Amide derivatives for inhibiting NLRP3 and their use

Abstract

This disclosure relates to compounds of formula (IA), as well as pharmaceutically acceptable salts and tautomers thereof (wherein ring A, ring B, R 1 , R 2a , R 2b , R 3 The disclosure relates to compounds of formula (IA), as well as methods for preparation, treatment and prevention, and pharmaceutical compositions comprising them (where m, n, and p are as described herein), and further to the use of compounds of formula (IA), as well as pharmaceutically acceptable salts and tautomers thereof, in the treatment and prevention of NLRP3-related diseases and disorders. TIFF2026510921000498.tif68170

Description

[Technical Field]

[0001] Related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 490,968, filed on 17 March 2023, and U.S. Provisional Patent Application No. 63 / 519,074, 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. [Overview of the Initiative]

[0005] An NLRP3 inhibitor of formula (IA): [ka] In the formula, ring A, ring B, R 1 , R 2a , R 2b , R 3NLRP3 inhibitors, m, n, and p as described herein, as well as pharmaceutically acceptable salts and tautomers thereof, are provided herein.

[0006] The present invention further provides methods for preparation, treatment and prevention, and pharmaceutical compositions containing the same.

[0007] definition The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the endpapers of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are referenced from Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th 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.

[0008] 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, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, 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.

[0009] For example, a compound described herein may be referred to as "Rac-X", which, for the purposes of the examples, means a mixture of two or more stereoisomers, such as the 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 a "Rac-X" molecule, the claims may include the racemic composition of the substance, but may also include, for example, a composition of a substance that is enantiomerically enriched in one stereoisomer over other stereoisomers that may be produced. For example, the claims may include 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%.

[0010] Unless otherwise specified, a compound described herein also means a compound that differs only in the presence of one or more isotope-enriched atoms. For example, substitution of hydrogen by deuterium or tritium, 19 substitution of 18 F by 13 F, or substitution of carbon by 14 C or

[0011] When ranges of values are recited, it is intended to include each value and subrange within that 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 , C 4-6 , C 4-5 , and C 5-6It is intended to include alkyl groups.

[0012] "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).

[0013] "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.

[0014] 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).

[0015] 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.

[0016] "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.

[0017] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I) radicals.

[0018] 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-.

[0019] 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 group, along with the atom to which they are bonded, is C 1-3 Alkylene crosslinking group or C 1-3 The phrase “may form a haloalkylene crosslinking group” is used herein to mean “two R 3 The group is C between the two atoms to which they are bonded. 1-3 Alkylene crosslinking group or C 1-3 This phrase is used interchangeably with the phrase "may form a haloalkylene crosslinking group." Both phrases are C 1-3 Alkylene crosslinking group or C 1-3 Two non-vicinal R groups are bonded together to form a haloalkylene crosslinking group. 3 This means that the group (bonded to two carbon atoms of ring B) is located on ring B. An example of this bridging group is the variable L in compounds of formula (IA-bridging).

[0020] Compounds of formula (IA), each containing a terminal tetrazolyl group, and their pharmaceutically acceptable salts are mixtures of tautomer isomers, for example [ka] It can exist as such.

[0021] Amino and oxygen protecting groups are described in detail in *Organic Synthesis*, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999.

[0022] 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).

[0023] 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.

[0024] Salts, pharmaceutically acceptable salts, and free bases of compounds of formula (IA) are intended herein.

[0025] "Salt" refers to any and all salts.

[0026] 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, and rhynchophosphate. Examples include ctobionates, lactates, laurates, lauryl sulfates, malic acid, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, valersates, etc. 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.

[0027] "Free base" refers to the neutral, non-ionized form of a compound that is not a salt or a pharmaceutically acceptable salt.

[0028] "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.

[0029] "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.

[0030] The terms "disease" and "disorder" are used synonymously in this specification.

[0031] "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 alleviate 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 or animal models in vitro. A reference to "to treat" or "to cure" includes the alleviation 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 reducing the disease in the object, i.e., causing regression of the disease or disorder, or at least one clinical or subclinical symptom thereof.

[0032] 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.

[0033] "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.

[0034] The phrase "at least one" refers to one example or two or more examples.

[0035] 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.

[0036] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean either "and" or "or". [Modes for carrying out the invention]

[0037] (i) Compound A compound of formula (IA), [ka] 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 two or fewer 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 G7 They independently form a 5-membered heteroaryl ring, R G1 , RG2 , 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, R G7 In each instance of, 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 In each instance of, is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C3-C4 carbocyclic, or 3- to 4-membered 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, R 3 In each instance of, 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, a compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0038] In some embodiments of formula (I-A), the compound is of the formula: [ka] or a pharmaceutically acceptable salt or tautomer thereof.

[0039] In some embodiments of formula (IA), the compound is of the following formula: [ka] or a pharmaceutically acceptable salt or tautomer thereof.

[0040] In some embodiments of formula (IA), the compound is one of the 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-.

[0041] In some embodiments of formula (IA), the compound is one of the 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-.

[0042] In some embodiments of formula (IA), the compound is one of the formula: [ka] [ka] or a pharmaceutically acceptable salt or tautomer thereof.

[0043] 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

[0044] 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 two or fewer of G1, G2, G3, and G4 are N.

[0045] In some embodiments, G1 is CR G1 In some embodiments, G1 is N.

[0046] In some embodiments, G2 is CR G2 In some embodiments, G2 is N.

[0047] In some embodiments, G3 is CR G3 In some embodiments, G3 is N.

[0048] In some embodiments, G4 is CR G4 In some embodiments, G4 is N.

[0049] 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.

[0050] In some embodiments, at least one of G1, G2, G3, and G4 is N.

[0051] 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.

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

[0053] 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 G3 And 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.

[0054] In some embodiments, G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is CR G4 And G1 is CR G1 G2 is CH, G3 is CH, G4 is CH, and G1 is CR G1 And G2 is CR G2 G3 is CH, G4 is CH, and G1 is CR G1 G2 is CH, and G3 is CR G3 G4 is CH, and G1 is CR G1 G2 is N, and G3 is CR G3 And G4 is CR G4 And G1 is CR G1 G2 is N, G3 is CH, G4 is CH, and G1 is CR. G1 And G2 is CR G2 G3 is N, and G4 is CR G4 And G1 is CR G1 G2 is CH, G3 is N, G4 is CH, and G1 is CR. G1 G2 is CH, G3 is N, G4 is CH, and G1 is CR. G1 And G2 is CR G2 And G3 is CR G3 G4 is N, or G1 is CR G1 Therefore, G2 is CH, G3 is CH, and G4 is N.

[0055] In some embodiments, G1 is CH, G2 is CH, G3 is CH, G4 is CH, or G1 is CH, G2 is CR G2 Therefore, G3 is CH, and G4 is CH.

[0056] As generally described herein, R 1 Hello, C 1-6 Alkyl, C1-6 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, -OR G5 , -SR G5 , or -N(R G5 )2, or R 1 And substituted with G2, and linked together with the atoms to which they bond, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , and -N(R G5 ) Select from the group consisting of 2, independently of 0, 1, 2, or 3 R G7 It forms a five-membered heteroaryl ring substituted with a group.

[0057] In some embodiments, R 1 It is a halo.

[0058] 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.

[0059] 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.

[0060] 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 21-6 It is alkyl.

[0061] In some embodiments, R 1 C is independently substituted by 1, 2, or 3 halos. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 )2.

[0062] In some embodiments, R 1 C 1-6 It is alkyl.

[0063] 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, R 1 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.

[0064] In some embodiments, R 1 C 1-6 It is a haloalkyl group.

[0065] 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.

[0066] In some embodiments, R 1 is -OR G5 That is the case.

[0067] In some embodiments, R 1 -SR G5 That is the case.

[0068] In some embodiments, R 1 is -N(R G5 )2.

[0069] In some embodiments, R 1 C3-C4 carbocyclyl or 3-4 membered heterocyclyl, where carbocycloyl or heterocyclyl 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 with 2.

[0070] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 There are C3-C4 carbocyclyls that are independently substituted in )2.

[0071] In some embodiments, R 1This 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 There is a C3 carbocyclyl that is independently substituted at )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 There is a C4 carbocykrill that is independently substituted at )2.

[0073] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 There are C3-C4 carbocyclyls that are independently substituted in )2.

[0074] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 There is a C3 carbocyclyl that is independently substituted at )2.

[0075] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 There is a C4 carbocykrill that is independently substituted at )2.

[0076] In some embodiments, R 1It is an unsubstituted C3-C4 carbocyclyl.

[0077] In some embodiments, R 1 R is an unsubstituted C3 carbocykyl. In some embodiments, R 1 It is an unsubstituted C4 carbocykyl.

[0078] 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 There is a C3-C4 carbocyclyl substituted with )2.

[0079] 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 C3 carbocykyl. 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 There is a C4 carbocykrill substituted with )2.

[0080] 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 There are C3-C4 carbocyclyls that are independently substituted in )2.

[0081] In some embodiments, R 1 This is two halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SRG5 , or -N(R G5 )2 independently substituted C3 carbocykrill. 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 There is a C4 carbocykrill that is independently substituted at )2.

[0082] 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 There are C3-C4 carbocyclyls that are independently substituted in )2.

[0083] 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 independently substituted C3 carbocykrill. 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 There is a C4 carbocykrill that is independently substituted at )2.

[0084] In some embodiments, R 1 This consists of 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.

[0085] In some embodiments, R 1 is a C3 carbocykyl substituted with at least one halo. In some embodiments, R 1 This is a C4 carbocyrill substituted with at least one halo.

[0086] 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.

[0087] In some embodiments, R 1 is a C3 carbocykyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R 1 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.

[0088] 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.

[0089] In some embodiments, R 1 is a C3-C4 carbocykyl substituted with at least one F. In some embodiments, R 1is 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.

[0090] 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.

[0091] In some embodiments, R 1 is a C4 carbocykyl substituted with at least one F. In some embodiments, R 1 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.

[0092] In some embodiments, R 1 is at least one C 1-6 It is an alkyl-substituted C3-C4 carbocyric.

[0093] In some embodiments, R 1 This consists of 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, where at least one substituent is C 1-6 The condition is that it must be alkyl.

[0094] 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 1 is 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.

[0095] 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 1 is 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.

[0096] In some embodiments, R 1 is a C4 carbocyric substituted with at least one methyl group. In some embodiments, R 1is 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 1 is 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.

[0097] In some embodiments, R 1 This consists of 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, where at least one substituent is C 1-6The condition is that it must be a haloalkyl group.

[0098] 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.

[0099] 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 1 is 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.

[0100] 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 1It is a C3 carbocyrill substituted with at least one halohexyl.

[0101] 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.

[0102] In some embodiments, R 1 This consists of 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, where at least one substituent is -OR G5 This is conditional on the following:

[0103] 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].

[0104] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SRG5 , or -N(R G5 )2 independently substituted C3-C4 carbocyric, where at least one substituent is -SR G5 This is conditional on the following:

[0105] 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].

[0106] In some embodiments, R 1 This consists of 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 independently substituted with )2, where at least one substituent is -N(R G5 ) Provided that it is 2.

[0107] 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.

[0108] 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.

[0109] In some embodiments, R 1 This is a combination of 0, 1, 2, or 3 halos, C1-6 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 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.

[0110] In some embodiments, R 1 This consists of 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 consists of 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 consists of 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 It is an unsubstituted 3-4 member heterocyclyl.

[0113] In some embodiments, R 1R is an unsubstituted three-membered heterocyclyl. In some embodiments, R 1 It is an unsubstituted four-membered heterocyclyl.

[0114] 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.

[0115] 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, 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 four-membered heterocyclyl substituted with )2.

[0116] 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.

[0117] 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 1This 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.

[0118] 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.

[0119] 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 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.

[0120] In some embodiments, R 1 This consists of 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.

[0121] In some embodiments, R 1 is a three-membered heterocyclyl substituted with at least one halo. In some embodiments, R1 It is a four-membered heterocyclyl substituted with at least one halo.

[0122] 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.

[0123] 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 1 is a three-membered heterocycline substituted with at least one of F, Cl, or Br. In some embodiments, R 1 It is a three-membered heterocyclyl substituted with at least one of F or Cl.

[0124] 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 heterocycline substituted with at least one of F or Cl.

[0125] 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 1It is a 3-4 member heterocycline substituted with at least one I.

[0126] 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.

[0127] In some embodiments, R 1 is a four-membered heterocycline substituted with at least one F. In some embodiments, R 1 is a four-membered heterocycline 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.

[0128] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) A 3-4 member heterocycline independently substituted with 2, where at least one substituent is C 1-6 The condition is that it must be alkyl.

[0129] 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.

[0130] 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, R 1 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.

[0131] In some embodiments, R 1is 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 1 is 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.

[0132] 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 1is 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 1 is 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.

[0133] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) A 3-4 member heterocyclyl independently substituted with 2, where at least one substituent is C 1-6 The condition is that it must be a haloalkyl group.

[0134] In some embodiments, R1 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.

[0135] 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 1 is 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.

[0136] 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.

[0137] 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.

[0138] In some embodiments, R 1 This consists of 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) A 3-4 member heterocyclyl independently substituted with 2, where at least one substituent is -OR G5 This is conditional on the following:

[0139] 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].

[0140] In some embodiments, R 1 This consists of 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, with at least one substituent being -SRG5 This is conditional on the following:

[0141] 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].

[0142] In some embodiments, R 1 This consists of 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, with at least one substituent being -N(R G5 ) Provided that it is 2.

[0143] 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.

[0144] 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 substituted 5-membered heteroaryl ring.

[0145] 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.

[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 ) One R selected from the group consisting of 2 G7 It forms a 5-membered heteroaryl ring substituted with [the specified compound].

[0147] 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 Two R selected from the group consisting of )2 G7 They independently form a substituted 5-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 Three R selected from the group consisting of )2 G7 They independently form a substituted 5-membered heteroaryl ring.

[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, -OR G5 , -SR G5 , and -N(R G5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7The following conditions apply: the substituted atoms independently form a 5-membered heteroaryl ring, and at least one substituent is a halo.

[0150] 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.

[0151] 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.

[0152] 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 G7The 5-membered heteroaryl ring is independently substituted with C, and at least one substituent is C 1-6 The condition is that it must be alkyl.

[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 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 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 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 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 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 sechexyl. 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.

[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 The 5-membered heteroaryl ring is independently substituted with C, and at least one substituent is C 1-6 The condition is that it must be a haloalkyl group.

[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 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 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 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.

[0156] 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 It forms a 5-membered heteroaryl ring independently substituted with a -OR group, and at least one substituent is -OR G5 This is conditional on the following:

[0157] 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 It forms a 5-membered heteroaryl ring independently substituted with a group, and at least one substituent is -SR G5 This is conditional on the following:

[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(RG5 )0, 1, 2, or 3 R selected from the group consisting of 2 G7 It forms a 5-membered heteroaryl ring independently substituted with a group, and at least one substituent is -N(R G5 ) Provided that it is 2.

[0159] 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.

[0160] In some embodiments, R G7 It is a halo.

[0161] 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.

[0162] 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.

[0163] In some embodiments, R G7 C 1-6 It is alkyl.

[0164] 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, RG7 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.

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

[0166] 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.

[0167] In some embodiments, R G7 is -OR G5 That is the case.

[0168] In some embodiments, R G7 -SR G5 That is the case.

[0169] In some embodiments, R G7 is -N(R G5 )2.

[0170] As generally defined herein, R G1 , R G2 , R G3 , and R G4 These are, independently, hydrogen, halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0171] 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.

[0172] In some embodiments, R G1 It is hydrogen.

[0173] In some embodiments, R G1 It is a halo.

[0174] 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 It is either F or Cl.

[0175] In some embodiments, R G1 F is F. In some embodiments, R G1 is Cl. In some embodiments, R G1 is Br. In some embodiments, R G1 It is I.

[0176] In some embodiments, R G1 C 1-6 It is alkyl.

[0177] In some embodiments, R G1 is methyl. In some embodiments, R G1is 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 G1 is sec-hexyl. In some embodiments, R G1 is tert-butyl.

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

[0179] In some embodiments, R G1 is halomethyl. In some embodiments, R G1 is haloethyl. In some embodiments, R G1 is halopropyl. In some embodiments, R G1 is halobutyl. In some embodiments, R G1 is halopentyl. In some embodiments, R<……​​​​​​​​​​​​​​​​​1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0182] In some embodiments, R G2 It is hydrogen.

[0183] In some embodiments, R G2 It is a halo.

[0184] 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.

[0185] In some embodiments, R G2 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.

[0186] In some embodiments, R G2 C 1-6 It is alkyl.

[0187] 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, RG2 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.

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

[0189] In some embodiments, R G2 is a halomethyl. In some embodiments, R G2 is haloethyl. In some embodiments, R G2 is a halopropyl. In some embodiments, R G2 is halobutyl. In some embodiments, R G2 is halopentyl. In some embodiments, R G2 It is a halohexyl.

[0190] In some embodiments, R G2 is -OR G6 That is the case.

[0191] In some embodiments, R G3 is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0192] In some embodiments, R G3 It is hydrogen.

[0193] In some embodiments, R G3 It is a halo.

[0194] In some embodiments, R G3is F, Cl, Br, or I. In some embodiments, R G3 is F, Cl, or Br. In some embodiments, R G3 is F or Cl.

[0195] In some embodiments, R G3 is F. In some embodiments, R G3 is Cl. In some embodiments, R G3 is Br. In some embodiments, R G3 is I.

[0196] In some embodiments, R G3 is C 1-6 alkyl.

[0197] In some embodiments, R G3 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 pentyl. In some embodiments, R G3 is hexyl. In some embodiments, R G3 is isopropyl. In some embodiments, R G3 is isobutyl. In some embodiments, R G3 is isopentyl. In some embodiments, R G3 is isohexyl. In some embodiments, R G3 is sec-butyl. In some embodiments, R G3 is sec-pentyl. In some embodiments, R G3 is sec-hexyl. In some embodiments, R G3 is tert-butyl.

[0198] In some embodiments, R G3 is C 1-6It is a haloalkyl group.

[0199] 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.

[0200] In some embodiments, R G3 is -OR G6 That is the case.

[0201] In some embodiments, R G4 is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR G6 It is selected from the group consisting of the following.

[0202] In some embodiments, R G4 It is hydrogen.

[0203] In some embodiments, R G4 It is a halo.

[0204] 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.

[0205] 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.

[0206] In some embodiments, R G4 C 1-6 It is alkyl.

[0207] 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 G4 is 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.

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

[0209] 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.

[0210] In some embodiments, R G4 is -OR G6 That is the case.

[0211] 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.

[0212] In some embodiments, R G5 It is hydrogen.

[0213] In some embodiments, R G5 C 1-6 It is alkyl.

[0214] 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.

[0215] In some embodiments, R G5C 1-6 It is a haloalkyl group.

[0216] 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.

[0217] In some embodiments, R G6 It is hydrogen.

[0218] In some embodiments, R G6 C 1-6 It is alkyl.

[0219] 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. G6It is tert-butyl.

[0220] In some embodiments, R G6 C 1-6 It is a haloalkyl group.

[0221] 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.

[0222] In some embodiments, the ring A of the formula: [ka] This is based on the following formula: [ka] That is the case.

[0223] 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.

[0224] In some embodiments, ring A is formula (a-2), (a-4), (a-5), or (a-6), where R G1 is -OR G6 That is the case.

[0225] In some embodiments, ring A is given by formula: [ka] It belongs to them.

[0226] In some embodiments, ring A is formula (a-2), (a-4), (a-5), or (a-6), where R G1 It is fluoro.

[0227] In some embodiments, ring A is given by formula: [ka] It belongs to them.

[0228] In some embodiments, the ring A of the formula: [ka] This is based on the following formula: [ka] That is the case.

[0229] 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.

[0230] 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.

[0231] In some embodiments, ring A is given by formula: [ka] It belongs to them.

[0232] In some embodiments, ring A is given by formula: [ka] It is 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, ring A, R 1 , and G 2 However, the basis of the following equation: [ka] Provided, During the ceremony, X is O, S, NH, or NR G7 And, Y is N, CH, or CR G7 And, z is 0 or 1, 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 It is a haloalkyl group.

[0233] In some embodiments, X is O or S.

[0234] In some embodiments, X is O. In some embodiments, X is S.

[0235] In some embodiments, X is NH or NR G7 That is the case.

[0236] In some embodiments, X is NH. In some embodiments, X is NR G7 That is the case.

[0237] In some embodiments, Y is N.

[0238] In some embodiments, Y is CH or CR G7 That is the case.

[0239] In some embodiments, Y is CH. In some embodiments, Y is CR G7 That is the case.

[0240] In some embodiments, z is 0.

[0241] In some embodiments, z is 1.

[0242] In some embodiments, R G7 If R is a group bonded to a nitrogen (N) atom, G7 C 1-6 It is alkyl.

