24. The rings A(a-2), (a-4), (a-5), (a-6) of the equation are the basis of the following equation: 【Transformation 8】 The compound according to claim 23, or a pharmaceutically acceptable salt or tautomer thereof.

25. Ring A of the equation: 【Chemistry 9】 However, the basis of the following equation: 【Chemistry 10】 And, In the formula, R Ｇ１ But, hello, C １－６ Alkyl, C １－６ Haloalkyl, or -OR Ｇ６ The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt or tautomer thereof.

26. The ring A(a-7N), (a-8N), or (a-9N) in the formula is one of the following: 【Chemistry 11】 The compound according to claim 25, or a pharmaceutically acceptable salt or tautomer thereof.

27. Ring A of the equation: 【Chemistry 12】 R １ and G ２ However, they are linked together with the atoms to which they bond, forming a five-membered heteroaryl ring, in the formula, ring A, R １ , and G ２ However, the basis of the following equation: 【Chemistry 13】 Obtained, During the ceremony, X is O, S, NH, or NR Ｇ７ And, Y is N, CH, or CR Ｇ７ And, z is either 0 or 1, However, R Ｇ７ However, if it is a group bonded to a nitrogen (N) atom, R Ｇ７ However, C １－６ Alkyl or C １－６ A compound according to any one of claims 1-22, provided that it is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

28. Ring A, R １ , and G ２ However, these are linked together with the atoms to which they bond, forming a five-membered heteroaryl ring, and the group is of the following formula: 【Chemistry 14】 The compound according to claim 27, or a pharmaceutically acceptable salt or tautomer thereof.

29. Ring A is the basis of the following equation: 【Chemistry 15】 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or tautomer thereof.

30. Ring A is the basis of the following equation: 【Chemistry 16-1】 【Chemistry 16-2】 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or tautomer thereof.

31. Ring B of the equation: 【Chemistry 17】 However, the basis of the following equation: [Chemistry 18] The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or tautomer thereof.

32. Ring B is the basis of the following equation: 【Chemistry 19】 And, In the formula, R ２ａ and R ２ｂ Each of these cases is independent of Halo, C １－６ Alkyl, C １－６ Haloalkyl, C ３ -C ４ The compound according to claim 31, which is a carbocyclyl or a 3-4 membered heterocyclyl, or a pharmaceutically acceptable salt or tautomer thereof.

33. The ring B(b-1), (b-2), (b-3), or (b-4) of the equation is two R ３ The bases are linked together, C １－３ Alkylene crosslinking group or C １－３ When forming a haloalkylene crosslinking group, the group is given by the following formula: 【Chemistry 20】 And, In the formula, L is C １－３ Alkylene crosslinking group or C １－３ The compound according to claim 31, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

34. Ring B is the basis of the following equation 【Chemistry 21】 And, In the formula, R ２ａ and R ２ｂ Each of these cases is independent of Halo, C １－６ Alkyl, C １－６ Haloalkyl, C ３ -C ４ The compound according to claim 33, which is a carbocyclyl or a 3-4 membered heterocyclyl, or a pharmaceutically acceptable salt or tautomer thereof.

35. Ring B is the basis of the following equation: 【Chemistry 22】 The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt or tautomer thereof.

36. Ring B is the basis of the following equation: 【Chemistry 23-1】 【Chemistry 23-2】 【Chemistry 23-3】 The compound according to claim 35, or a pharmaceutically acceptable salt or tautomer thereof.

37. The compound according to any one of claims 1-36, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is selected from the compounds listed in Table 1 or Table 2.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.

39. A method for regulating NLRP3 activity, comprising administering to a subject a compound described in any one of claims 1 to 37, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition described in claim 38.

40. A method for treating or preventing a disease or disorder, comprising administering to a subject a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 38.

41. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 38, for use in treating or preventing a disease or disorder.

42. Use of a compound according to any one of claims 1-37, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for the treatment or prevention of a disease or disorder.

43. Use of a compound according to any one of claims 1-37, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment or prevention of a disease or disorder.

44. The method, compound, or use according to any one of claims 39-43, wherein the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disorder of the muscle, an inflammatory disorder, an autoimmune disorder, cancer, an infectious disease, obesity, a metabolic disorder, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disorder, a rheumatic disease, a psychological disorder, a graft-versus-host disease, pain (including disorders related to pain management), or an NLRP3-related disorder in a subject determined to have germline or somatic nonsilent mutations in NLRP3.

45. A process for preparing a compound of formula (I-B) according to any one of claims 1-37, or a salt or tautomer thereof, wherein the compound is synthesized according to general scheme A or B.

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