[0243] In some embodiments, R G7 If R is a group bonded to a nitrogen (N) atom, G7 C 1-6 It is a haloalkyl group.

[0244] 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, in the formula, ring A, R 1 , and G 2 However, the basis of the following equation: [ka] To provide.

[0245] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[0246] In some embodiments, ring A is based on the following formula: [ka] That is the case.

[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] [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] That is the case.

[0251] 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 2a , and R 2b

[0252] As is generally described herein, n is either 0 or 1.

[0253] In some embodiments, n is 0 or 1.

[0254] In some embodiments, n is 0. In some embodiments, n is 1.

[0255] As is generally described herein, p is 1 or 2.

[0256] In some embodiments, p is 1. In some embodiments, p is 2.

[0257] As is generally described herein, m is 0, 1, 2, or 3.

[0258] 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.

[0259] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0260] 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.

[0261] 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.

[0262] In some embodiments, R 2a It is, independently, hydrogen.

[0263] In some embodiments, R 2a It is, independently, a halo.

[0264] In some embodiments, R 2a These are independently F, Cl, Br, or I. In some embodiments, R 2a These are independently F, Cl, or Br. In some embodiments, R 2a These are independently either F or Cl.

[0265] In some embodiments, R 2a Independently, F. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a It is independently I.

[0266] In some embodiments, R 2a Independently, C 1-6 It is alkyl.

[0267] 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 is independently propyl. 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, R2a In some embodiments, R 2a In some embodiments, R 2a is independently sec hexyl. In some embodiments, R 2a It is independently tertbutyl.

[0268] In some embodiments, R 2a Independently, C 1-6 It is a haloalkyl group.

[0269] 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.

[0270] In some embodiments, R 2a It is independently a C3-C4 carbocycline.

[0271] In some embodiments, R 2a is independently C3 carbocykyl. In some embodiments, R 2a It is independently C4 carbocyclyl.

[0272] In some embodiments, R 2a These are independently 3-4 member heterocyclines.

[0273] In some embodiments, R 2a R is independently a three-membered heterocycline. In some embodiments, R 2a It is an independent four-membered heterocycline.

[0274] 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.

[0275] In some embodiments, R 2b It is, independently, hydrogen.

[0276] In some embodiments, R 2b It is, independently, a halo.

[0277] In some embodiments, R 2b These are independently 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.

[0278] In some embodiments, R 2b Independently, F. In some embodiments, R 2b In some embodiments, R 2b In some embodiments, R 2b It is independently I.

[0279] In some embodiments, R 2b Independently, C 1-6 It is alkyl.

[0280] 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 is independently propyl. 2b is independently butyl. In some embodiments, R 2bIn 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 2b is 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.

[0281] In some embodiments, R 2b Independently, C 1-6 It is a haloalkyl group.

[0282] 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.

[0283] In some embodiments, R 2b It is independently a C3-C4 carbocycline.

[0284] In some embodiments, R 2b is independently C3 carbocykyl. In some embodiments, R 2bIt is independently C4 carbocyclyl.

[0285] In some embodiments, R 2b These are independently 3-4 member heterocyclines.

[0286] In some embodiments, R 2b R is independently a three-membered heterocycline. In some embodiments, R 2b It is an independent four-membered heterocycline.

[0287] In some embodiments, R 2a and R 2b They are the same. In some embodiments, R 2a and R 2b They are different.

[0288] In some embodiments, R 2a and R 2b These are linked together to form a C3 carbocykyl independently substituted with 0, 1, 2, or 3 halos.

[0289] 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 bases are connected, C 1-3 Alkylene crosslinking group or C 1-3 Forms haloalkylene crosslinking groups.

[0290] In some embodiments, R 3 It is a halo.

[0291] 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.

[0292] In some embodiments, R3 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.

[0293] In some embodiments, R 3 C 1-6 It is alkyl.

[0294] 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.

[0295] In some embodiments, R 3 C 1-6 It is a haloalkyl group.

[0296] In some embodiments, R 3 is a halomethyl. In some embodiments, R 3 is haloethyl. In some embodiments, R 3is 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.

[0297] As is generally described herein, two R 3 The base is connected, C 1-3 Alkylene crosslinking group or C 1-3 Forms haloalkylene crosslinking groups.

[0298] In some embodiments, two R 3 The linking of groups to form a bridging group is defined as L.

[0299] In some embodiments, two R 3 The bases are linked together, C 1-3 Forms alkylene crosslinking groups.

[0300] 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 3 The groups are linked together to form a propylene crosslinking group.

[0301] In some embodiments, two R 3 The bases are linked together, C 1-3 Forms haloalkylene crosslinking groups.

[0302] 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 a halopropylene crosslinking group.

[0303] In some embodiments, the ring B of the formula: [ka] This is based on the following formula: [ka] That is the case.

[0304] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0305] In some embodiments, ring B is the base (b-1-i), (b-1-ii), (b-1-iii), or (b-1-iv) of the following formula, where 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.

[0306] In some embodiments, ring B is of formula (b-1), (b-2), (b-3), or (b-4), where two R's are present in the formula. 3 The groups are linked together with the atoms to which they are bonded, C 1-3 Alkylene crosslinking group or C 1-3 Forms haloalkylene crosslinking groups.

[0307] 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.

[0308] In some embodiments, L is C 1-3 It is an alkylene crosslinking group.

[0309] In some embodiments, L is C 1-3 It is a haloalkylene crosslinking group.

[0310] 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.

[0311] In some embodiments, ring B is the base (b-1-BR-i), (b-1-BR-ii), or (b-1-BR-iii) of the following formula, where 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.

[0312] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0313] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0314] 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.

[0315] In some embodiments, ring B is based on the following formula: [ka] [ka] [ka] That is the case.

[0316] In some embodiments, ring B is based on the following formula: [ka] That is the case.

[0317] 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. (c) Subgenus

[0318] 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 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, R 1 , R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , R G7 , ring B, n, p, m, R 3 , 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 2a and R 2bIt 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.

[0319] For example, in a particular embodiment, the formulas are (I-A'), (IAa), (I-A'-bridge), (I-A'''-bridge), (IA-bridge-a), or (IA-bridge-c): [ka] The compound, Alternatively, pharmaceutically acceptable salts or tautomers thereof are provided.

[0320] In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), G1 is CH, G2 is CH, G3 is CH, and G4 is CH. In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), G1 is CR G1 And G2 is CH, G3 is CH, and G4 is CH. In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), G1 is CR G2 And G2 is CH, G3 is CH, and G4 is CH. In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), G1 is CR G1 And G2 is CR G2 And G3 is CH and G4 is CH. In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), G1 is CR G1 G2 is CH, and G3 is CR G3And G4 is CH. In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), G1 is CR G1 And G2 is CR G2 And G3 is CR G3 And G4 is CR G4 That is the case.

[0321] In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), and in any of the embodiments described in this section, R G1 is either a halo or -OR G6 And R 1 Hello, C 1-6 Haloalkyl, C 1-6 Alkyl, C3-C4 carbocyric, -OR G5 In some embodiments, R G1 It is a halo, and R 1 is -OR G5 In some embodiments, R G1 It is a halo, and R 1 is a halo. In some embodiments, R G1 It is a halo, and R 1 C 1-6 In some embodiments, R G1 is -OR G6 And R 1 is a halo. In some embodiments, R G1 is -OR G6 And R 1 C 1-6 In some embodiments, R G1 is -OR G6 And R 1 C 1-6 It is alkyl. In some embodiments, R G1 is -OR G6 And R 1 is C3-C4 carbocyclyl. In some embodiments, R G1 is -ORG6 And R 1 is -OR G5 That is the case.

[0322] In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), and in any of the embodiments described in this section, R G2 is a halo or C 1-6 It is alkyl, R 1 Hello, C 1-6 Haloalkyl or -OR G5 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 -OR G5 In some embodiments, R G2 is -OR G6 And R 1 C 1-6 In some embodiments, R G2 is C 1-6 It is alkyl, R 1 C 1-6 It is a haloalkyl group.

[0323] In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), and in any of the embodiments described in this section, R G1 is either a halo or -OR G6 And R G2 is a halo or C 1-6 It is alkyl. In some embodiments, R G1 It is a halo, and R G2 is a halo. In some embodiments, R G1 It is a halo, and R G2 It is a halo, and R 1is a halo. In some embodiments, R G1 It is a halo, and R G2 It is a halo, and R 1 C 1-6 It is alkyl. In some embodiments, R G1 is -OR G6 And R G2 is a halo. In some embodiments, R G1 is -OR G6 And R G2 It is a halo, and R 1 is a halo. In some embodiments, R G1 is -OR G6 And R G2 It is a halo, and R 1 C 1-6 It is alkyl. In some embodiments, R G1 is -OR G6 And R G2 It is a halo, and R 1 is -OR G5 In some embodiments, R G1 is -OR G6 And R G2 It is a halo, and R 1 C 1-6 In some embodiments, R G1 is -OR G6 And R G2 It is a halo, and R 1 is C3-C4 carbocyclyl. In some embodiments, R G1 is -OR G6 And R G2 C 1-6 It is alkyl. In some embodiments, R G1 is -OR G5 And R G2 C 1-6 It is alkyl, R 1 It is a halo.

[0324] In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), and in any of the embodiments described in this section, R G1 is either a halo or -OR G6 And R G3 is a halo. In some embodiments, R G1 It is a halo, and R G3 is a halo. In some embodiments, R G1 It is a halo, and R G3 It is a halo, and R 1 C 1-6 In some embodiments, R G1 is -OR G6 And R G3 is a halo. In some embodiments, R G1 is -OR G6 And R G3 It is a halo, and R 1 It is a halo.

[0325] In some embodiments of formula (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), and in any of the embodiments described in this section, R G1 is either a halo or -OR G6 And R G4 C 1-6 It is alkyl. In some embodiments, R G1 is -OR G6 And R G4 C 1-6 It is alkyl. In some embodiments, R G1 is -OR G6 And R G4 C 1-6 It is alkyl, R 1 It is a halo.

[0326] In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), 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 groups are linked together with the atoms to which they are bonded, 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 groups are linked together with the atoms to which they are bonded, 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.

[0327] In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), and in any of the embodiments described in this section, n is 1 and p is 1. In some embodiments, n is 1 and p is 1, and R 2a and R 2b At least one of them is C1-6 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 H. In some embodiments, n is 1, p is 1, and there are two R 3 The groups are linked together with the atoms to which they are bonded, C 1-3 Forms alkylene (e.g., ethylene crosslinks). In some embodiments, n is 1, p is 1, and 2 R 3 The groups are linked together with the atoms to which they are bonded, 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.

[0328] In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), ring A is a ring system, where, R 1 But, hello, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , C3-C4 carbocyclyl, where carbocyclyl 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 with 2, R G1 , R G2 , R G3 , and R G4 However, each is independent of hydrogen, halo, and C. 1-6 Alkyl 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 group.

[0329] In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), ring A is a ring system, where, R 1 However, it is Cl, Br, methyl, isopropyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, OCF2H, OCF3, CF2H, CF3, SCF3, or SCF2H. R G1 , R G2 , R G3 , and R G4 However, each is independently selected from the group consisting of hydrogen, F, Cl, methyl, OH, OCH3, and OCF2H.

[0330] In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), ring B is a ring system, where, R 2a and R 2b Each of these cases independently involved hydrogen, halo, and C. 1-6 Alkyl, C 1-6 It is a haloalkyl or C3-C4 carbocyacrylic. R 3 Each case is independent of C 1-6 Is it alkyl? or two R 3 The groups are linked together with the atoms to which they are bonded, C 1-3 It can form alkylene crosslinking groups.

[0331] In some embodiments of formulas (I-A'), (IAa), (I-A'-bridged), (I-A'''-bridged), (IA-bridged-a), or (IA-bridged-c), ring B is a ring system, where, R 2a and R 2b Each of these cases is independently hydrogen, F, CF3, methyl, or cyclopropyl. R 3 Each of these cases, independently, is methyl, or two R 3 The groups can be linked together with the atoms to which they are bonded to form ethylene crosslinking groups.

[0332] In a particular embodiment of formula (IAa), n is 0, p is 1, and m is 0 (wherein R 3 (It does not exist) and G1 is CR G1 And G2 is CR G2 G3 is CH, and G4 is CR G4 The compound of formula (II-A-a1): [ka] Or a pharmaceutically acceptable salt or tautomer thereof is provided. In a particular embodiment, R 2b is not hydrogen. In a particular embodiment, 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 1-3It is a haloalkyl. In a particular embodiment, R G1 is hydrogen, -OH, or a halogen (e.g., fluoro or chloro). In certain embodiments, R G1 is hydrogen, -OH, or fluoro. In certain embodiments, R G1 is -OH or fluoro. In certain embodiments, 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 -OH or fluoro, R G2 is hydrogen, and R G4 is hydrogen or fluoro, and R 1 C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl group.

[0333] In a particular embodiment of formula (IBa), n is 1, p is 1, and m is 0 (wherein 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 The compound of formula (II-B-a2): [ka] Or a pharmaceutically acceptable salt or tautomer thereof is provided. In a particular embodiment, R 2b is not hydrogen. In a particular embodiment, 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 RG5 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, -OH, or a halogen (e.g., fluoro or chloro). In certain embodiments, R G1 is hydrogen, -OH, or fluoro. In certain embodiments, R G1 is -OH or fluoro. In certain embodiments, 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 -OH or fluoro, R G2 is hydrogen, and R G4 is hydrogen or fluoro, and R 1 C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl group.

[0334] In a particular embodiment of formula (IB-bridge-a), n is 0, p is 1, and m is 0 (additional R 3 (does not exist), G1 is CR G1 And G2 is CR G2 G3 is CH, and G4 is CR G4 The compound of formula (II-B-bridge-a): [ka] Or a pharmaceutically acceptable salt or tautomer thereof is provided. In a particular embodiment, R 2a is not hydrogen. In a particular embodiment, 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 1-3 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, -OH, or a halogen (e.g., fluoro or chloro). In certain embodiments, R G1 is hydrogen, -OH, or fluoro. In certain embodiments, R G1 is -OH or fluoro. In certain embodiments, 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 -OH or fluoro, R G2 is hydrogen, and R G4 is hydrogen or fluoro, and R 1 C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl group.

[0335] In a particular embodiment of formula (IA-bridge-c), n is 0, p is 1, and m is 0 (wherein R 3 (and does not exist) and R 2a and R 2b Both are hydrogen, and G1 is CR G1 And G2 is CR G2 G3 is CH, and G4 is CR G4 The compound of formula (II-A-bridge-c): [ka] Or a pharmaceutically acceptable salt or tautomer thereof is provided. 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, -OH, or a halogen (e.g., fluoro or chloro). In certain embodiments, R G1 is hydrogen, -OH, or fluoro. In certain embodiments, R G1 is -OH or fluoro. In certain embodiments, 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 -OH or fluoro, R G2 is hydrogen, and R G4is hydrogen or fluoro, and R 1 C 1-3 Haloalkyl or -OR G5 And R G5 C 1-3 Alkyl or C 1-3 It is a haloalkyl group.

[0336] In some embodiments, the compound of formula (IA) is selected from any one of the compounds listed in Tables 1, 2, or 3, or from pharmaceutically acceptable salts or tautomers thereof.

[0337] In some embodiments, the compound of formula (IA) is a pharmaceutically acceptable salt of any one of the compounds listed in Tables 1, 2, or 3, or a tautomer thereof.

[0338] In some embodiments, the compound of formula (IA) is a free base selected from one of the compounds in Tables 1, 2, or 3, or from their tautomers.

[0339] Tables 1, 2, or 3 below also provide the position of the compounds provided in Example (Ex) by Example Number (Ex), or in Table A (TA) of the Example. 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 1-69

Table 1-90

Table 1-100

Table 1-110

Table 1-120

Table 1-123

[0340] In a particular embodiment, the compounds are compound 2A*, compound 3A*, compound 4A*, compound 5A*, compound 7A*, compound 12A*, compound 18A*, compound 21A*, compound 22A*, compound 27A*, compound 29A*, compound 30A*, compound 32A*, compound 36A*, compound 52A, compound 53A*, compound 54A*, compound 55A*, compound 56A*, compound 57A*, compound 58A*, compound 59A*, compound 60A*, and The compounds are selected from the group consisting of substance 61A*, compound 62A*, compound 63A*, compound 64A*, compound 65A*, compound 66A*, compound 67A*, compound 68A*, compound 69A*, compound 70A*, compound 71A*, compound 73A*, compound 74A*, compound 88A*, compound 89A*, compound 90A*, compound 91A*, compound 92A*, and compound 104A*, or any of the pharmaceutically acceptable salts or tautomers described above.

[0341] In a particular embodiment, the compound is selected from the group consisting of compound 16A, compound 17A, compound 19A, compound 20A, compound 23A, compound 33A, compound 47A, and compound 48A, or any pharmaceutically acceptable salt or tautomer described above.

[0342] In certain embodiments, the compound is selected from the group consisting of compound 34C*, compound 75C*, compound 77C*, and compound 78C*, or any pharmaceutically acceptable salt or tautomer described above.

[0343] In a particular embodiment, the compound is selected from the group consisting of compound 35A*, compound 43A*, compound 79A*, compound 80A*, compound 81A*, compound 82A*, compound 83A*, compound 84A*, compound 86A*, compound 87A*, compound 101A, compound 102A*, and compound 103A*, or any pharmaceutically acceptable salt or tautomer described above.

[0344] (ii) Pharmaceutical composition Pharmaceutical compositions comprising a compound of formula (IA), or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier are further intended herein.

[0345] For example, in some embodiments, a pharmaceutical composition is provided comprising a compound of formula (IA), or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0346] 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.

[0347] 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 (IA), or a pharmaceutically acceptable salt or tautomer thereof, may be in solid, semi-solid, or liquid dosage forms.

[0348] The compound of formula (IA), or a pharmaceutically acceptable salt or tautomer thereof, may be administered alone in a pharmaceutical composition as a monotherapy, or in combination with another therapy. Combination therapy may be achieved by simultaneous administration (e.g., two drugs administered simultaneously) or sequential administration (e.g., one drug administered first, followed by the other). In the case of simultaneous administration, the compound of formula (IA), or a pharmaceutically acceptable salt or tautomer thereof, may be administered in the same pharmaceutical composition as the other therapy, or in a different pharmaceutical composition. The specific selection of the other therapy depends on the physician's diagnosis, assessment of the patient's condition, and an appropriate treatment protocol.

[0349] (iii) Treatment methods Compounds of formula (IA), as well as their pharmaceutically acceptable salts and tautomers, have been found to be useful as inhibitors of NLRP3 activity.

[0350] In some embodiments, a method is provided for treating a disease or disorder in a subject that requires treatment, comprising administering a compound of formula (IA), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing thereof, to the subject. In some embodiments, a method is provided for treating a disease or disorder in a subject that requires treatment, comprising administering an effective amount of a compound of formula (IA), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing thereof, 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.

[0351] 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.

[0352] In some embodiments, the disease or disorder is a disease or disorder of the central 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 encephalomyelitis, transverse osteomyelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), Huntington's disease ("HD"), spinal cord injury, or obesity associated with neuroinflammation.

[0353] In some embodiments, the disease or disorder is a primary neurological disorder of the muscles, such as dystrophy or spinal muscular atrophy.

[0354] In some embodiments, the disease or disorder is an inflammatory disorder such as gout or inflammatory anemia.

[0355] In some embodiments, the disease or disorder is an autoimmune disease such as ulcerative colitis.

[0356] In some embodiments, the disease or disorder is a cancer such as skin cancer or colon cancer.

[0357] In some embodiments, the disease or disorder is an infection, such as a neurological infection.

[0358] In some embodiments, the disease or disorder is a metabolic disorder such as diabetes, for example, type 2 diabetes.

[0359] 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.

[0360] In some embodiments, the disease or disorder is a cardiovascular disease such as stroke, arteriosclerosis, or atherosclerotic cardiovascular disease (ASCVD).

[0361] 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").

[0362] 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.

[0363] 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).

[0364] In some embodiments, the disease or disorder is an eye disease such as optic neuritis or macular degeneration.

[0365] In some embodiments, the disease or disorder is a skin condition such as psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0366] In some embodiments, the disease or disorder is a lymphatic system disorder.

[0367] In some embodiments, the disease or disorder is a rheumatic disease such as osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0368] 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.

[0369] In some embodiments, the disease or disorder is a graft-versus-host disease.

[0370] In some embodiments, the disease or disorder is pain (including disorders related to pain management), such as pain management dependence, osteoarthritis pain, or allodynia.

[0371] 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).

[0372] 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 conditions (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 obesity associated with neuroinflammation.

[0373] 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 (IA), 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.

[0374] (iv) Preparation method Compounds of formula (IA), as well as their salts and tautomers, can be synthesized according to general schemes A-C, as provided below. The examples further illustrate non-limiting examples of this general synthesis.

[0375] 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. General Scheme A. [ka]

[0376] This reaction involves peptide coupling an amine(i) reagent, or a salt or tautomer thereof, with a carboxyl(ii) reagent, or a salt thereof (wherein R' is a hydrogen or oxygen protecting group) to obtain a compound of formula (IA), or a salt or tautomer thereof.

[0377] General method, Protocol B Another preferred general route for the preparation of the compounds described herein follows Protocol B shown in General Scheme B. General Scheme B. [ka]

[0378] Step 1 involves reacting a cyanoamine(iii) reagent or a salt thereof with a carboxyl(ii) reagent or a salt thereof in which R' is a hydrogen or oxygen protecting group to obtain a cyanoamide(iv) intermediate or a salt thereof. Step 2 involves subsequent treatment of the cyanoamide(iv) intermediate or a salt thereof with an azide reagent such as NaN3 or trimethylsilyl azide (TMS-N3) to obtain a compound of formula (IA), a salt thereof, or a tautomer.

[0379] General method, protocol C Another preferred general route for the preparation of the compounds described herein follows Protocol C shown in General Scheme C. General scheme C. [ka]

[0380] Step 1 involves peptide coupling a carboxyl(ii) reagent or a salt thereof (wherein R' is a hydrogen or oxygen protecting group) with a protected amine(iv) reagent or a salt thereof (wherein R' is an amine protecting group) to obtain a protected amide(v) intermediate or a salt thereof. Step 2 involves deprotecting the protected amide(v) intermediate or a salt thereof to obtain a deprotected amide(vi) intermediate or a salt thereof. Step 3 involves treating the deprotected amide(vi) intermediate or a salt thereof with cyanobromide to obtain a cyanoamide(iv) intermediate or a salt thereof. Step 4 involves treating the cyanoamide(iv) intermediate or a salt thereof with an azide reagent such as NaN3 or trimethylsilyl azide (TMS-N3) to obtain a compound of formula (IA), a salt thereof, or a tautomer.

[0381] (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 potency, unbinding clearance, solubility, and permeability of NLRP3.

[0382] 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.

[0383] In some embodiments, the compounds of this disclosure 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 ("CL" in mL / min / kg) measured in blood or plasma by the unbound fraction (fu) in plasma. In some embodiments, the solubility of the compounds of this disclosure can be determined by known procedures, such as those 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, dynamic solubility in physiologically relevant media can be measured using serial dilution and a 2-hour incubation period, followed by filtration, and may be reported in μM units by LC-MS / MS. Thermodynamic solubility in physiologically relevant media can be measured by LC-MS / MS after a 24-hour incubation, followed by filtration, and may be reported in mg / mL units.

[0384] (vi) Exemplary Embodiments Additional exemplary embodiments are as described below. Other embodiments are contemplated in the claims.

[0385] Exemplary Embodiment 1. A compound of formula (IA): [ka] 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 two or fewer 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 to which they are bonded to form a 5-membered heteroaryl ring that is independently substituted with 0, 1, 2, or 3 atoms. 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 G6However, 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 , -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 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 The compound, or a pharmaceutically acceptable salt or tautomer thereof, capable of forming a haloalkylene crosslinking group.

[0386] 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.

[0387] 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.

[0388] 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.

[0389] Exemplary Embodiment 5. 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 4, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

[0390] Exemplary Embodiment 6. The compound is of the following formula: [ka] [ka] The compound described in Exemplary Embodiment 4, or a pharmaceutically acceptable salt or tautomer thereof.

[0391] Exemplary Embodiment 7. Ring A is a ring system, in formula, R 1 But, hello, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5, 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 replaced with 2, R G1 , R G2 , R G3 , and R G4 However, each is independent of hydrogen, halo, and C. 1-6 Alkyl 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 A compound described in any one of the exemplary embodiments 1 to 6, which is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0392] Exemplary Embodiment 8. Ring A is a ring system, in formula, R 1 However, it is Cl, Br, methyl, isopropyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, OCF2H, OCF3, CF2H, CF3, SCF3, or SCF2H. R G1 , R G2 , R G3 , and R G4 However, each is independently selected from the group consisting of hydrogen, F, Cl, methyl, OH, OCH3, and OCF2H, and is a compound according to exemplary embodiment 7, or a pharmaceutically acceptable salt or tautomer thereof.

[0393] Exemplary Embodiment 9. Ring B is a ring system, in formula, R 2a and R 2b Each of these cases independently involved hydrogen, halo, and C. 1-6 Alkyl, C 1-6 It is a haloalkyl or C3-C4 carbocyacrylic. R 3 Each case is independent of C 1-6Alkyl or 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 8, or a pharmaceutically acceptable salt or tautomer thereof, that can form an alkylene crosslinking group.

[0394] Exemplary Embodiment 10. Ring B is a ring system, in formula, R 2a and R 2b Each of these cases is independently hydrogen, F, CF3, methyl, or cyclopropyl. R 3 Each case is independently either methyl or two R 3 A compound according to exemplary embodiment 9, or a pharmaceutically acceptable salt or tautomer thereof, wherein groups are linked to form an ethylene crosslinking group between the two atoms to which they are linked.

[0395] 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.

[0396] 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.

[0397] 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.

[0398] Exemplary Embodiment 14. G1 is CH, and G2 is CR G2The compound described in Exemplary Embodiment 11, wherein G3 is CH and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0399] 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.

[0400] Exemplary embodiment 16.G1 is CR G1 G2 is CH, and G3 is CR G3 The compound described in Exemplary Embodiment 11, or a pharmaceutically acceptable salt or tautomer thereof, wherein G4 is CH.

[0401] Exemplary embodiment 17.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.

[0402] Exemplary embodiment 18.G1 is CR G1 The compound described in Exemplary Embodiment 17, wherein G2 is N, G3 is CH, and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0403] Exemplary embodiment 19.G1 is CR G1 And G2 is CR G2 G3 is N, and G4 is CR G4 A compound according to any one of the exemplary embodiments 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof.

[0404] Exemplary embodiment 20.G1 is CR G1The compound described in Exemplary Embodiment 19, wherein G2 is CH, G3 is N, and G4 is CH, or a pharmaceutically acceptable salt or tautomer thereof.

[0405] Exemplary embodiment 21.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.

[0406] Exemplary embodiment 22.G1 is CR G1 The compound described in Exemplary Embodiment 21, wherein G2 is CH, G3 is CH, and G4 is N, or a pharmaceutically acceptable salt or tautomer thereof.

[0407] Exemplary Embodiment 23.R 1 But, hello, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , C3-C4 carbocyclyl, where carbocyclyl independently has 0, 1, 2, or 3 halos, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR G5 , -SR G5 , or -N(R G5 ) Replaced with 2, for example A compound described in any one of the 1 to 22 embodiments, or a pharmaceutically acceptable salt or tautomer thereof.

[0408] Exemplary Embodiment 24.R 1 The compound described in Exemplary Embodiment 23, wherein the compound is Cl, Br, methyl, isopropyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, OCF2H, OCF3, CF2H, CF3, SCF3, or SCF2H, or a pharmaceutically acceptable salt or tautomer thereof.

[0409] Exemplary Embodiment 25.R G1 , RG2 , R G3 , and R G4 However, each is independent of hydrogen, halo, and C. 1-6 Alkyl and -OR G6 A compound according to any one of the exemplary embodiments 1 to 22, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

[0410] Exemplary Embodiment 26.R G1 , R G2 , R G3 , and R G4 However, each is independently selected from the group consisting of hydrogen, F, Cl, methyl, OH, OCH3, and OCF2H, and is one of the compounds described in Exemplary Embodiment 25, or a pharmaceutically acceptable salt or tautomer thereof.

[0411] Exemplary Embodiment 27.R G5 and R G6 However, each independently, hydrogen, C 1-6 Alkyl, or C 1-6 A compound described in any one of the exemplary embodiments 1 to 22, which is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0412] Exemplary Embodiment 28.R G5 However, the compound described in Exemplary Embodiment 27, which is CF2H or CF3, or a pharmaceutically acceptable salt or tautomer thereof.

[0413] Exemplary Embodiment 29.R G6 The compound described in Exemplary Embodiment 27, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is hydrogen, methyl, or CF2H.

[0414] Exemplary Embodiment 30.R 2a and R 2b Each of these cases independently involved hydrogen, halo, and C. 1-6 Alkyl, C 1-6 A compound according to any one of the exemplary embodiments 1 to 29, which is a haloalkyl or a C3-C4 carbocyclyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0415] Exemplary Embodiment 31.R 2a and R 2b Each of these examples is hydrogen, F, CF3, methyl, or cyclopropyl, and is a compound according to exemplary embodiment 30, or a pharmaceutically acceptable salt or tautomer thereof.

[0416] Exemplary Embodiment 32.R 3 Each case is independent of C 1-6 A compound described in any one of the exemplary embodiments 1 to 31, which is alkyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0417] Exemplary Embodiment 33.R 3 Each of these examples is independently methyl, the compound described in Exemplary Embodiment 32, or a pharmaceutically acceptable salt or tautomer thereof.

[0418] Exemplary Embodiment 34. 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 31, or a pharmaceutically acceptable salt or tautomer thereof, that can form an alkylene crosslinking group.

[0419] Exemplary Embodiment 35. Two R 3 A compound according to exemplary embodiment 34, or a pharmaceutically acceptable salt or tautomer thereof, wherein groups are linked to form an ethylene crosslinking group between the two atoms to which they are linked.

[0420] A compound according to any one of Exemplary Embodiments 1 to 35, or a pharmaceutically acceptable salt or tautomer thereof, wherein Exemplary Embodiment 36.n is 0.

[0421] Exemplary Embodiment 37.n is 1, a compound according to any one of Exemplary Embodiments 1 to 35, or a pharmaceutically acceptable salt or tautomer thereof.

[0422] Exemplary Embodiment 38.p is a compound according to any one of Exemplary Embodiments 1 to 37, or a pharmaceutically acceptable salt or tautomer thereof.

[0423] Exemplary Embodiment 39.p is a compound according to any one of Exemplary Embodiments 1 to 37, or a pharmaceutically acceptable salt or tautomer thereof.

[0424] Exemplary Embodiment 40. A compound according to any one of Exemplary Embodiments 1 to 39, or a pharmaceutically acceptable salt or tautomer thereof, wherein m is 0.

[0425] Exemplary Embodiment 41.m is a compound according to any one of Exemplary Embodiments 1 to 39, or a pharmaceutically acceptable salt or tautomer thereof.

[0426] Exemplary Embodiment 42.m is a compound according to any one of Exemplary Embodiments 1 to 39, or a pharmaceutically acceptable salt or tautomer thereof.

[0427] Exemplary Embodiment 43. 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 exemplary embodiments 1 to 42, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

[0428] Exemplary Embodiment 44. Ring A of formula (a-2), (a-4), (a-5), or (a-6) is based on the following formula: [ka] The compound described in Exemplary Embodiment 43, or a pharmaceutically acceptable salt or tautomer thereof.

[0429] Exemplary Embodiment 45. 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 42, or a pharmaceutically acceptable salt or tautomer thereof.

[0430] Exemplary Embodiment 46. Ring A of formula (a-7N), (a-8N), or (a-9N) is of the following formula: [ka] The compound described in Exemplary Embodiment 45, or a pharmaceutically acceptable salt or tautomer thereof.

[0431] Exemplary Embodiment 47. 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 five-membered heteroaryl ring, where ring A, R1, and G2 are the bases of the following formula: [ka] Provided, During the ceremony, X is O, S, NH, or NR G7 And, Y is N, CH, or CR G7 And, z is 0 or 1, 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 described in any one of the exemplary embodiments 1 to 42, which is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0432] Exemplary Embodiment 48. Ring A is R 1 When G2 and G2 are linked together with the atoms to which they are bonded to form a 5-membered heteroaryl ring, the base of the following formula: [ka] The compound described in Exemplary Embodiment 47, or a pharmaceutically acceptable salt or tautomer thereof.

[0433] Exemplary Embodiment 49. Ring A is based on the following formula: [ka] The compound described in any one of the exemplary embodiments 1 to 42, or a pharmaceutically acceptable salt or tautomer thereof.

[0434] Exemplary Embodiment 50. Ring A is based on the following formula: [ka] [ka] The compound described in any one of the exemplary embodiments 1 to 42, or a pharmaceutically acceptable salt or tautomer thereof.

[0435] Exemplary Embodiment 51. Ring B of the 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.

[0436] Exemplary Embodiment 52. 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 51, which is a haloalkyl, a C3-C4 carbocykrill, or a 3-4 membered heterocycline, or a pharmaceutically acceptable salt or tautomer thereof.

[0437] Exemplary Embodiment 53. Ring B of formula (b-1), (b-2), (b-3), or (b-4) is two R 3 The bases are linked together to form 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 51, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

[0438] Exemplary Embodiment 54. 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, C1-6 A compound according to exemplary embodiment 53, which is a haloalkyl, a C3-C4 carbocykrill, or a 3-4 membered heterocycline, or a pharmaceutically acceptable salt or tautomer thereof.

[0439] Exemplary Embodiment 55. 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.

[0440] Exemplary Embodiment 56. 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.

[0441] Exemplary Embodiment 57. The compound is selected from the compounds listed in Tables 1, 2, or 3, and is one of the compounds described in any one of the preceding exemplary embodiments, or a pharmaceutically acceptable salt or tautomer thereof.

[0442] Exemplary Embodiment 58. A pharmaceutical composition comprising a compound described in any one of Exemplary Embodiments 1 to 57, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.

[0443] Exemplary Embodiment 59. A method for preparing NLRP3, comprising administering to a subject a compound described in any one of Exemplary Embodiments 1 to 57, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition described in Exemplary Embodiment 58.

[0444] Exemplary Embodiment 60. 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 57, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition described in Exemplary Embodiment 58.

[0445] Exemplary Embodiment 61. A compound according to any one of Exemplary Embodiments 1 to 57, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to Exemplary Embodiment 58, for use in treating or preventing a disease or disorder.

[0446] Exemplary Embodiment 62. Use of a compound described in any one of Exemplary Embodiments 1 to 57, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for the treatment or prevention of a disease or disorder.

[0447] Exemplary Embodiment 63. Use of any one of the exemplary embodiments 1 to 57, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment or prevention of a disease or disorder.

[0448] Exemplary Embodiment 64. The method, compound, or use according to any one of Exemplary Embodiments 59 to 63, wherein the disease or disorder is an NLRP3-related disease or disorder.

[0449] Exemplary Embodiment 65. The method, compound, or use according to any one of Exemplary Embodiments 59 to 64, wherein the subject is a human.

[0450] Exemplary Embodiment 66. The method, compound, or use according to any one of Exemplary Embodiments 59 to 65, 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.

[0451] Exemplary Embodiment 67. The method, compound, or use according to Exemplary Embodiment 66, 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 osteomyelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), Huntington's disease ("HD"), or spinal cord injury.

[0452] Exemplary Embodiment 68. The method, compound, or use according to Exemplary Embodiment 66, wherein the primary neurological disorder of the muscle is dystrophy or spinal muscular atrophy.

[0453] Exemplary Embodiment 69. The method, compound, or use according to Exemplary Embodiment 66, wherein the inflammatory disorder is gout or inflammatory anemia.

[0454] Exemplary Embodiment 70. The method, compound, or use according to Exemplary Embodiment 66, wherein the autoimmune disease is ulcerative colitis.

[0455] Exemplary Embodiment 71. The method, compound, or use according to Exemplary Embodiment 66, wherein the cancer is skin cancer or colon cancer.

[0456] Exemplary Embodiment 72. The method, compound, or use according to Exemplary Embodiment 66, wherein the infection is a neurological infection.

[0457] Exemplary Embodiment 73. The method, compound, or use according to Exemplary Embodiment 66, wherein the metabolic disorder is diabetes mellitus.

[0458] Exemplary Embodiment 74. The method, compound, or use according to Exemplary Embodiment 66, wherein the cardiovascular disease is stroke.

[0459] Exemplary Embodiment 75. The method, compound, or use according to Exemplary Embodiment 66, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.

[0460] Exemplary Embodiment 76. The method, compound, or use according to Exemplary Embodiment 66, wherein the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease.

[0461] Exemplary Embodiment 77. The method, compound, or use according to Exemplary Embodiment 66, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0462] Exemplary Embodiment 78. The method, compound, or use according to Exemplary Embodiment 66, wherein the eye disease is optic neuritis or macular degeneration.

[0463] Exemplary Embodiment 79. The method, compound, or use according to Exemplary Embodiment 66, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0464] Exemplary Embodiment 80. The method, compound, or use according to Exemplary Embodiment 66, wherein the rheumatic disease is osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0465] Exemplary Embodiment 81. The method, compound, or use according to Exemplary Embodiment 66, wherein the psychological disorder is a neuropsychiatric condition selected from the group consisting of depression, major depressive disorder, and treatment-resistant depression.

[0466] Exemplary Embodiment 82. The method, compound, or use according to Exemplary Embodiment 66, wherein the pain is pain management dependence, osteoarthritis pain, or allegorrhea.

[0467] Exemplary Embodiment 83. The method, compound, or use according to Exemplary Embodiment 66, wherein the NLRP3-related disorder is present in a subject who has been determined to have a germline or somatic nonsilent mutation in NLRP3 and is a cryopyrin-associated autoinflammatory syndrome.

[0468] Exemplary Embodiment 84. The method, compound, or use according to Exemplary Embodiment 66, 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 state, 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.

[0469] Exemplary Embodiment 85. A process for preparing a compound of formula (IA) described in any one of the preceding exemplary embodiments, or a salt or tautomer thereof, wherein the compound is synthesized according to general scheme A, B, or C. [Examples]

[0470] 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.

[0471] 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).

[0472] Gas chromatography-mass spectrometry (GCMS) chromatograms and spectra were recorded using an Agilent GCMS8890-5977 and a FID detector channel. GC parameters: DB-5MS, 12m × 0.20mm × 0.33um, column oven temperature: 50.0°C, injection volume: 0.5 μL, column flow: 1.2 ml / min, injection temperature: 300°C, injection mode: split, split ratio: 20:1, detector temperature: 300°C, initial temperature: 50°C for 1 minute, then 40°C / min to 300°C for 1.75 minutes. Makeup gas: He, makeup flow: 25.0 mL / min, H2, flow: 30.0 mL / min, air flow: 400.0 mL / min, final temperature: 300°C. MS detector acquisition mode: Start time: 2.00 min, End time: 9.00 min, Acquisition mode: Scan, Interface type: EI threshold: 150, Scan rate: 1562, Start m / z: 50.00, End m / z: 550.00, MS source: 230.00°C, MS Quad: 150.00°C, Solvent cut time: 2.00 min.

[0473] 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 in yield of 0.01–0.04%). ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (minutes).

[0474] 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); Preparation = Preparative High-Performance Liquid Chromatography.

[0475] The compounds are numbered according to the following numbering system, where R 2a and R 2b It is not hydrogen. [Table 4-1] [Table 4-2]

[0476] 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. Synthesis example Example 1. Synthesis of 1-(4-chlorophenyl)-N-[1-(1H-1,2,3,4-tetrazole-5-yl)-5-(trifluoromethyl)azepan-3-yl]cyclopropane-1-carboxamide (compound 1, rac-1) and compounds 1A*, 1B*, 1C*, and 1D* [ka] [ka]

[0477] Example 1 follows Protocol A. Step 1: 4-(trifluoromethyl)cyclohexane-1-one (5 g, 30.1 mmol, 1 equivalent), water (50 mL), ethanol (EtOH) (70 mL), CH3C(=O)ONa (3.70 g, 45.14 mmol, 1.5 equivalents), and hydroxylamine hydrochloride (3.14 g, 45.14 mmol, 1.5 equivalents) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at 100 °C for 3 hours. The progress of the reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate (SiO) (2 × 200 mL). The combined organic layers were washed with water (1 × 500 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water (10 mmol / L NH₄HCO₃), gradient from 0% to 100% over 40 minutes, detector, UV 220 nm) to obtain N-[4-(trifluoromethyl)cyclohexylidene]hydroxylamine (4 g, yield 73%). LCMS (ES, m / z): RT=0.681 min, m / z=182 [M+1] + .

[0478] Step 2: In a 2 L round-bottom flask, N-[4-(trifluoromethyl)cyclohexylidene]hydroxylamine (10 g, 55.2 mmol, 1 equivalent), benzenesulfonyl chloride (19.5 g, 110.40 mmol, 2 equivalents), Na2CO3 (23.4 g, 220.8 mmol, 4 equivalents), propan-2-one (500 mL), and water (500 mL) were added at 0°C. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate (SiO) (2 × 500 mL), the combined organic layers were washed with brine (1 × 1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was then subjected to reverse flash chromatography (column, C18 gel, mobile phase, water (0.1% NH4)). 3. Purification by acetonitrile (MeCN) in water, 0% to 100% gradient within 40 minutes, detector, UV 220 nm) yielded 5-(trifluoromethyl)azepan-2-one (9 g, 90% yield). LC-MS (ES, m / z): RT = 0.530 min, m / z = 182 [M + H] + .

[0479] Step 3: 5-(trifluoromethyl)azepan-2-one (8 g, 44.2 mmol, 1 equivalent), CHCl3 (250 mL), and PCl5 (18.4 g, 88.32 mmol, 2 equivalents) were added to a 500 mL round-bottom flask at 0°C. The resulting mixture was stirred at 0°C for 30 minutes under a nitrogen atmosphere. ZnI2 (0.51 g, 1.59 mmol, 0.036 equivalents) was added to the mixture at 0°C. The resulting mixture was stirred for a further 30 minutes at 0°C. Br2 (14.11 g, 88.32 mmol, 2 equivalents) was added to the mixture at 0°C. The resulting mixture was stirred overnight at room temperature. The progress of the reaction was monitored by LC-MS. The reaction was quenched at room temperature with saturated sodium hyposulfite (500 mL aqueous solution, 0.5 mol / L), extracted with dichloromethane (DCM) (3 × 500 mL), washed with water (1 × 1 L), dried over anhydrous Na₂SO₄, filtered, and concentrated the filtrate under reduced pressure to obtain 3,3-dibromo-5-(trifluoromethyl)azepan-2-one (6 g, 40% yield). LCMS (ES, m / z): RT = 0.785 min, m / z = 338 [M + H] + .

[0480] Step 4: 3,3-dibromo-5-(trifluoromethyl)azepan-2-one (10 g, 29.50 mmol, 1 equivalent), dichloromethane (DCM) (100 mL), dichloroethylamine (diisopropylethylamine (DIEA)) (3.81 g, 29.50 mmol, 1 equivalent), and diethoxyphosphinic acid (8.15 g, 59.006 mmol, 2 equivalents) were added to a 250 mL vial at 0°C. The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere, and then stirred again at 50°C for another 1 hour under a nitrogen atmosphere. The progress of the reaction was monitored by LC-MS. The resulting mixture was extracted with dichloromethane (DCM) (2 × 200 mL), the combined organic layer was washed with water (1 × 500 mL), dried over anhydrous sodium 2SO4, filtered, concentrated under reduced pressure, and the residue was purified by reverse flash chromatography (column, silica gel, mobile phase, acetonitrile (MeCN) in water, gradient from 0% to 100% over 40 minutes, detector, UV 254 nm) to obtain 3-bromo-5-(trifluoromethyl)azepan-2-one (5 g, yield 65%). LCMS (ES, m / z): RT = 0.680 min, m / z = 260 [M+1] + .

[0481] Step 5: 3-bromo-5-(trifluoromethyl)azepan-2-one (7 g, 26.91 mmol, 1 equivalent), dimethylformamide (DMF) (70 mL), and tetrabutylazidoamine (11.49 g, 40.37 mmol, 1.5 equivalents) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. The progress of the reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate (siRNA) (2 × 200 mL), and the combined organic layer was washed with water (1 × 500 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 3-azido-5-(trifluoromethyl)azepan-2-one was used directly in the next step without further purification (4 g, 67% yield). LCMS(ES,m / z): RT=0.371 min, m / z=223 [M+1] + .

[0482] Step 6: 3-Azido-5-(trifluoromethyl)azepan-2-one (6 g, 27.00 mmol, 1 equivalent), Pd / C (1437 mg, 13.50 mmol, 0.5 equivalents), and methanol (MeOH) (200 mL) were added to a 500 mL round-bottom flask at room temperature. The resulting mixture was stirred for 1 hour under a hydrogen atmosphere at room temperature. The progress of the reaction was monitored by LC-MS, and upon completion, the resulting mixture was filtered, and the filter cake was washed with methanol (MeOH) (1 × 50 mL). 3-Amino-5-(trifluoromethyl)azepan-2-one was obtained. The resulting mixture was used directly in the next step without further purification. LC-MS (ES, m / z): RT = 0.675 min, m / z = 197 [M+1] + .

[0483] Step 7: The reaction mixture from Step 6, consisting of 3-amino-5-(trifluoromethyl)azepan-2-one (25.48 mmol, 1 equivalent), diterbutyl dicarbonate (Boc2O) (11.13 g, 50.97 mmol, 2 equivalents), and triethylamine (TEA) (7.74 g, 76.46 mmol, 3 equivalents), was added to a 500 mL round-bottom flask at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LC-MS, and upon completion, the resulting mixture was extracted with ethyl acetate (SiO2) (2 × 100 mL). The combined organic layers were washed with brine (1 × 100 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 (PE) / ethyl acetate (EA) (1:1) to obtain tert-butyl N-[2-oxo-5-(trifluoromethyl)azepan-3-yl]carbamate (3g, 40% yield). LCMS (ES, m / z): RT=0.675 min, m / z=197 [M+1] + .

[0484] Step 8: In an 8 mL vial, add tert-butyl N-[2-oxo-5-(trifluoromethyl)azepan-3-yl]carbamate (120 mg, 0.40 mmol, 1 equivalent) and boranetetrahydrofuran complex (BH3. Tetrahydrofuran (THF) (2 mL) was added at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The progress of the reaction was monitored by LC-MS, and upon completion, the reaction was quenched with methanol (MeOH) (3 mL) at 0°C. The resulting mixture was extracted with ethyl acetate ( Depositphotos) (3 × 20 mL). The combined organic layers were washed with water (1 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded tert-butyl N-[5-(trifluoromethyl)azepan-3-yl]carbamate (80 mg, yield 70%), which was crudely prepared and used in the next step. LC-MS (ES, m / z): RT = 0.603 min, m / z = 283 [M+1] + .

[0485] Step 9: In an 8 mL vial, tert-butyl N-[5-(trifluoromethyl)azepan-3-yl]carbamate (80 mg, 0.28 mmol, 1 equivalent), K2CO3 (117.49 mg, 0.84 mmol, 3 equivalents), acetonitrile (MeCN) (2 mL), and BrCN (60.03 mg, 0.56 mmol, 2 equivalents) were added at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate ( Depositphotos) (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded tert-butyl N-[1-cyano-5-(trifluoromethyl)azepan-3-yl]carbamate (50 mg, yield 57%). LCMS(ES,m / z): RT=0.874 min, m / z=308 [M+1] + .

[0486] Step 10: In an 8 mL vial, tert-butyl N-[1-cyano-5-(trifluoromethyl)azepan-3-yl]carbamate (60 mg, 0.19 mmol, 1 equivalent), NH4Cl (31.33 mg, 0.58 mmol, 3 equivalents), azidotrimethylsilane (67.48 mg, 0.58 mmol, 3 equivalents), and DMF (2 mL) were added at room temperature. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 hour. The progress of the reaction was monitored by LC-MS. The crude mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (RINKAN) (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 gel, mobile phase, acetonitrile (MeCN) in water (0.1% NH3 in water), gradient from 0% to 100% over 40 minutes, detector, UV 220 nm) to obtain tert-butyl N-[1-(1H-1,2,3,4-tetrazole-5-yl)-5-(trifluoromethyl)azepan-3-yl]carbamate (40 mg, yield 58%). LCMS (ES, m / z): RT=0.751 min, m / z=351 [M+1] + .

[0487] Step 11: In an 8 mL vial, tert-butyl N-[1-(1H-1,2,3,4-tetrazole-5-yl)-5-(trifluoromethyl)azepan-3-yl]carbamate (50 mg, 0.14 mmol, 1 equivalent) and HCl (gas) were added to 1,4-dioxane (2 mL) at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum to obtain the crude product 1-(1H-1,2,3,4-tetrazole-5-yl)-5-(trifluoromethyl)azepan-3-amine (30 mg HCl salt) ("Amine(i) Reagent"), which was used directly in the next step without further purification. LC-MS (ES, m / z): RT = 0.184 min, m / z = 251 [M+1] + .

[0488] Step 12: 1-(1H-1,2,3,4-tetrazole-5-yl)-5-(trifluoromethyl)azepan-3-amine (30 mg, 0.120 mmol, 1 equivalent) and 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (23.57 mg, 0.12 mmol, 1 equivalent), acetonitrile (MeCN) (1.5 mL), N-methylimidazole (NMI) (39.37 mg, 0.48 mmol, 4 equivalents), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (40.37 mg, 0.14 mmol, 1.2 equivalents) were added to an 8 mL vial at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LC-MS. The crude mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (HCl) (3 × 20 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. The residue was purified by reverse flash chromatography (C18 gel, mobile phase, acetonitrile (MeCN) in water (0.1% NH3 in water), gradient from 0% to 100% over 40 minutes, detector, UV 220 nm) to obtain the crude product 1-(4-chlorophenyl)-N-[1-(1H-1,2,3,4-tetrazole-5-yl)-5-(trifluoromethyl)azepan-3-yl]cyclopropane-1-carboxamide (compound 1, rac-1), (15 mg, 60% purity). This was further purified by preparative HPLC (XBridge preparative OBD C18 column, 30 × 150 mm, 5 μm, mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (27% to 37% over 8 minutes), detector, UV 220 nm) to obtain a mixture of trans and cis isomers (2.8 mg). LCMS(ES,m / z): RT=1.642 min, m / z=429 [M+1] + . 1H NMR (400MHz, methanol-d4) δ 7.45-7.33(m,4H),4.19-4.04(m,1H),3.82-3.63(m,2H),3.56-3.42(m,2H),2.28(q,J=10.4Hz,1H ),2.19-2.09(m,1H),2.07-1.95(m,1H),1.82-1.68(m,1H),1.59-1.37(m,3H),1.17-1.02(m,2H).

[0489] Step 13: Compounds 1A*, 1B*, 1C*, and 1D* can be isolated from rac-1 by chiral HPLC. Assign their stereochemistry as desired. Example 2. Synthesis of 1-(4-cyclopropylphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 2, rac-2), and compounds 2A*, 2B*, 2C*, and 2D* Scheme 2A. [ka] Scheme 2B. [ka] Scheme 2C. [ka]

[0490] Example 2 follows Protocol A. Step 1: Ethyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (1.00 g, 3.72 mmol, 1 equivalent), tetrahydrofuran (THF) (10 mL), bromo(cyclopropyl)zinc (1.73 g, 9.29 mmol, 2.50 equivalents), and bis(tri-tert-butylphosphine)palladium(0)(Pd(t-Bu3P)2) (0.57 g, 1.12 mmol, 0.30 equivalents) were added to a 40 mL vial under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80 °C for 4 hours. The resulting mixture was concentrated under vacuum and then extracted with ethyl acetate (SiO) (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 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 (5:1) to obtain ethyl 1-(4-cyclopropylphenyl)cyclopropane-1-carboxylate (560 mg, 65% yield). LCMS (ESI): RT=1.42 min, m / z=231.0 [M+H] + .

[0491] Step 2: Ethyl 1-(4-cyclopropylphenyl)cyclopropane-1-carboxylate (260 mg, 1.13 mmol, 1 equivalent), ethanol (EtOH) (4 mL), water (1 mL), and NaOH (135.46 mg, 3.39 mmol, 3 equivalents) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 3 with HCl (aqueous solution). The resulting mixture was extracted with ethyl acetate (SiO) (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 20% to 55% gradient over 10 minutes, detector, UV 254 nm) to obtain 1-(4-cyclopropylphenyl)cyclopropane-1-carboxylic acid (220 mg, yield 96%). LCMS (ESI): RT=0.84 min, m / z=203.0 [M+H] + .

[0492] Step 3: In an 8 mL vial, add 1-(4-cyclopropylphenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (123.67 mg, 0.61 mmol, 1 equivalent), dimethylformamide (DMF) (2 mL), 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepan-3-amine ("Amine(i) Reagent") (120 mg, 0.61 mmol, 1 equivalent), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (302.24 mg, 0.79 mmol, 1.3 equivalents) and triethylamine (TEA) (185.62 mg, 1.83 mmol, 3 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 4 hours and then extracted with ethyl acetate (RINKAN) (3 × 5 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain crude 1-(4-cyclopropylphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 2, rac-2) (70 mg, purity 85%).

[0493] Step 4: The residue was purified by preparative HPLC (Xselect CSH C18 OBD column 30*150 mm 5 μm, mobile phase: acetonitrile (MeCN) and water (0.05% trifluoroacetic acid (TFA)) (37% water, 0.05% trifluoroacetic acid (TFA), max 47% at 8 min, max 54% at 4 min), detector: UV 254 nm) to obtain a mixture of the assumed trans isomers (RT(min) = 7.82, 40 mg) and a mixture of the assumed cis isomers (RT(min) = 14.35, 40 mg), and their stereochemistry was arbitrarily assigned.

[0494] Step 5: The expected trans mixture product (40 mg) was purified by chiral preparative HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA), mobile phase B: isopropanol, flow rate: 20 mL / min, gradient: 50%B to 50%B at 17 min, wavelength: 220 / 254 nm) to obtain compound 2B* (RT(min): 9.58, 2.8 mg) and compound 2C* (RT(min): 14.35, 2.8 mg). Stereochemistry was arbitrarily assigned.

[0495] Compound 2B*:LCMS(ESI): RT=0.84 min, m / z=381.0[M+H] + , 1H NMR (400MHz, methanol-d4) δ 7.10-7.03(m,2H),6.95-6.88(m,2H),4.19(d,J=5.0Hz,1H),3.85-3.76(m,1H),3.54(dd,J=15.0,1.7Hz,1H),3.45-3.35(m,1H),3. 12-3.00(m,1H),1.93-1.82(m,1H),1.81-1.57(m,3H),1.56-1.28(m,5H),1.07-1.00(m,2H),1.00-0.93(m,5H),0.76-0.62(m,2H).

[0496] Compound 2C*:LCMS(ESI): RT=0.83 min, m / z=381.0[M+H] + ;1H NMR(400MHz, methanol-d4) δ 7.09-7.03(m,2H),6.91(d,J=7.9Hz,2H),4.19(d,J=5.0Hz,1H),3.85-3.76(m,1H),3.58-3.50(m,1H),3.45-3.35(m,1H),3.12- 3.00(m,1H),1.93-1.82(m,1H),1.80-1.57(m,3H),1.55-1.25(m,5H),1.07-1.01(m,2H),1.00-0.92(m,5H),0.76-0.61(m,2H).

[0497] Step 6: The expected cis-compound product (40 mg) was further purified by chiral-preparative HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase: hexane (0.1% trifluoroacetic acid (TFA)) and methanol (MeOH):ethanol (EtOH) (1:1) (50% MeOH:EtOH = 1:1 maintained at 8 mins), detector: UV 254 nm) to obtain compound 2D* (RT(min) = 6.59, 8.9 mg) and compound 2A* (RT(min) = 7.56, 17.5 mg). Stereochemistry was arbitrarily assigned.

[0498] Compound 2A*:LCMS(ESI): RT=1.63 min, m / z=381.0[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 7.32-7.25(m,2H),7.14-7.07(m,2H),4.01-3.90(m,1H),3.64-3.53(m,2H),3.53-3.40(m,2H),1.99-1.88(m,1H),1.88-1.80(m,1) H),1.71-1.60(m,2H),1.58-1.40(m,3H),1.31(s,0H),1.28-1.16(m,1H),1.16-1.03(m,2H),1.03-0.88(m,5H),0.76-0.67(m,2H).

[0499] Compound 2D*:LCMS(ESI): RT=0.94 min, m / z=381.0[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.31-7.25(m,2H),7.14-7.07(m,2H),4.01-3.90(m,1H),3.69-3.53(m,2H),3.53-3.39(m,3H),1.99-1.88(m,1H),1.85(d,J=14. 5Hz,1H),1.67(d,J=13.9Hz,2H),1.58-1.48(m,3H),1.28-1.15(m,1H),1.13-1.03(m,2H),1.03-0.93(m,5H),0.76-0.67(m,2H). Example 3. Synthesis of 1-(4-(difluoromethoxy)-2-fluorophenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 3, rac-3) and compounds 3A*, 3B*, 3C*, and 3D* Scheme 3A. [ka] Scheme 3B. [ka] Scheme 3C. [ka]

[0500] Example 3 follows Protocol A. Step 1: Methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (450 mg, 2.443 mmol, 1 equivalent), sodium 2-chloro-2,2-difluoroacetate (558.79 mg, 3.665 mmol, 1.5 equivalents), K2CO3 (1013.09 mg, 7.329 mmol, 3 equivalents), and dimethylformamide (DMF) (3 mL) were added to an 8 mL vial. The resulting mixture was stirred for 2 hours under an air atmosphere at 80°C. The desired product could be detected by LC-MS. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 15 mL). The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (6:1) to obtain 2-[4-(difluoromethoxy)-2-fluorophenyl]acetate (300 mg, yield 52%).

[0501] Step 2: Methyl 2-[4-(difluoromethoxy)-2-fluorophenyl]acetate (320 mg, 1.367 mmol, 1 equivalent), diphenylvinylsulfonium triflate (594.23 mg, 1.640 mmol, 1.2 equivalents), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (624.11 mg, 4.101 mmol, 3 equivalents), and dimethyl sulfoxide (DMSO) (5 mL, 4.224 mmol) were added to a 20 mL vial. The resulting mixture was stirred for 1 hour under an air atmosphere at room temperature. The desired product could be detected by LC-MS. The aqueous layer was extracted with ethyl acetate (siRNA) (3 × 10 mL). The residue was purified by silica gel column chromatography eluted with dichloromethane (DCM):petroleum ether (1:4) to obtain 1-[4-(difluoromethoxy)-2-fluorophenyl]cyclopropane-1-carboxylic acid (305 mg, yield 86%).

[0502] Step 3: 1-[4-(difluoromethoxy)-2-fluorophenyl]cyclopropane-1-carboxylic acid (300 mg, 1.153 mmol, 1 equivalent), NaOH (138.34 mg, 3.459 mmol, 3 equivalents), methanol (MeOH) (5 mL), and water (1 mL) were added to a 20 mL vial. The resulting mixture was stirred overnight under an air atmosphere at 40°C. The desired product could be detected by LC-MS. The resulting residue was dried under vacuum. The mixture was acidified to pH 3 with concentrated HCl. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 10 mL) to obtain 1-[4-(difluoromethoxy)-2-fluorophenyl]cyclopropane-1-carboxylic acid (284 mg, yield 85%).

[0503] Steps 4-5: 1-[4-(difluoromethoxy)-2-fluorophenyl]cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (156.80 mg, 0.637 mmol, 1 equivalent), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (242.18 mg, 0.637 mmol, 1 equivalent), triethylamine (TEA) (193.36 mg, 1.911 mmol, 3 equivalents), and dimethylformamide (DMF) (2.5 mL) were added to an 8 mL vial at room temperature for 30 minutes. To the above mixture, 5-methyl-1-(1H-1,2,3,4-tetra (Zol-5-yl)azepan-3-amine ("Amine(i) Reagent") (150 mg, 0.764 mmol, 1.2 equivalents) was added. The resulting mixture was stirred at room temperature for a further 2 hours. The desired product could be detected by LC-MS. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN):water = 3:7) to obtain 1-(4-(difluoromethoxy)-2-fluorophenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 3, rac-3) as a mixture of cis and trans isomers. The crude product was subjected to preparative HPLC (XBridge The samples were purified using a Shield RP18 OBD 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: 20%B to 35%B, 35%B over 8 min, wavelength: 254 nm, RT(min): 7.5 min for trans isomers and RT(min): 9.8 min for cis isomers) to obtain a mixture of the cis isomer (12 mg, yield 4.4%), which is assumed to be the second elution peak, and a mixture of the trans isomer (22 mg, yield 8.1%), which is assumed to be the first elution peak, and their stereochemistry was arbitrarily assigned.

[0504] Step 6: The mixture of trans isomers expected from Step 5 was purified by preparative-CHIRAL HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: isopropyl alcohol (IPA), flow rate: 20 mL / min, gradient: 30%B to 30%B at 13 min, wavelength: 220 - 254 nm) to obtain compound 3B* (RT(min): 8.71, 5.20 mg, yield 2%) and compound 3C* (RT(min): 11.29, 4.9 mg, yield 2%). Stereochemistry was arbitrarily assigned.

[0505] Compound 3B*:LCMS(ES,m / z): RT=0.99 min, m / z=425.2[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.33-7.26(m,1H),7.14-6.73(m,3H),4.22-4.13(m,1H),3.83-3.74(m,1H),3.61-3.54(m,1H),3.49-3.41(m,1H), 3.26-3.17(m,1H),1.86-1.77(m,2H),1.69-1.50(m,4H),1.47-1.38(m,1H),1.18-1.10(m,1H),1.04-0.95(m,4H).

[0506] Compound 3C*:LCMS(ES,m / z): RT=0.99 min, m / z=425.2[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.33-7.26(m,1H),7.14-6.73(m,3H),4.22-4.13(m,1H),3.83-3.74(m,1H),3.61-3.54(m,1H),3.49-3.41(m,1H), 3.26-3.17(m,1H),1.86-1.77(m,2H),1.69-1.50(m,4H),1.47-1.38(m,1H),1.18-1.10(m,1H),1.04-0.95(m,4H).

[0507] Step 7: The mixture of cis isomers from Step 5 was purified by chiral HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: isopropanol (IPA); flow rate: 20 mL / min, gradient: 30%B to 30%B at 11 min, wavelength: 220 - 254 nm) to obtain compound 3A* (RT(min): 9.57, 2.0 mg) and compound 3D* (RT(min): 7.64, 2.0 mg). Stereochemistry was arbitrarily assigned.

[0508] Compound 3A*: LCMS (ES, m / z): RT=1.11 min, m / z=425.2[M+H]+, 1 H NMR (400MHz, methanol-d4) δ 7.48-7.41(m,1H),7.19-6.78(m,3H),4.13-3.95(m,1H),3.68-3.59(m,2H),3.59-3.49(m,1H),3.43-3.35(m,1H),1.84-1.75 (m,1H),1.75-1.68(m,1H),1.67-1.60(m,1H),1.61-1.55(m,2H),1.49-1.36(m,1H),1.17-1.03(m,3H),0.97(d,J=6.8Hz,3H).

[0509] Compound 3D*:LCMS(ES,m / z): RT=1.11 min, m / z=425.2[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.48-7.41(m,1H),7.18-6.78(m,3H),4.13-3.99(m,1H),3.67-3.57(m,2H),3.57-3.49(m,1H),3.43-3.35(m,1H),1.84-1.7 5(m,1H),1.74-1.68(m,1H),1.68-1.61(m,1H),1.61-1.54(m,2H),1.49-1.37(m,1H),1.17-1.02(m,3H),0.99-0.91(m,3H). Example 4.1 Synthesis of 1-(4-chloro-2,3-difluorophenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 4, rac-4) and compounds 4A*, 4B*, 4C*, and 4D* Scheme 4A. [ka] Scheme 4B. [ka] Scheme 4C. [ka]

[0510] Example 4 follows Protocol A. Step 1: 1-Bromo-4-chloro-2,3-difluorobenzene (100 mg, 0.44 mmol, 1 equivalent), bis(tri-tert-butylphosphine)palladium(0)(Pd(t-Bu3P)2) (22.47 mg, 0.04 mmol, 0.1 equivalent), tetrahydrofuran (THF) (3 mL), and tert-butyl 2-(bromodinthio)acetate (229.03 mg, 0.88 mmol, 2 equivalents) were added to a 40 mL round-bottom flask at room temperature. The mixture was stirred under a nitrogen atmosphere at 80°C for 2 hours. The desired product could be detected by GC-MS. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (8:1) to obtain tert-butyl 2-(4-chloro-2,3-difluorophenyl)acetate (30 mg, yield 26%).

[0511] Step 2: In a 25 mL round-bottom flask, tert-butyl 2-(4-chloro-2,3-difluorophenyl) acetate (180 mg, 0.68 mmol, 1 equivalent), ethenyldiphenylsulfanium (292.35 mg, 1.37 mmol, 2 equivalents, triflate), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (312.97 mg, 2.05 mmol, 3 equivalents), and dimethyl sulfoxide (DMSO) (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 6 hours. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 10:1) to obtain tert-butyl 1-(4-chloro-2,3-difluorophenyl)cyclopropane-1-carboxylate (100 mg, yield 51%).

[0512] Step 3: In a 100 mL round-bottom flask, tert-butyl 1-(4-chloro-2,3-difluorophenyl)cyclopropane-1-carboxylate (150 mg, 0.52 mmol, 1 equivalent), trifluoroacetic acid (TFA) (1.50 mL), and dichloromethane (DCM) (2 mL) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. This yielded 1-(4-chloro-2,3-difluorophenyl)cyclopropane-1-carboxylic acid (130 mg, yield >100%). LC-MS (ES, m / z): RT = 0.82 min, m / z = 231 [M-1] - .

[0513] Step 4: 1-(4-chloro-2,3-difluorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (130 mg, 0.55 mmol, 1 equivalent), hydroxybenzotriazole (HOBT) (151 mg, 1.11 mmol, 2 equivalents), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (214.27 mg, 1.11 mmol, 2 equivalents), diisopropylethylamine (DIEA) (216.70 mg, 1.67 mmol, 3 equivalents), dimethylformamide (DMF) (0.50 mL), and 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepan-3-amine ("Amine(i) Reagent") (120.65 mg, 0.61 mmol, 1.1 equivalents) were added to a 40 mL round-bottom flask at room temperature. The mixture was stirred at room temperature for 2 hours. The desired product could be detected by LC-MS. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient over 30 mins, detector, UV 254 nm) to obtain 1-(4-chloro-2,3-difluorophenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 4, rac-4) (110 mg, yield 48%). LC-MS (ES, m / z): RT=0.83 min, m / z=411 [M+1] + .

[0514] Step 5: Crude rac-4 (100 mg) is purified by preparative HPLC (Xselect CSH C18 OBD column, 30 × 150 mm 5 μm, mobile phase A: acetonitrile (MeCN), mobile phase B: water (0.05% trifluoroacetic acid (TFA)), flow rate: 60 mL / min, gradient: 36%B~46%B at 8 min, 46%B~56%B, 56%B at 12 min, wavelength: 254 / 220 nm) to obtain a mixture of the expected trans isomers (25 mg, LCMS (ES, m / z): RT=0.63 min, m / z=411 [M+1]). + ) is used as the first elution peak, and the cis mixture of the suspected isomers (18 mg, LCMS (ES, m / z): RT=0.66 min, m / z=411 [M+1]) +) was obtained as the second elution peak.

[0515] Step 6: The trans mixture of isomers expected from Step 5 was purified by preparative-CHIRAL HPLC (CHIRAL ART cellulose-SB, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: isopropanol (IPA): dichloromethane (DCM) = 1:1, flow rate: 20 mL / min, gradient: 20%B to 20%B at 11 min, wavelength: 254 / 220 nm) to obtain compound 4B* (RT(min): 9.05, 11.5 mg) and compound 4C* (RT(min): 10.70, 9.6 mg). Stereochemistry was arbitrarily assigned.

[0516] Compound 4B*:LCMS(ES,m / z): LCMS RT=1.38 min, m / z=411[M+1] + , 1 H NMR(400MHz,DMSO-d6) δ 7.36(d,J=8.7,6.8,1.8Hz,1H),7.20(d,J=8.9,7.2,2.0Hz,1H),6.89(d,J=7.7Hz,1H),4.19(q,J=7.1 ,5.1Hz,1H),3.55(t,J=14.9,9.7,6.3Hz,3H),3.24(d,J=13.7,8.8,4.6Hz,1H),1.82-1.75(m,1H),1.7 1(d,J=14.6,6.8Hz,1H),1.58-1.51(m,1H),1.43(t,J=13.5,7.0,6.2,3.7Hz,3H),1.32(d,J=13.9,9. 0,4.6Hz,1H),1.11(d,J=10.2,6.2,3.3Hz,1H),0.99(d,J=8.9,6.3,3.0Hz,1H),0.87(d,J=6.9Hz,2H).

[0517] Compound 4C*:LCMS(ES,m / z): RT=1.37 min, m / z=411[M+1] + , 1H NMR(400MHz,DMSO-d6) δ 7.36(d,J=8.8,6.8,1.9Hz,1H),7.20(d,J=9.0,7.0,2.0Hz,1H),6.88(s,1H),4.20(d,J=6.0H z,1H),3.58(d,J=14.9,5.1Hz,3H),3.52(d,J=6.9Hz,1H),1.79(d,J=7.0Hz,1H),1.69(d,J=1 4.9Hz,1H),1.59-1.51(m,1H),1.43(t,J=16.0,6.1,3.5Hz,3H),1.32(d,J=13.8,8.9,4.5Hz, 1H),1.11(d,J=10.2,6.3,3.2Hz,1H),0.99(d,J=9.0,6.3,3.0Hz,1H),0.87(d,J=6.8Hz,3H).

[0518] Step 7: The cis mixture of the isomers expected from Step 5 was purified by preparative-CHIRAL HPLC (CHIRAL ART cellulose-SB, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: isopropanol (IPA): dichloromethane (DCM) = 1:1, flow rate: 20 mL / min, gradient: 12%B to 12%B at 20 min, wavelength: 220 / 254 nm) to obtain compound 4A* (RT(min): 16.46, 5.2 mg) and compound 4D* (RT(min): 18.42, 5.8 mg). Stereochemistry was arbitrarily assigned.

[0519] Compound 4A*:LCMS(ES,m / z): RT=1.53 min, m / z=411[M+1] + , 1 H NMR(400MHz,DMSO-d6) δ 7.47-7.32(m,1H),7.29-7.20(m,1H),3.58(dd,J=14.3,5.5Hz,1H),3.53-3.47(m,1H),3.45-3.40(m,1H),3.33-3.27(m,1H),1.72(d,J=13. 6Hz,1H),1.54(dd,J=13.3,4.3Hz,1H),1.44(d,J=3.1Hz,1H),1.37-1.22(m,1H),1.07(ddd,J=20.0,12.8,9.8Hz,2H),0.88(d,J=6.6Hz,2H).

[0520] Compound 4D*:LCMS(ES,m / z): RT=1.53 min, m / z=411[M+1] + , 1 H NMR(400MHz,DMSO-d6) δ 7.45-7.36(m,2H),7.29-7.20(m,1H),4.00(s,1H),3.58(dd,J=14.4,5. 5Hz,1H),3.51(d,J=13.6Hz,1H),3.45-3.40(m,2H),3.39(s,1H),1.73( d,J=14.1Hz,1H),1.54(d,J=12.8Hz,1H),1.44(d,J=3.1Hz,2H),1.36-1.24(m,1H),1.07(ddd,J=19.8,12.8,9.8Hz,3H),0.88(d,J=6.7Hz,3H). Example 5. Synthesis of 1-(4-(difluoromethyl)phenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 5, rac-5) and compounds 5A*, 5B*, 5C*, and 5D* Scheme 5A. [ka] Scheme 5B. [ka] Scheme 5C. [ka]

[0521] Example 5 follows Protocol A. Step 1: Methyl 2-(4-formylphenyl)acetate (1 g, 5.61 mmol, 1 equivalent), diethylaminosulfur trifluoride (DAST) (17 mL, 0.105 mmol, 0.02 equivalents), and dichloromethane (DCM) (20 mL) were added to a 100 mL round-bottom flask at 0°C. The mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The reaction was quenched with NaHCO3 (aqueous solution) at room temperature. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to obtain methyl 2-[4-(difluoromethyl)phenyl]acetate (800 mg, yield 71%).

[0522] Step 2: Methyl 2-[4-(difluoromethyl)phenyl]acetate (800 mg, 3.99 mmol, 1 equivalent), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3650.41 mg, 23.97 mmol, 6 equivalents), dimethyl sulfoxide (DMSO) (5 mL), and ethenyldiphenylsulfanium triflate (2896.36 mg, 7.99 mmol, 2 equivalents) were added to a 100 mL round-bottom flask at room temperature. The mixture was stirred at room temperature for 2 hours. The desired product could be detected by GC-MS. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain methyl 1-[4-(difluoromethyl)phenyl]cyclopropane-1-carboxylate (500 mg, yield 55%).

[0523] Step 3: Methyl 1-[4-(difluoromethyl)phenyl]cyclopropane-1-carboxylate (450 mg, 1.98 mmol, 1 equivalent), methanol (MeOH) (5 mL), water (1 mL), and NaOH (795.62 mg, 19.89 mmol, 10 equivalents) were added to a 50 mL round-bottom flask at room temperature. The desired product could be detected by LC-MS. The resulting mixture was extracted with water (3 × 10 mL). To the above mixture, HCl (aqueous solution) (10 mL, 1 mol / L) was added at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 20 mL), and the layers were combined. After filtration, the filtrate was dried over sodium sulfate and concentrated under reduced pressure. This yielded 1-[4-(difluoromethyl)phenyl]cyclopropane-1-carboxylic acid (400 mg, 95% yield). LCMS(ES,m / z): RT=0.72 min, m / z=211[M-1] - .

[0524] Step 4: 1-[4-(difluoromethyl)phenyl]cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (100 mg, 0.47 mmol, 1 equivalent), diisopropylethylamine (DIEA) (182.73 mg, 1.41 mmol, 3 equivalents), dimethylformamide (DMF) (4 mL), and 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepane-3-amine ("Amine(i) Reagent") (101.74 mg, 0.51 mmol, 1.1 equivalents) were added to a 40 mL round-bottom flask at room temperature. The mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient over 30 minutes, detector, UV 254 nm) to obtain 1-(4-(difluoromethyl)phenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 5, rac-5) (100 mg, yield 48%). LCMS (ES, m / z): RT=0.84 min, m / z=391 [M+1] + .

[0525] Step 5: The crude product rac-5 (100 mg) was purified by preparative HPLC (XBridge preparative phenyl OBD column, 19 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile (MeCN), flow rate: 60 mL / min, gradient: 20%B~28%B, 28%B at 8 min, wavelength: 254 nm) to obtain a mixture of the expected trans isomers (26 mg, LCMS (ES, m / z): RT=0.78 min, m / z=391 [M+1]). + ) is used as the first elution peak, and the mixture of cis isomers is expected to be (40 mg, LCMS (ES, m / z): RT=0.79 min, m / z=391 [M+1] + ) was obtained as the second elution peak, and its stereochemistry was arbitrarily assigned.

[0526] Step 6: The mixture of the trans isomers of rac-5 was separated by chiral HPLC (CHIRAL ART cellulose-SC, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: isopropanol (IPA): dichloromethane (DCM) = 1:1, flow rate: 20 mL / min, gradient: 35%B~35%B at 43 min, wavelength: 254 / 220 nm) to obtain compound 5B* (RT(min): 29.35, 3.7 mg) and compound 5C* (RT(min): 38.07, 5.6 mg). Stereochemistry was arbitrarily assigned.

[0527] Compound 5B*:LCMS(ES,m / z): RT=1.23 min, m / z=391[M+1] + , 11H NMR (400MHz, DMSO-d6) δ 7.44(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),6.99(s,1H),6.55(d,J=8.2Hz,1 H),4.19(dp,J=10.3,5.1Hz,1H),3.58(d,J=1.5Hz,2H),3.49(dt,J=13.4,4.7 Hz,1H),3.11(ddd,J=13.7,10.2,4.2Hz,1H),1.65(dd,J=11.2,7.0Hz,2H),1. 61-1.41(m,2H),1.41-1.24(m,3H),1.07-0.94(m,2H),0.87(d,J=6.7Hz,3H).

[0528] Compound 5C*:LCMS(ES,m / z): RT=0.73 min, m / z=391[M+1] + , 1 H NMR(400MHz,DMSO-d6) δ 7.44(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),6.55(d,J=8.2Hz,1H),4.19(d,J=10.1,5.0Hz,1H),3.52-3.47(m,3H),3.11(d,J=13.7,10 .3,4.2Hz,1H),1.69-1.58(m,2H),1.49(d,J=20.1,14.9,10.2,4.8Hz,2H),1.42-1.22(m,3H),1.09-0.94(m,2H),0.87(d,J=6.7Hz,3H).

[0529] Step 7: The mixture of cis isomers of rac-5 was separated by chiral HPLC (LUX 5μm cellulose-4, 2.12 × 25 cm, 5μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: isopropanol (IPA), flow rate: 20 mL / min, gradient: 50%B to 50%B at 13.5 min, wavelength: 254 / 220 nm) to obtain compound 5A* (RT(min): 11.63, 4.3 mg) and compound 5D* (RT(min): 8.02, 7.2 mg). Stereochemistry was arbitrarily assigned.

[0530] Compound 5A*LCMS (ES, m / z): RT=1.40 min, m / z=391[M+1]+ , 1 1H NMR (400MHz, DMSO-d6) δ 7.55(d,J=8.0Hz,2H),7.48(d,J=8.0Hz,2H),7.20-6.88(m,2H),3.96(d,J=12 .0,3.7Hz,1H),3.57(d,J=14.1,5.2Hz,1H),3.41(d,J=24.4,18.7,14.4,9.9, 4.6Hz,3H),1.74(d,J=13.4,3.9Hz,1H),1.52(td,J=11.6,10.5,6.1Hz,2H),1 .41-1.31(m,2H),1.29-1.12(m,2H),1.08-0.97(m,2H),0.88(d,J=6.6Hz,3H).

[0531] Compound 5D*LCMS (ES, m / z): RT=1.39 min, m / z=391[M+1] + , 1 H NMR(400MHz,DMSO-d6) δ 7.55(d,J=8.0Hz,2H),7.48(d,J=8.0Hz,2H),7.19-6.87(m,2H),3.97(d,J=11.3,4.1Hz,1H),3.57(d,J=14.1,5.2Hz,2H),3.46-3.34 (m,2H),1.75(d,J=14.2,4.0Hz,1H),1.52(td,J=11.3,9.8,5.9Hz,2H),1.45-1.13(m,4H),1.08-0.97(m,2H),0.88(d,J=6.7Hz,3H). Example 6. Synthesis of N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)-1-(3-methyl-4-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide (compound 6, rac-6) and compounds 6A*, 6B*, 6C*, and 6D* Scheme 6A. [ka] Scheme 6B. [ka] Scheme 6C. [ka]

[0532] Example 6 follows Protocol A. Step 1: 4-bromo-2-methyl-1-(trifluoromethyl)benzene (700 mg, 2.92 mmol, 1 equivalent), bis(tri-tert-butylphosphine)palladium(0)(Pd[(t-Bu)3P]2) (448.98 mg, 0.87 mmol, 0.3 equivalents), bromo[1-(methoxycarbonyl)cyclopropyl]zinc (7156.82 mg, 29.28 mmol, 10 equivalents), and tetrahydrofuran (THF) (7 mL) were added to a 20 mL vial. The resulting mixture was stirred overnight under a nitrogen atmosphere at 60°C. The desired product could be detected by LC-MS. The resulting mixture was extracted with ethyl acetate (siRNA) (2 × 30 mL). The combined organic layers were washed with water (1 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 5:1) to obtain methyl 1-[3-methyl-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate (360 mg, yield 43%). LCMS: (ES, m / z): RT=1.05 min, m / z=259.0 [M+1] + .

[0533] Step 2: 1-[3-methyl-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate (350 mg, 1.35 mmol, 1 equivalent), LiOH (194.76 mg, 8.13 mmol, 6 equivalents), methanol (MeOH) (3.5 mL), and water (0.7 mL) were added to a 20 mL vial. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The mixture was acidified to pH 3 with HCl (aqueous solution). The resulting mixture was extracted with ethyl acetate (RINKAN) (3 × 20 mL). The combined organic layers were washed with water (1 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded 1-[3-methyl-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid (200 mg, 51% yield). LCMS:(ES,m / z): RT=1.07 min, m / z=245.0[M+1] + .

[0534] Step 3: 1-[3-methyl-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (150 mg, 0.61 mmol, 1 equivalent), hydroxybenzotriazole (HOBT) (165.99 mg, 1.22 mmol, 2 equivalents), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (235.49 mg, 1.22 mmol, 2 equivalents), diisopropylethylamine (DIEA) (238.16 mg, 1.84 mmol, 3 equivalents), dimethylformamide (DMF) (1.5 mL), and 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepan-3-amine ("Amine(i) Reagent") (120.55 mg, 0.61 mmol, 1 equivalent) were added to an 8 mL vial. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 40%-50% gradient over 10 minutes, detector, UV 254 nm) to obtain the crude product N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)-1-(3-methyl-4-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide (compound 6, rac-6), (140 mg, purity 80%).

[0535] Step 4: The crude product rac-6 was purified by preparative HPLC (Xselect CSH C18 OBD column 30 × 150 mm 5 μm, mobile phase: water (0.05% trifluoroacetic acid (TFA)) and acetonitrile (MeCN) (40% acetonitrile (MeCN), max 50% at 10 min, max 60% at 2 min), detector: UV 254 nm) to obtain a mixture of the cis isomer (second elution peak) and trans isomer (first elution peak). The stereochemistry was arbitrarily assigned.

[0536] Step 5: The expected trans mixture (26 mg) was purified by chiral preparative HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: isopropanol (IPA), flow rate: 20 mL / min, gradient: 50%B to 50%B at 10 min, wavelength: 220 / 254 nm) to obtain compound 6B* (RT(min): 6.93, 4.90 mg) and compound 6C* (RT(min): 8.82, 6.20 mg). Stereochemistry was arbitrarily assigned.

[0537] Compound 6B*:LCMS:(ES,m / z): RT=0.80 min, m / z=423.0[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 7.50(d,J=8.0Hz,1H),7.27-7.19(m,2H),4.21(s,1H),3.85-3.75(m,1H),3.61-3.52(m,1H),3.50-3.40(m,1H),3.20-3.08(m,1H),2.46 -2.40(m,3H),1.77(t,J=17.0Hz,2H),1.71-1.36(m,4H),1.19-1.14(m,1H),1.15-1.10(m,1H),1.10-1.01(m,1H),0.99(d,J=6.6Hz,3H).

[0538] Compound 6C*:LCMS:(ES,m / z): RT=0.80 min, m / z=423.0[M+H] + . 1 1H NMR (400MHz, methanol-d4) δ 7.50(d,J=8.0Hz,1H),7.27-7.19(m,2H),4.22(d,J=5.6Hz,1H),3.85-3.7 5(m,1H),3.61-3.52(m,1H),3.50-3.40(m,1H),3.20-3.08(m,1H),2.46-2 .41(m,3H),1.84-1.71(m,2H),1.71-1.60(m,1H),1.63-1.37(m,3H),1.19 -1.15(m,1H),1.14-1.10(m,1H),1.10-1.01(m,1H),0.99(d,J=6.6Hz,3H).

[0539] Step 6: A cis mixture (19 mg) of suspected isomers was purified by chiral preparative HPLC (LUX 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase: hexane (0.1% trifluoroacetic acid (TFA)) and isopropanol (IPA) (50% isopropanol (IPA) retained within 12 minutes), detector: UV 254 nm) to obtain compound 6D* (RT(min): 7.83, 2.0 mg) and compound 6A* (RT(min): 9.78, 2.4 mg). Stereochemistry was arbitrarily assigned.

[0540] Compound 6A*:LCMS:(ES,m / z): RT=1.31 min, m / z=423.0[M+1] + , 1 H NMR(400MHz,DMSO-d6) δ 14.69(s,1H),7.62(d,J=8.1Hz,1H),7.39(s,1H),7.34(d,J=8.1Hz,1H),7.24(s,1H) ),3.98(s,1H),3.63-3.54(m,1H),3.54-3.38(m,2H),3.29(s,1H),2.45(d,J=2.0Hz, 3H),1.73(d,J=13.9Hz,1H),1.55(d,J=13.7Hz,2H),1.44-1.36(m,1H),1.40-1.28( m,1H),1.24(s,1H),1.22-1.08(m,1H),1.04(d,J=2.3Hz,2H),0.88(d,J=6.7Hz,3H).

[0541] Compound 6D*:LCMS:(ES,m / z): RT=1.31 min, m / z=423.0[M+1] + , 1H NMR (400MHz, methanol-d4) δ 7.65(d,J=8.1Hz,1H),7.44-7.35(m,2H),4.02(s,1H),3.60(s,1H),3.6 1-3.45(m,2H),3.49-3.37(m,1H),2.54-2.48(m,3H),1.83(d,J=14.4Hz, 1H),1.70(d,J=13.9Hz,1H),1.64(s,1H),1.62-1.42(m,3H),1.33(d,J=1 7.2Hz,1H),1.28-1.16(m,1H),1.19-1.09(m,2H),0.97(d,J=6.7Hz,3H). Example 7.1 Synthesis of 1-(2,5-difluoro-4-(trifluoromethyl)phenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 7, rac-7) and compounds 7A*, 7B*, 7C*, and 7D* Scheme 7A. [ka] Scheme 7B. [ka] Scheme 7C. [ka]

[0542] Example 7 follows Protocol A. Step 1: 1-Bromo-2,5-difluoro-4-(trifluoromethyl)benzene (500 mg, 1.916 mmol, 1 equivalent), bis(tri-tert-butylphosphine)palladium(0)(Pd[(t-Bu)3P]2) (293.73 mg, 0.575 mmol, 0.3 equivalents), bromo[1-(methoxycarbonyl)cyclopropyl]zinc (9 mL, 28.740 mmol, 15 equivalents), and tetrahydrofuran (THF) (0.5 mL) were added to a 20 mL vial. The resulting mixture was stirred overnight under a nitrogen atmosphere at 60°C. The desired product could be detected by GC-MS. The resulting mixture was filtered, and the filtrate was washed with dichloromethane (DCM) (3 × 3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 7:1) to obtain methyl 1-[2,5-difluoro-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate (500 mg, yield 93%).

[0543] Step 2: Methyl 1-[2,5-difluoro-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate (500 mg, 1.784 mmol, 1 equivalent), NaOH (214.12 mg, 5.352 mmol, 3 equivalents), methanol (MeOH) (10 mL), and water (2 mL) were added to a 40 mL vial. The resulting mixture was stirred overnight under an air atmosphere at 40°C. The desired product could be detected by LC-MS. The resulting liquid was dried under vacuum. The mixture was acidified to pH 2 with concentrated HCl to obtain 1-[2,5-difluoro-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid (450 mg, 95% yield). The crude product was used directly in the next step without further purification.

[0544] Step 3: 1-[2,5-difluoro-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (150 mg, 0.564 mmol, 1 equivalent), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (214.28 mg, 0.564 mmol, 1 equivalent), triethylamine (TEA) (171.08 mg, 1.692 mmol, 3 equivalents), and dimethylformamide (DMF) (1.5 mL) were added to an 8 mL vial. 5-methyl-1-(1H-1,2,3,4-tetra Zole-5-yl)azepan-3-amine ("Amine(i) Reagent") (132.72 mg, 0.677 mmol, 1.2 equivalents) was partially added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The desired product could be detected by LC-MS. The resulting oil was dried under vacuum, and the residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN):water = 1:1) to obtain 1-(2,5-difluoro-4-(trifluoromethyl)phenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 7, rac-7).

[0545] Step 4: The crude product rac-7 was purified by preparative HPLC (Xselect CSH F-phenyl OBD column, 19 × 250 mm, 5 μm, mobile phase A: water (0.05% trifluoroacetic acid (TFA), mobile phase B: methanol (MeOH), flow rate: 20 mL / min, gradient: 56%B~61%B, 61%B at 8 min, wavelength: 254 nm) to obtain a mixture of cis isomers (30 mg) as the first elution peak and a mixture of trans isomers (40 mg) as the second elution peak. The stereochemistry of the cis and trans isomers was arbitrarily assigned.

[0546] Step 5: The expected trans mixture (40 mg) was purified by preparative-CHIRAL HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: isopropanol (IPA), flow rate: 20 mL / min, gradient: 25%B to 25%B at 13 min, wavelength: 254 / 220 nm) to obtain compound 7B* (RT(min): 8.99, 7.8 mg) and compound 7C* (RT(min): 12.16, 8.4 mg). Stereochemistry was arbitrarily assigned.

[0547] Compound 7B*:LCMS:(ES,m / z):1.59 min, m / z=445.1[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.46-7.33(m,2H),4.25-4.17(m,1H),3.75-3.67(m,1H),3.32-3.27(m,1H),1.90-1.73(m,3H),1 .69-1.55(m,3H),1.54-1.45(m,1H),1.26-1.19(m,1H),1.14-1.07(m,1H),0.98(d,J=6.8Hz,3H).

[0548] Compound 7C*:LCMS:(ES,m / z):1.59 min, m / z=445.1[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.46-7.33(m,2H),4.25-4.17(m,1H),3.75-3.67(m,1H),3.32-3.27(m,1H),1.90-1.73(m,3H),1 .69-1.55(m,3H),1.54-1.45(m,1H),1.26-1.19(m,1H),1.14-1.07(m,1H),0.98(d,J=6.8Hz,3H).

[0549] Step 6: The expected cis mixture (30 mg) was purified by preparative-CHIRAL HPLC (CHIRALPAK IF, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: ethanol, flow rate: 20 mL / min, gradient: 5%B to 5%B at 30 min, wavelength: 254 / 220 nm) to obtain compound 7A* (RT(min): 18.82, 5.0 mg) and compound 7D* (RT(min): 22.40, 4.0 mg). Stereochemistry was arbitrarily assigned.

[0550] Compound 7A*: LCMS: (ES, m / z): 1.05 min, m / z=445.2[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.55-7.40(m,2H),4.11-4.00(m,1H),3.67-3.56(m,2H),3.56-3.49(m,1H),3.47-3.37(m,1H),1.82(d,J=14.2 Hz,1H),1.77-1.69(m,1H),1.64(d,J=3.1Hz,2H),1.52-1.36(m,1H),1.26-1.10(m,3H),0.98(d,J=6.7Hz,3H).

[0551] Compound 7D*:LCMS:(ES,m / z):1.05 min, m / z=445.2[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.55-7.40(m,2H),4.11-4.00(m,1H),3.67-3.56(m,2H),3.56-3.49(m,1H),3.47-3.37(m,1H),1.82(d,J=14.2 Hz,1H),1.77-1.69(m,1H),1.64(d,J=3.1Hz,2H),1.52-1.36(m,1H),1.26-1.10(m,3H),0.98(d,J=6.7Hz,3H). Example 8. Synthesis of 1-(4-cyclobutylphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 8, rac-8), and compounds 8A*, 8B*, 8C*, and 8D* Scheme 8A. [ka] Scheme 8B. [ka] Scheme 8C. [ka]

[0552] Example 8 follows Protocol A. Step 1: Ethyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (600 mg, 2.22 mmol, 1 equivalent), cyclobutylboronic acid (668.27 mg, 6.68 mmol, 3 equivalents), 4-(anthracene-9-yl)-3-tert-butyl-2H-1,3-benzoxaphosphorus (165.16 mg, 0.44 mmol, 0.2 equivalents), K3PO4 (1419.63 mg, 6.68 mmol, 3 equivalents), palladium(II) acetate (Pd(OAc)2) (50.05 mg, 0.22 mmol, 0.1 equivalent), and toluene (5 mL) were added to a 20 mL vial. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The desired product could be detected by LC-MS. The resulting mixture was extracted with ethyl acetate (SiO) (2 × 30 mL). The combined organic layers were washed with water (1 × 20 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 dichloromethane (DCM) / petroleum ether (9:1) to obtain ethyl 1-(4-cyclobutylphenyl)cyclopropane-1-carboxylate (410 mg, yield 67%). LCMS: (ES, m / z): RT = 1.19 min, m / z = 245.0 [M+1] + .

[0553] Step 2: Ethyl 1-(4-cyclobutylphenyl)cyclopropane-1-carboxylate (400 mg, 1.63 mmol, 1 equivalent), methanol (MeOH) (4 mL), NaOH (327.40 mg, 8.18 mmol, 5 equivalents), and water (1.25 mL) were added to an 8 mL vial. The resulting mixture was stirred at 40°C for 2 hours. The desired product could be detected by LC-MS. The mixture was acidified to pH 3 with HCl (aqueous solution). The resulting mixture was extracted with ethyl acetate (HCl) (3 × 10 mL). The combined organic layers were washed with water (1 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded 1-(4-cyclobutylphenyl)cyclopropane-1-carboxylic acid (280 mg, 68% yield). LCMS:(ES,m / z): RT=0.70 min, m / z=217.0[M+1] + .

[0554] Step 3: 1-(4-cyclobutylphenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (270 mg, 1.24 mmol, 1 equivalent), 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepan-3-amine ("Amine(i) Reagent") (245 mg, 1.24 mmol, 1 equivalent), hydroxybenzotriazole (HOBT) (337.38 mg, 2.49 mmol, 2 equivalents), diisopropylethylamine (DIEA) (484.05 mg, 3.74 mmol, 3 equivalents), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (478.63 mg, 2.49 mmol, 2 equivalents), and dimethylformamide (DMF) (2.7 mL) were added to an 8 mL vial. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 40%–50% gradient over 10 mins, detector, UV 254 nm) to obtain the crude product 1-(4-cyclobutylphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 8, rac-8) (240 mg, yield 80%) as a mixture of cis and trans isomers.

[0555] Step 4: The crude product rac-8 was purified by preparative HPLC (XBridge preparative phenyl OBD column, 19 × 250 mm, 5 μm, mobile phase: water (0.1% trifluoroacetic acid (TFA)) and acetonitrile (MeCN) (43% acetonitrile (MeCN), up to 53% in 10 minutes), detector: UV 254 nm) to obtain a mixture of the trans isomer (30 mg), which is assumed to be the first elution peak, and the cis isomer (25 mg), which is assumed to be the second elution peak. The stereochemistry was arbitrarily assigned.

[0556] Step 5: The expected trans mixture (30 mg) was purified by chiral preparative HPLC (CHIRAL ART cellulose-SB, 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: 15%B to 15%B in 10 mins, wavelength: 220 / 254 nm) to obtain compound 8B* (RT(min): 7.10, 9.7 mg) and compound 8C* (RT(min): 8.35, 9.8 mg). Stereochemistry was arbitrarily assigned.

[0557] Compound 8B*:LCMS:(ES,m / z): RT=0.84 min, m / z=395.0[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 7.12(d,J=8.2Hz,2H),7.05(d,J=8.0Hz,2H),4.22-4.14(m,1H),3.85-3.75(m, 1H),3.60-3.50(m,2H),3.42-3.35(m,1H),3.10-2.99(m,1H),2.42-2.30(m,2H ),2.20-2.03(m,3H),1.94-1.85(m,1H),1.79-1.69(m,2H),1.69-1.56(m,1H), 1.56-1.44(m,2H),1.43-1.28(m,2H),1.10-1.00(m,2H),0.97(d,J=6.1Hz,3H).

[0558] Compound 8C*:LCMS:(ES,m / z): RT=0.84 min, m / z=395.0[M+H] + . 11H NMR (400MHz, methanol-d4) δ 7.15-7.09(m,2H),7.05(d,J=8.1Hz,2H),4.22-4.14(m,1H),3.83-3.74(m,1H ),3.59-3.49(m,2H),3.44-3.36(m,1H),3.09-2.99(m,1H),2.41-2.31(m,2H), 2.21-2.03(m,3H),1.94-1.85(m,1H),1.81-1.70(m,2H),1.69-1.58(m,1H),1 .54-1.43(m,2H),1.41-1.32(m,2H),1.08-1.01(m,2H),0.97(d,J=6.3Hz,3H).

[0559] Step 6: The expected cis mixture (25 mg) was purified by chiral preparative HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid), mobile phase B: methanol:ethanol = 1:1, flow rate: 20 mL / min, gradient: 40%B to 40%B at 7.2 min, wavelength: 220 / 254 nm) to obtain compound 8D* (RT(min): 7.22, 8.4 mg) and compound 8A* (RT(min): 8.52, 9.9 mg). Stereochemistry was arbitrarily assigned.

[0560] Compound 8A*:LCMS:(ES,m / z): RT=1.48 min, m / z=395.0[M+1] + . 1 H NMR (400MHz, methanol-d4) δ 7.36-7.29(m,2H),7.26(d,J=8.1Hz,2H),4.03-3.92(m,1H),3.65-3.5 0(m,3H),3.50-3.40(m,2H),2.43-2.31(m,2H),2.26-2.12(m,2H),2.1 5-1.99(m,1H),1.96-1.80(m,2H),1.66(s,1H),1.58-1.43(m,3H),1.3 1(s,1H),1.28-1.14(m,1H),1.14-1.03(m,2H),0.96(d,J=6.7Hz,3H).

[0561] Compound 8D*:LCMS:(ES,m / z): RT=1.04 min, m / z=395.0[M+1] + . 1 1H NMR (400MHz, methanol-d4) δ 7.37-7.29(m,2H),7.29-7.22(m,2H),4.03-3.92(m,1H),3.65-3.51(m,3 H),3.51-3.40(m,2H),2.43-2.31(m,2H),2.26-2.12(m,2H),2.15-1.99(m ,1H),1.96-1.80(m,1H),1.72-1.59(m,2H),1.58-1.43(m,3H),1.34(d,J= 22.9Hz,1H),1.28-1.14(m,1H),1.14-1.03(m,2H),0.96(d,J=6.8Hz,3H). Example 9. Synthesis of N-(9-(1H-tetrazole-5-yl)-9-azabicyclo[4.2.1]nonane-2-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (compound 9, rac-9), and 9A*, 9B*, 9C*, and 9D*. [ka]

[0562] Example 9 follows Protocol C. Step 1: In a 40 mL vial, tert-butyl 2-amino-9-azabicyclo[4.2.1]nonane-9-carboxylate ("Amine(iv) Reagent") (500 mg, 2.080 mmol, 1 equivalent), 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (449.96 mg, 2.288 mmol, 1.1 equivalents), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (1167.40 mg, 4.160 mmol, 2 equivalents), N-methylimidazole (NMI) (341.61 mg, 4.160 mmol, 2 equivalents), and acetonitrile (MeCN) (15 mL) were added at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector, UV254nm) to obtain tert-butyl 2-(1-(4-chlorophenyl)cyclopropane-1-carboxamide)-9-azabicyclo[4.2.1]nonane-9-carboxylate (400 mg, yield 46%).

[0563] Step 2: In a 40 mL vial, tert-butyl 2-[1-(4-chlorophenyl)cyclopropanamide]-9-azabicyclo[4.2.1]nonane-9-carboxylate (400 mg, 0.955 mmol, 1 equivalent), dichloromethane (DCM) (15 mL), and trifluoroacetic acid (TFA) (3 mL) were added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This yielded N-{9-azabicyclo[4.2.1]nonane-2-yl}-1-(4-chlorophenyl)cyclopropane-1-carboxamide (300 mg, 99% yield), which was used directly in the next step without further purification.

[0564] Step 3: N-{9-azabicyclo[4.2.1]nonane-2-yl}-1-(4-chlorophenyl)cyclopropane-1-carboxamide (300 mg, 0.94 mmol, 1 equivalent), BrCN (199.32 mg, 1.88 mmol, 2 equivalents), K2CO3 (260.07 mg, 1.88 mmol, 2 equivalents), and acetonitrile (MeCN) (10 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The reaction was monitored by LC-MS. The reaction was quenched with water (10 ml) at room temperature. The resulting mixture was extracted with ethyl acetate (HCl) (3 × 40 mL), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(4-chlorophenyl)-N-[9-cyano-9-azabicyclo[4.2.1]nonane-2-yl]cyclopropane-1-carboxamide (280 mg, yield 87%). The resulting mixture was used directly in the next step without further purification. LCMS (ESI): RT=0.950 min, m / z=344 [M+H] + .

[0565] Step 4: 1-(4-chlorophenyl)-N-[9-cyano-9-azabicyclo[4.2.1]nonane-2-yl]cyclopropane-1-carboxamide (200 mg, 0.582 mmol, 1 equivalent), NH4Cl (93.33 mg, 1.746 mmol, 3 equivalents), trimethylsilyl azide (TMS-N3) (407.57 mg, 1.746 mmol, 3 equivalents), and dimethylformamide (DMF) (10 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 120 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The reaction was quenched by adding water (0.5 mL) at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase: acetonitrile (MeCN) in water, gradient of 40% to 50% over 10 minutes, detector: UV 220nm) to obtain a crude product (250 mg), which was then purified by preparative HPLC (Sunfire preparative C18 column, 30*150 mm, 5 μm, mobile phase A: acetonitrile, mobile phase B: water (0.05% trifluoroacetic acid (TFA)), flow rate: 60 mL / min, gradient: 40%B to 50%B over 8 minutes, 50%B to 50%B over 9 minutes, 50%B, wavelength: Purification by 254 / 220 nm, RT (min): 8.22 yielded N-(9-(1H-tetrazole-5-yl)-9-azabicyclo[4.2.1]nonane-2-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (compound 9, rac-9) as a mixture of stereoisomers (150 mg, yield 47%). LCMS (ESI): RT=88, m / z=387 [M+H] + .

[0566] Step 5: The mixture product rac-9 was purified by preparative chiral HPLC (CHIRALPAK IE, 2 × 25 cm, 5 μm, mobile phase A: methyl tert-butyl ether (MBTE) (0.1% formic acid), mobile phase B: methanol:dichloromethane = 1:1, flow rate: 20 mL / min, gradient: 20%B to 20%B at 25 min, wavelength: 220 / 254 nm) to obtain the assumed mixture of trans isomer compounds 9B* and 9C* (RT(min): 10.72, 100 mg), assumed compound 9A* (RT(min): 16.14, 6.7 mg), and assumed compound 9D* (RT(min): 22.38, 6.2 mg). The assumed mixture of compounds 9B* and 9C* was further purified by preparative chiral HPLC (CHIRAL ART amylose-SA, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.2% formic acid), mobile phase B: ethanol:dichloromethane = 1:1, flow rate: 20 mL / min, gradient: 15%B to 15%B at 12 mins, wavelength: 220 / 254 nm) to obtain compound 9B* (RT(min): 7.32, 27.7 mg) and compound 9C* (RT(min): 10.11, 33.1 mg). The stereochemistry was arbitrarily assigned to each isomer.

[0567] Compound 9A*LCMS (ESI): RT=1.529 min, m / z=387[M+H] + , 1 H NMR (400MHz, methanol-d4) δ 7.43(s,4H),4.32(t,J=8.4Hz,1H),4.25(dd,J=8.5,4.6Hz,1H),4.09(dt,J=9.4,4.3Hz,1H),2.43-2.28(m,2H) ,2.01-1.86(m,1H),1.76(dd,J=10.4,8.0Hz,2H),1.68-1.47(m,6H),1.13(dtdd,J=12.7,9.8,6.1,3.5Hz,3H).

[0568] Compound 9D*LCMS (ESI): RT=1.512 min, m / z=387[M+H] + , 1H NMR(400MHz,メタノール-d4) δ 7.47-7.38(m,4H),4.20(dt,J=11.6,5.5Hz,1H),4.06-3.99(m,1H),2.16-1.97(m,2H),1.99-1.86(m,2H),1.80(ddd,J=18.4 ,12.6,5.4Hz,2H),1.66(d,J=8.8Hz,1H),1.51(dtdd,J=13.3,9.5,6.0,3.4Hz,4H),1.12(dddd,J=31.5,9.0,5.9,3.1Hz,2H).

[0569] Compound 9B* (27.7 mg, yield 18.47%). LCMS (ESI): RT = 1.505 min, m / z = 387 [M+H] + , 1 H NMR(400MHz,メタノール-d4) δ 7.48-7.38(m,4H),4.21(dt,J=11.6,5.6Hz,1H),4.03(d,J=6.6Hz,2H), 2.16-2.00(m,1H),1.96(dq,J=17.7,6.8,6.1Hz,3H),1.79(hept,J=6.5, 5.9Hz,2H),1.64(d,J=8.7Hz,1H),1.51(dtdd,J=13.3,9.6,6.1,3.4Hz,4H),1.16(ddd,J=9.8,6.1,3.4Hz,1H),1.08(ddd,J=9.1,6.1,3.1Hz,1H).

[0570] Compound 9C*LCMS (ESI): RT = 1.51 min, m / z = 387 [M+H] + ,1H NMR(400MHz,メタノール-d4) δ 7.47-7.38(m,4H),4.20(d,J=11.6Hz,1H),4.06-3.99(m,1H),2.16-1.97(m,2H),1.99-1.86(m,2 H),1.80(d,J=18.4Hz,2H),1.66(d,J=8.8Hz,1H),1.51(d,J=13.3Hz,4H),1.12(d,J=31.5Hz,2H). Example 10. Synthesis of (R)-N-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (compound 10A) and (S)-N-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (compound 10B) Scheme 10A. [ka] Scheme 10B. [ka]

[0571] Example 10 follows Protocol C. Step 1: In an 8 mL vial, tert-butyl(R)-3-aminopiperidine-1-carboxylate ("Amine(iv) Reagent") (565 mg, 2.82 mmol, 1 equivalent), 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (782.22 mg, 3.38 mmol, 1.2 equivalents), dichloromethane (DCM) (5 mL, 78.65 mmol), and triethylamine (TEA) (856.38 mg, 8.46 mmol, 3 equivalents) were added. The resulting mixture was stirred at 30°C for 2 hours. The reaction was monitored by LC-MS. The reaction product was then quenched by adding 20 mL of water. The resulting solution was extracted with ethyl acetate (3 × 20 mL). The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (2:3) as the eluent. This yielded tert-butyl(R)-3-(1-(4-chlorophenyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate (400 mg, 37% yield). LCMS (ES, m / z): RT=1.04 min, m / z=379.0 [M+1] + .

[0572] Step 2: In a 50 mL round-bottom flask, tert-butyl 3-[1-(4-chlorophenyl)cyclopropanamide]piperidine-1-carboxylate (400 mg, 1.05 mmol, 1 equivalent) and HCl (gas) were added to 1,4-dioxane (4 mL, 131.64 mmol). The resulting solution was stirred at 25°C for 2 hours and then concentrated under vacuum. The desired product could be detected by LC-MS. This yielded (R)-1-(4-chlorophenyl)-N-(piperidine-3-yl)cyclopropane-1-carboxamide (290 mg, 99% yield). LC-MS (ES, m / z): RT = 0.57 min, m / z = 279.0 [M+1] + .

[0573] Step 3: 1-(4-chlorophenyl)-N-(piperidine-3-yl)cyclopropan-1-carboxamide (300 mg, 1.076 mmol, 1 equivalent), cyanogen bromide (136.78 mg, 1.291 mmol, 1.2 equivalents), triethylamine (TEA) (326.68 mg, 3.228 mmol, 3 equivalents), and dichloromethane (DCM) (3 mL, 47.190 mmol) were placed in a 20 mL vial. The resulting solution was stirred at 25°C for 2 hours. The desired product could be detected by LC-MS. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2:3) as the eluent. This yielded (R)-1-(4-chlorophenyl)-N-(1-cyanopiperidine-3-yl)cyclopropane-1-carboxamide (200 mg, 61% yield). LCMS (ES, m / z): RT=0.99 min, m / z=304.0 [M+1] + .

[0574] Step 4: In an 8 mL microwave tube that was purged and maintained under an inert nitrogen atmosphere, (R)-1-(4-chlorophenyl)-N-(1-cyanopiperidine-3-yl)cyclopropane-1-carboxamide (180 mg, 0.59 mmol, 1 equivalent), azidotrimethylsilane (81.92 mg, 0.71 mmol, 1.2 equivalents), NH4Cl (95.08 mg, 1.77 mmol, 3 equivalents), and dimethylformamide (DMF) (2 mL, 25.84 mmol, 43.62 equivalents) were added. The resulting solution was stirred in an oil bath at 120°C for 2 hours. The desired product could be detected by LC-MS. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase: triethylamine (TEA) in water, gradient from 10% to 50% over 10 minutes, detector: UV 254 nm) to obtain (R)-N-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (compound 10A) (150 mg). Compound 10A was further purified by chiral preparative HPLC (CHIRAL ART cellulose-SB, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.1% formic acid), mobile phase B: ethanol (EtOH), flow rate: 20 mL / min, gradient: 10%B to 10%B over 16 minutes, wavelength: 220 / 254 nm) to obtain compound 10A (21.9 mg, yield 11%). LCMS(ES,m / z): RT=0.66 min, m / z=347.0[M+1] + . 1 H NMR(400MHz,DMSO-d6) δ 14.86(s,1H),7.61-7.17(m,4H),6.84(d,J=8.0Hz,1H),3.89-3.72(m,1H),3.70-3.52(m,2H),3.00 -2.81(m,2H),1.68(t,J1=J2=14.0Hz,2H),1.57-1.39(m,2H),1.38-1.28(m,2H),1.10-0.82(m,2H).

[0575] Steps 5-8: Following the synthesis of Example 10 and Compound 10A, Compound 10B was synthesized using tert-butyl(S)-3-aminopiperidine-1-carboxylate as the starting material. LCMS (ES, m / z): RT=0.66 min, m / z=347.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6) δ14.89(s,1H),7.41-7.36(m,2H),7.35-7.30(m,2H),6.82(d,J=8.2Hz,1H),3.85-3.73(m,1H),3.68-3.57(m ,2H),2.90(dt,J=12.2,9.2Hz,2H),1.76-1.60(m,2H),1.54-1.40(m,2H),1.35(m,2H),0.99(q,J=3.8Hz,2H). Example 11. Synthesis of 1-(4-chlorophenyl)-N-(3-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 11, rac-11) and compounds 11A* and 11B* [ka]

[0576] Example 11 follows Protocol C. Step 1: 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (330 mg, 1.67 mmol, 1 equivalent), dichloromethane (DCM) (5 mL), and SOCl2 (1.80 g, 16.70 mmol, 10 equivalents) were placed in a 20 mL vial. The resulting solution was stirred at room temperature for 2 hours. The progress of the reaction was monitored by LC-MS. The resulting solution was concentrated under vacuum, and the residue was then dissolved in DCM (2 mL). This residue was then added dropwise to a solution of tert-butyl 3-amino-3-methylpiperidine-1-carboxylate ("Amine(iv) Reagent") (280 mg, 1.30 mmol, 1 equivalent) and triethylamine (528 mg, 5.22 mmol, 4 equivalents) in DCM (2.5 mL) at 0°C. The reaction was slowly warmed to room temperature for 1 hour, and the progress of the reaction was monitored by LC-MS. The reaction was quenched with 5 ml of H2O, extracted with DCM (2 × 30 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2:3). This yielded tert-butyl 3-[1-(4-chlorophenyl)cyclopropanamide]-3-methylpiperidine-1-carboxylate (380 mg, yield 74%). LCMS (ES, m / z): RT = 1.17 min, m / z = 393.0 [M+1] + .

[0577] Step 2: In a 25 mL round-bottom flask, tert-butyl 3-[1-(4-chlorophenyl)cyclopropanamide]-3-methylpiperidine-1-carboxylate (320 mg, 0.81 mmol, 1 equivalent) and HCl (gas) were added in 1,4-dioxane (4 M, 3 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours. The progress of the reaction was monitored by LC-MS. The resulting solution was concentrated under vacuum. This yielded 1-(4-chlorophenyl)-N-(3-methylpiperidine-3-yl)cyclopropane-1-carboxamide HCl salt (238 mg). LC-MS (ES, m / z): RT = 0.70 min, m / z = 293.0 [M+1] + .

[0578] Step 3: 1-(4-chlorophenyl)-N-(3-methylpiperidine-3-yl)cyclopropane-1-carboxamide HCl (240.00 mg, 0.82 mmol, 1 equivalent), cyanogen bromide (521 mg, 4.92 mmol, 6 equivalents), acetonitrile (3 mL), and potassium carbonate (678.96 mg, 4.92 mmol, 6 equivalents) were added to a 20 mL vial at room temperature. The resulting solution was stirred at 80 °C for 16 hours. The progress of the reaction was monitored by LC-MS. The reaction was quenched with 5.00 ml of H2O, extracted with DCM (2 × 30 ml), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2:3). This yielded 1-(4-chlorophenyl)-N-(1-cyano-3-methylpiperidine-3-yl)cyclopropane-1-carboxamide (250 mg, 96% yield).

[0579] Step 4: 1-(4-chlorophenyl)-N-(1-cyano-3-methylpiperidine-3-yl)cyclopropane-1-carboxamide (220 mg, 0.69 mmol, 1 equivalent), trimethylsilyl azide (239 mg, 2.07 mmol, 3 equivalents), NH4Cl (111 mg, 2.07 mmol, 3 equivalents), and dimethylformamide (DMF) (2.5 mL) were added to a 10 mL microwave tube. The resulting solution was stirred at 120 °C for 2.5 hours. The progress of the reaction was monitored by LC-MS. The reaction was quenched with 5.00 mL of H2O, extracted with DCM (2 × 30 ml), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile in H2O, gradient from 0% to 100% over 30 minutes, detector, UV220 / 254nm) to obtain 1-(4-chlorophenyl)-N-(3-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropanecarboxamide (compound 11, rac-11) (100 mg, yield 40%, purity 95%).

[0580] Step 5: The two stereoisomers of the product, rac-11 (99 mg, 95% purity), were separated by chiral preparative HPLC (CHIRAL ART cellulose-SC, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.2% formic acid), mobile phase B: methanol (MeOH):ethanol (EtOH) = 1:1, flow rate: 20 mL / min, gradient: 20%B to 20%B in 14 mins, wavelength: 220 / 254 nm) to obtain compound 11B* (RT(min): 13.27, 23.9 mg, yield 12%) and compound 11A* (RT(min): 10.89, 31.9 mg, yield 16%). Stereochemistry was arbitrarily assigned.

[0581] Compound 11A*:LCMS(ES,m / z): RT=0.87 min, m / z=361.0[M+1] + . 1 H NMR(400MHz,DMSO-d6) δ 7.38-7.09(m,4H),5.80(s,1H),3.85(d,J=12.8Hz,1H),3.61(d,J=12.4Hz,1H),3.08-2 .89(m,2H),2.06(d,J=10.4Hz,1H),1.54-1.31(m,3H),1.25(m,5H),0.96-0.83(m,2H).

[0582] Compound 11B*:LCMS(ES,m / z): RT=0.90 min, m / z=361.0[M+1] + . 1 H NMR(400MHz,DMSO-d6) δ 7.41-7.06(m,4H),5.81(s,1H),3.84(d,J=12.8Hz,1H),3.61(d,J=12.4Hz,1H),3.08-2.85(m,2H),2.06(d,J =11.2Hz,1H),1.56-1.30(m,3H),1.30-1.18(m,5H),0.97-0.82(m,2H). Example 12. Synthesis of 1-(4-chlorophenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 12, rac-12) and compounds 12A*, 12B*, 12C*, and 12D* Scheme 12A. [ka] Scheme 12B. [ka] Scheme 12C. [ka]

[0583] Example 12 follows Protocol C. Step 1: In a 500 mL round-bottom flask, n-butyllithium (n-BuLi) (3.08 mL, 7.71 mmol, 1.1 equivalents) was added to a solution of bromo(methyl)triphenyl-lambda-5-phosphan (2.75 g, 7.71 mmol, 1.1 equivalents) in tetrahydrofuran (THF) (200 mL) at 0°C under an N2 atmosphere. The reaction mixture was stirred at 0°C for 30 minutes. Next, a solution of 1-tert-butyl 3-ethyl 5-oxoazepan-1,3-dicarboxylate (2.00 g, 7.00 mmol, 1 equivalent) in tetrahydrofuran (THF) was added, and the mixture was stirred for a further 60 minutes at 0°C. The progress of the reaction was monitored by LC-MS. The reaction was quenched with 100 mL of NH4Cl (aqueous solution). The resulting mixture was extracted with ethyl acetate (SiO2) (3 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, mobile phase, ethyl acetate in petroleum ether, gradient from 0% to 100% over 40 minutes, detector, UV 254 nm) to obtain 1-tert-butyl 3-ethyl 5-methylideneazepane-1,3-dicarboxylate (1.00 g, yield 50%). LCMS (ES, m / z): RT = 1.050 min, m / z = 284 [M+1] + .

[0584] Step 2: 1-tert-butyl3-ethyl5-methylideneazepane-1,3-dicarboxylate (1 g, 3.52 mmol, 1 equivalent), NaOH (282 mg, 7.05 mmol, 2 equivalents), methanol (MeOH) (50 mL), and water (10 mL) were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LC-MS. The resulting mixture was quenched with 100 mL of water and extracted with ethyl acetate ( Depositphotos) (2 × 200 mL). The aqueous layer was acidified to pH=6 with HCl (1 M). The resulting mixture was extracted with Depositphotos (3 × 200 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain 5-methylideneazepane-1,3-dicarboxylic acid (500 mg, crude), which was used in the next step without purification. LCMS(ES,m / z): RT=0.805 min, m / z=256 [M+1] + .

[0585] Step 3: 1-(tert-butoxycarbonyl)-5-methylideneazepane-3-carboxylic acid (500 mg, 1.95 mmol, 1 equivalent), benzyl alcohol (2 mL, 18.49 mmol, 9.44 equivalents), diphenyl phosphoryl azide (DPPA) (1077.90 mg, 3.91 mmol, 2 equivalents), triethylamine (TEA) (990.87 mg, 9.79 mmol, 5 equivalents), and toluene (20 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred under N2 at 100°C for 2 hours. The progress of the reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, gradient from 0% to 50% over 30 minutes, detector, UV 254 nm) to obtain tert-butyl 3-{[(benzyloxy)carbonyl]amino}-5-methylideneazepane-1-carboxylate (400 mg, yield 57%). LCMS (ES, m / z): RT=1.061 min, m / z=361 [M+1] + .

[0586] Step 4: In a 25 mL vial, tert-butyl 3-{[(benzyloxy)carbonyl]amino}-5-methylideneazepane-1-carboxylate (400 mg, 1.11 mmol, 1 equivalent), Pd / C (100 mg), and methanol (MeOH) (15 mL) were added at room temperature. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with methanol (MeOH) (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-amino-5-methylazepane-1-carboxylate (250 mg, 99% yield). LC-MS (ES, m / z): RT = 0.596 min, m / z = 229 [M+1] + .

[0587] Step 5: In an 8 mL vial, tert-butyl 3-amino-5-methylazepane-1-carboxylate ("Amine(iv) Reagent") (250 mg, 1.09 mmol, 1 equivalent), 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (258.34 mg, 1.31 mmol, 1.2 equivalents), N-methylimidazole (NMI) (269.69 mg, 3.28 mmol, 3 equivalents), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (399.36 mg, 1.42 mmol, 1.3 equivalents), and acetonitrile (MeCN) (5 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by LC-MS. The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, gradient from 0% to 100% over 40 minutes, detector, UV 254 nm) to obtain tert-butyl 3-[1-(4-chlorophenyl)cyclopropanamide]-5-methylazepane-1-carboxylate (200 mg, yield 45%). LCMS (ES, m / z): RT=1.176 min, m / z=407 [M+1] + .

[0588] Step 6: In an 8 mL vial, tert-butyl 3-[1-(4-chlorophenyl)cyclopropanamide]-5-methylazepan-1-carboxylate (180 mg, 0.44 mmol, 1 equivalent) and HCl (gas) were added to 1,4-dioxane (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum to obtain 1-(4-chlorophenyl)-N-(5-methylazepan-3-yl)cyclopropane-1-carboxamide (130 mg, HCl salt). LC-MS (ES, m / z): RT = 0.687 min, m / z = 307 [M+1] + .

[0589] Step 7: 1-(4-chlorophenyl)-N-(5-methylazepan-3-yl)cyclopropane-1-carboxamide (120 mg, 0.39 mmol, 1 equivalent), BrCN (82.85 mg, 0.78 mmol, 2 equivalents), and acetonitrile (MeCN) (3 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LC-MS. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, MeCN in water, gradient from 0% to 100% over 30 minutes, detector, UV 254 nm) to obtain 1-(4-chlorophenyl)-N-(1-cyano-5-methylazepan-3-yl)cyclopropane-1-carboxamide (120 mg, yield 92%). LCMS(ES,m / z): RT=0.923 min, m / z=332 [M+1] + .

[0590] Step 8: 1-(4-chlorophenyl)-N-(1-cyano-5-methylazepan-3-yl)cyclopropane-1-carboxamide (80 mg, 0.24 mmol, 1 equivalent), trimethylsilyl azide (55.6 mg, 0.48 mmol, 2 equivalents), dimethylformamide (DMF) (3 mL), and NH4Cl (51.6 mg, 0.96 mmol, 4 equivalents) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at 120 °C for 2 hours. The progress of the reaction was monitored by LC-MS. The reaction was quenched with 1 mL of water. The resulting mixture was filtered and concentrated to obtain the crude product 1-(4-chlorophenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 12, rac-12) as a mixture of cis and trans stereoisomers.

[0591] Step 8: The crude product rac-12 was purified by preparative HPLC (XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, mobile phase: water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (maximum 40% 25% acetonitrile (MeCN) at 8 mins), detector: UV 254 nm) to obtain a mixture expected to be the cis isomer as the first elution peak and the expected trans isomer as the second elution peak. Arbitrarily assigned stereochemistry.

[0592] Step 9: The expected trans-isomer mixture of rac-12 was purified by chiral-preparative HPLC (CHIRALPAK IG, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.2% formic acid), mobile phase B: ethanol:dichloromethane = 1:1, flow rate: 20 mL / min, gradient: 15%B~15%B at 22.2 mins, wavelength: 220 / 254 nm) to obtain compound 12B* (RT(min): 16.3, 2.6 mg) and compound 12C* (RT(min): 19.7, 5.1 mg). Stereochemistry was arbitrarily assigned.

[0593] Compound 12B*:LCMS(ES,m / z): RT=1.432 min, m / z=375 [M+1] +.1H NMR (400MHz, methanol-d4) δ 7.40(s,4H),4.05-4.93(m,1H),3.66-3.54(m,2H),3.53-3.40(m,2H),1.89-1.79(m,1H),1.74-1.59 (m,2H),1.58-1.52(m,2H),1.31(s,1H),1.14-1.06(m,2H),0.97(d,J=6.7Hz,3H),0.95-0.88(m,1H).

[0594] Compound 12C*:LCMS(ES,m / z): RT=1.101 min, m / z=375 [M+1] + .1H NMR (400MHz, methanol-d4) δ 7.26-7.14(m,4H),4.24-4.17(m,1H),3.88-3.78(m,1H),3.59-3.52(m,1H),3.48-3.39(m,1H),3.18-3.07(m,1H),1 .83-1.71(m,2H),1.71-1.60(m,1H),1.58-1.45(m,3H),1.43-1.37(m,1H),1.12-1.02(m,2H),0.98(d,J=6.7Hz,3H).

[0595] Step 10: The expected cis-isomer mixture of rac-12 was purified by chiral preparative HPLC (CHIRAL ART cellulose-SB, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.2% formic acid), mobile phase B: isopropanol, flow rate: 20 mL / min, gradient: 10%B to 10%B at 24 mins, wavelength: 220 / 254 nm) to obtain compound 12A* (RT(min): 18.03, 2.60 mg) and compound 12D* (RT(min): 21.84, 5.1 mg). Stereochemistry was arbitrarily assigned.

[0596] Compound 12A*:LCMS(ES,m / z): RT=1.551 min, m / z=375 [M+1] + . 1H NMR (400MHz, methanol-d4) δ 7.40(s,4H),4.05-4.93(m,1H),3.66-3.53(m,2H),3.53-3.40(m,2H),1.89-1.80(m,1H),1.74 -1.60(m,2H),1.59-1.43(m,3H),1.22-1.16(m,1H),1.16-1.06(m,2H),0.97(d,J=6.7Hz,3H).

[0597] Compound 12D*:LCMS(ES,m / z): RT=0.802 min, m / z=375 [M+1] + .1H NMR (400MHz, methanol-d4) δ 7.28-7.13(m,4H),4.20(q,J=5.0,3.7Hz,1H),3.89-3.78(m,1H),3.61-3.52(m,1H),3.49-3.40(m,1H),3.18-3.06(m,1H) ),1.83-1.71(m,2H),1.70-1.60(m,1H),1.58-1.45(m,3H),1.43-1.35(m,1H),1.11-1.02(m,2H),0.98(d,J=6.6Hz,3H). Example 13. Synthesis of 1-(4-chlorophenyl)-N-(5-cyclopropyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 13, rac-13), and compounds 13A*, 13B*, 13C*, and 13D* [ka]

[0598] Example 13 follows Protocol C. Step 1: To a stirred solution of methyl 5-bromopyridine-3-carboxylate (1 g, 4.629 mmol, 1 equivalent) and cyclopropylboronic acid (2.39 g, 27.774 mmol, 6 equivalents) in dioxane (10 mL) and water (1 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride (Pd(dppf)Cl2), dichloromethane (DCM) (1.35 g, 1.852 mmol, 0.4 equivalents), and Na2CO3 (0.98 g, 9.258 mmol, 2 equivalents) were added. The resulting mixture was stirred overnight under a nitrogen atmosphere at 80°C. The resulting mixture was poured into water and extracted with ethyl acetate (SiO2) (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and brine (3 × 10 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 (56:44) to obtain methyl 5-cyclopropylpyridine-3-carboxylate (0.68 g, yield 83%). LCMS (ES, m / z): RT=0.71 min, m / z=178.2 [M+1] + .

[0599] Step 2: To a stirred solution of methyl 5-cyclopropylpyridine-3-carboxylate (300 mg, 1.693 mmol, 1 equivalent) in methanol (MeOH) (1.5 mL) and acetic acid (AcOH) (1.5 mL), PtO2 (192.22 mg, 0.847 mmol, 0.5 equivalent) was partially added at room temperature. The resulting mixture was stirred overnight under a hydrogen atmosphere at 50°C. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. Diterbutyl dicarbonate (Boc2O) (2.86 g, 13.10 mmol, 1.20 equivalent) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred for a further 1 hour at room temperature. The reaction was monitored by LC-MS. The resulting mixture was quenched with water (10 mL) and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with brine (30 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 and eluted with (dichloromethane / petroleum ether = 6:4) to obtain 1-tert-butyl 3-methyl 5-cyclopropylpiperidine-1,3-dicarboxylate (800 mg, yield 42%). LCMS (ES, m / z): RT = 0.66 min, m / z = 284.2 [M + H] + .

[0600] Step 3: 1-(tert-butyl)3-methyl5-cyclopropylpiperidine-1,3-dicarboxylate (600 mg, 2.12 mmol, 1 equivalent), methanol (MeOH) (8 mL), water (2 mL), and LiOH (152.12 mg, 6.35 mmol, 3 equivalents) were added to a 40 mL vial at room temperature. The resulting mixture was stirred overnight at room temperature and then concentrated under vacuum. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 30 mL). The resulting mixture was concentrated under vacuum. This yielded (tert-butoxycarbonyl)-5-cyclopropylpiperidine-3-carboxylic acid (506 mg, 89% yield). LCMS (ES, m / z): RT = 0.85 min, m / z = 268.0 [M-1] - .

[0601] Step 4: (tert-butoxycarbonyl)-5-cyclopropylpiperidine-3-carboxylic acid (400 mg, 1.49 mmol, 1 equivalent), toluene (0.40 mL), benzyl alcohol (4 mL), diphenyl phosphoryl azide (DPPA) (1226.10 mg, 4.46 mmol, 3 equivalents), and triethylamine (TEA) (450.83 mg, 4.46 mmol, 3 equivalents) were added to an 8 mL vial under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C for 2 hours. The reaction product was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The aqueous layer was extracted with ethyl acetate (ELISA) (3 × 20 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with dichloromethane (DCM):petroleum ether (PE) (5:4) to obtain tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-cyclopropylpiperidine-1-carboxylate (140 mg, yield 25%). LCMS (ES, m / z): RT=1.10 min, m / z=375.0 [M-1] - .

[0602] Step 5: To a solution of tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-cyclopropylpiperidine-1-carboxylate (300 mg, 0.80 mmol, 1 equivalent) in methanol (MeOH) (5 mL), Pd / C (10%, 225.76 mg) from a pressurized tank was added. The mixture was hydrogenated at room temperature for 2 hours under a hydrogen pressure of 10 psi, filtered through a Celite pad, and concentrated under reduced pressure. This yielded tert-butyl 3-amino-5-cyclopropylpiperidine-1-carboxylate (180 mg, yield 98.40%). LCMS (ES, m / z): RT = 0.87 min, m / z = 241.0 [M+1] + .

[0603] Step 6: In an 8 mL vial, tert-butyl 3-amino-5-cyclopropylpiperidine-1-carboxylate ("Amine(iv) Reagent") (100 mg, 0.416 mmol, 1 equivalent), acetonitrile (MeCN) (1 mL), 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (81.81 mg, 0.416 mmol, 1 equivalent), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (151.76 mg, 0.541 mmol, 1.30 equivalents), and N-methylimidazole (NMI) (102.48 mg, 1.248 mmol, 3 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with dichloromethane (DCM):methanol (MeOH) (4:1) to obtain tert-butyl 3-(1-(4-chlorophenyl)cyclopropane-1-carboxamide)-5-cyclopropylpiperidine-1-carboxylate (80 mg, yield 45.8%). LCMS (ES, m / z): RT=1.19 min, m / z=419.1 [M+1] + .

[0604] Step 7: A mixture of tert-butyl 3-(1-(4-chlorophenyl)cyclopropane-1-carboxamide)-5-cyclopropylpiperidine-1-carboxylate (70 mg, 0.024 mmol, 1 equivalent) and HCl (gas) in 1 mL of 1,4-dioxane was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS, and then concentrated under reduced pressure. This yielded 1-(4-chlorophenyl)-N-(5-cyclopropylpiperidine-3-yl)cyclopropane-1-carboxamide (50 mg, 96% yield). LC-MS (ES, m / z): RT = 1.07 min, m / z = 319.1 [M-1] - .

[0605] Step 8: A mixture of 1-(4-chlorophenyl)-N-(5-cyclopropylpiperidine-3-yl)cyclopropan-1-carboxamide (50 mg, 0.157 mmol, 1 equivalent), cyanogen bromide (49.83 mg, 0.471 mmol, 3 equivalents), triethylamine (TEA) (47.61 mg, 0.471 mmol, 3 equivalents), and acetonitrile (MeCN) (2 mL) was stirred at 80°C for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with RINKAN (3 × 10 mL), the organic layers were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to obtain 1-(4-chlorophenyl)-N-(1-cyano-5-cyclopropylpiperidine-3-yl)cyclopropane-1-carboxamide (35 mg, 65% yield). LCMS (ES, m / z): RT=1.14 min, m / z=344.1 [M+1] + .

[0606] Step 9: A mixture of 1-(4-chlorophenyl)-N-(1-cyano-5-cyclopropylpiperidine-3-yl)cyclopropan-1-carboxamide (50 mg, 0.145 mmol, 1 equivalent), trimethylsilyl azide (50.26 mg, 0.435 mmol, 3 equivalents), and NH4Cl (23.33 mg, 0.435 mmol, 3 equivalents) in dimethylformamide (DMF) (1 mL) was stirred at 120°C for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was filtered, the filtered cake was washed with methanol (MeOH) (3 × 4 mL), and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by reverse flash chromatography (silica gel, mobile phase, acetonitrile (MeCN) in water, 50% to 70% gradient over 10 minutes, detector, UV 254 nm) to obtain crude 1-(4-chlorophenyl)-N-(5-cyclopropyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 13, rac-13) (30 mg) as a mixture of cis and trans isomers.

[0607] Step 10. The crude product rac-13 was purified by preparative HPLC (Xselect CSH C18 OBD column, 30 × 150 mm, 5 μm, n, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile (MeCN), flow rate: 60 mL / min, gradient: 8 min, 24%B~34%B, 34%B, wavelength: 254 nm) to obtain a mixture of cis isomers (compounds 13A* and 13D*) as the first elution peak and a mixture of trans isomers (compounds 13B* and 13C*) as the second elution peak, and the stereochemistry was arbitrarily assigned.

[0608] Mixture of compounds 13A* and 13D*: LCMS (ES, m / z): RT = 0.72 min, m / z = 387.1 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.24 (m, 4H), 6.58 (d, J = 7.7 Hz, 1H), 4.03 (s, 1H), 3.24 - 3.21 (m, 2H), 3.20 - 3.16 (m, 2H), 3.00 - 2.90 (m, 1H), 1.73 - 1.63 (m, 1H), 1.53 - 1.42 (m, 1H), 1.37 - 1.22 (m, 2H), 0.97 (td, J = 8.3, 6.9, 4.6 Hz, 2H), 0.80 - 0.70 (m, 1H), 0.64 (m, J = 8.4, 4.8 Hz, 1H), 0.47 - 0.33 (m, 2H), 0.07 (d, J = 4.9 Hz, 1H).

[0609] Mixture of compounds 13B* and 13C*: LC-MS (ES, m / z): RT = 0.81 min, m / z = 387.1 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.37 (m, 2H), 7.40 - 7.31 (m, 2H), 6.86 (d, J = 7.8 Hz, 1H), 3.83 - 3.71 (m, 3H), 2.66 - 2.54 (m, 2H), 1.80 (d, J = 12.6 Hz, 1H), 1.35 (d, J = 3.0 Hz, 2H), 1.25 (t, J = 12.1 Hz, 1H), 1.05 - 0.93 (m, 2H), 0.86 (s, 1H), 0.47 (td, J = 8.6, 4.7Hz, 1H), 0.43 - 0.34 (m, 2H), 0.21 - 0.07 (m, 2H). Example 14. Synthesis of N-(1-(1H-tetrazole-5-yl)azocan-3-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (compound 14, rac-14) and compounds 14A* and 14B* [ka]

[0610] Example 14 follows Protocol C. Step 1: To a stirred solution of tert-butyl 3-hydroxyazocane-1-carboxylate (350 mg, 1.53 mmol, 1 equivalent) and pyridine (363.07 mg, 4.59 mmol, 3 equivalents) in dichloromethane (DCM) (15 mL), anhydrous methanesulfate (398.79 mg, 2.29 mmol, 1.5 equivalents) was added under a nitrogen atmosphere at 0°C. The final reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (Â) (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 1:1) to obtain tert-butyl 3-(methanesulfonyloxy)azocane-1-carboxylate (230 mg, yield 49%). LCMS(ES,m / z): RT= 1.06 min, m / z = 308[M+H]+ .

[0611] Step 2: A mixture of tert-butyl 3-(methanesulfonyloxy)azocane-1-carboxylate (230 mg, 0.75 mmol, 1 equivalent) and tetrabutylammonium azide (319.28 mg, 1.12 mmol, 1.5 equivalents) in dimethylformamide (DMF) (7.0 mL) was stirred overnight at 100°C. The mixture was cooled to room temperature. The resulting mixture was diluted with water (70 mL). The resulting mixture was extracted with ethyl acetate (SiO) (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded tert-butyl 3-azidozocane-1-carboxylate (140 mg, yield 74%). LCMS (ES, m / z): RT = 1.29 min, m / z = 255 [M + H] + .

[0612] Step 3: A solution of tert-butyl 3-azidoazokane-1-carboxylate (150 mg, 0.59 mmol, 1 equivalent) and Pd / C (50 mg, 0.47 mmol, 0.8 equivalents) in methanol (MeOH) (5.0 mL) was stirred at room temperature for 2 hours. The resulting mixture was filtered, and the filter cake was washed with methanol (MeOH) (3 × 20 mL). The filtrate was concentrated under reduced pressure. This yielded tert-butyl 3-aminoazokane-1-carboxylate (100 mg, 74% yield). LCMS (ES, m / z): RT = 0.62 min, m / z = 229 [M + H] + .

[0613] Step 4: To a stirred solution of tert-butyl 3-aminoazocane-1-carboxylate ("Amine(iv) Reagent") (110 mg, 0.48 mmol, 1.1 equivalents) and 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (86.11 mg, 0.44 mmol, 1 equivalent) in dimethylformamide (DMF) (5 mL), add triethylamine (TEA) (132.95 mg, 1.31 mmol, 3 equivalents), followed by (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU) (183.17 mg, 0.48 mmol) (1.1 equivalents) was added. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate ( Depositphotos) (3 × 50 mL). The combined organic layers were washed with brine (1 × 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 dichloromethane (DCM) / petroleum ether (PE) (1:5) to obtain tert-butyl 3-[1-(4-chlorophenyl)cyclopropanamide]azocane-1-carboxylate (110 mg, yield 40%). LCMS (ES, m / z): RT = 1.22 min, m / z = 407 [M + H] + .

[0614] Step 5: A solution of tert-butyl 3-[1-(4-chlorophenyl)cyclopropanamide]azocan-1-carboxylate (110 mg, 0.27 mmol, 1 equivalent) in dichloromethane (DCM) (3.0 mL) was bubbling with HCl (gas). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This yielded N-(azocan-3-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (80 mg, yield 66%). LCMS (ES, m / z): RT = 0.69 min, m / z = 307 [M+H] + .

[0615] Step 6: To a stirred solution of N-(azocan-3-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (80 mg, 0.26 mmol, 1 equivalent) in acetonitrile (MeCN) (3.0 mL), K2CO3 (108.10 mg, 0.78 mmol, 3 equivalents) and cyanogen bromide (138.09 mg, 1.31 mmol, 5 equivalents) were added. The resulting mixture was stirred at 80°C for 2 hours. The resulting mixture was diluted with water (20 mL) and then extracted with  (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain 1-(4-chlorophenyl)-N-(1-cyanoazocan-3-yl)cyclopropane-1-carboxamide (51 mg, yield 59%). LCMS (ES, m / z): RT=0.93 min, m / z=332 [M+H] + .

[0616] Step 7: Trimethylsilyl azide (62.49 mg, 0.54 mmol, 2 equivalents) and NH4Cl (43.52 mg, 0.81 mmol, 3 equivalents) were added to a stirred solution of 1-(4-chlorophenyl)-N-(1-cyanoazocan-3-yl)cyclopropane-1-carboxamide (90 mg, 0.27 mmol, 1 equivalent) in dimethylformamide (DMF) (2 mL). The resulting mixture was stirred overnight at 120°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, mobile phase: water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (21% acetonitrile (MeCN) to a maximum of 38% at 8 min), detector: UV 254 nm) to obtain N-(1-(1H-tetrazole-5-yl)azocan-3-yl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide (compound 14, rac-14) as a mixture of two stereoisomers.

[0617] Step 8. The crude product rac-14 was purified by chiral preparative HPLC (CHIRAL ART cellulose-SB, 2 × 25 cm, 5 μm, mobile phase, Hex- and EtOH- (retaining 10% EtOH- after 15 minutes), detector, UV 254 nm) to obtain compound 14A* (8.7 mg) as the first elution peak and compound 14B* (6.8 mg) as the second elution peak, and the stereochemistry was arbitrarily assigned.

[0618] Compound 14A*:LCMS(ES,m / z): RT=1.47 min, m / z=375[M+H] + , 1 H NMR(400MHz,DMSO-d6) δ 7.43-7.29(m,4H),7.18(d,J=8.1Hz,1H),3.97(s,1H),3.44(q,J=4.0,3.1Hz,3H),1.75-1.61(m,2H),1. 54(d,J=9.2Hz,2H),1.44(t,J=10.2Hz,2H),1.37(d,J=2.5Hz,2H),1.30-1.22(m,2H),1.05-0.95(m,2H).

[0619] Compound 14B*:LCMS(ES,m / z): RT=1.47 min, m / z=375[M+H] + , 1 H NMR(400MHz,DMSO-d6) δ 7.41-7.31(m,4H),7.17(d,J=7.9Hz,1H),3.97(d,J=8.5Hz,1H),3.48-3.42(m,3H),1.77-1.61(m,2H), 1.53(t,J=9.0Hz,2H),1.48-1.39(m,2H),1.37(d,J=2.6Hz,2H),1.31-1.22(m,2H),1.04-0.93(m,2H). Example 15. Synthesis of (R)-N-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chloro-2-methoxyphenyl)cyclopropane-1-carboxamide (compound 15A-OMe), (R)-N-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chloro-2-hydroxyphenyl)cyclopropane-1-carboxamide (compound 15A), and compounds 15B-OMe and 15B-OMe. [ka]

[0620] Example 15 follows Protocol A. Step 1: (4-chloro-2-methoxyphenyl)acetic acid (1 g, 4.99 mmol, 1 equivalent), methanol (MeOH) (10 mL), and H2SO4 (2 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 100 mL). The resulting mixture was concentrated under reduced pressure to obtain methyl 2-(4-chloro-2-methoxyphenyl)acetate (900 mg, yield 84%).

[0621] Step 2: Methyl 2-(4-chloro-2-methoxyphenyl)acetate (200 mg, 0.932 mmol, 1 equivalent), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (284 mg, 1.86 mmol, 2 equivalents), dimethyl sulfoxide (DMSO) (10 mL), and diphenylvinylsulfonium triflate (371 mg, 1.03 mmol, 1.1 equivalents) were added to an 8 mL vial at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The residue was purified by reverse-phase flash chromatography (water:acetonitrile (MeCN) = 1:1) to obtain methyl 1-(4-chloro-2-methoxyphenyl)cyclopropane-1-carboxylate (190 mg, yield 85%).

[0622] Step 3: Methyl 1-(4-chloro-2-methoxyphenyl)cyclopropane-1-carboxylate (200 mg, 0.831 mmol, 1 equivalent), NaOH (66.5 mg, 1.66 mmol, 2 equivalents), methanol (MeOH) (5 mL), and water (5 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 5 hours. The mixture was acidified to pH 3 with concentrated HCl. The aqueous layer was extracted with ethyl acetate (Â) (3 × 50 mL), dried, and concentrated under reduced pressure to obtain 1-(4-chloro-2-methoxyphenyl)cyclopropane-1-carboxylic acid (150 mg, yield 80%).

[0623] Step 4: 1-(4-chloro-2-methoxyphenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (70.0 mg, 0.30 mmol, 1 equivalent), (3R)-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine ("Amine(i) Reagent") (52 mg, 0.3 mmol, 1 equivalent), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (95.3 mg, 0.34 mmol, 1.1 equivalents), N-methylimidazole (NMI) (76.1 mg, 0.92 mmol, 3 equivalents), and acetonitrile (5 mL) were added to a 20 mL vial at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LC-MS. The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 35%-45% gradient over 10 mins, detector, UV220 / 254 nm) to obtain (R)-N-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chloro-2-methoxyphenyl)cyclopropane-1-carboxamide (compound 15A-OMe) (60 mg, yield 52%). LCMS (ESI): RT=0.785 min, m / z=377 [M+H] + .

[0624] Step 5: Compound 15A-OMe (60 mg, 0.15 mmol, 1 equivalent), dichloromethane (DCM) (3 mL), and BBr3 (199.43 mg, 0.75 mmol, 5 equivalents) were added to an 8 mL vial at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The progress of the reaction was monitored by LC-MS. The reaction was quenched by adding water (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (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: 8 min, 17%B~27%B, 27%B, wavelength: 254 nm, RT (min): 7) to obtain (R)-N-(1-(1H-tetrazole-5-yl)piperidine-3-yl)-1-(4-chloro-2-hydroxyphenyl)cyclopropane-1-carboxamide (compound 15A) (9.2 mg). LC-MS (ESI): RT = 0.640 min, m / z = 363.1 [M + H] + . 1 H NMR (400MHz, methanol-d4) δ 7.18(d,J=8.6Hz,1H),6.81-6.80(m,2H),4.01(s,1H),3.40(d,J=12.2Hz,1H),3.25(s,2H),3.18-3.09 (m,1H),1.71(s,2H),1.58(td,J=14.9,14.4,9.6Hz,2H),1.50(d,J=3.5Hz,2H),1.00(q,J=3.1Hz,2H).

[0625] Compound 15B-OMe and compound 15 can be synthesized according to Example 15, by using (3S)-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R)-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4. Example 16. Synthesis of 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 16A-OMe) and 1-(2-hydroxy-4-(trifluoromethyl)phenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 16A), as well as compounds 16B, 16C, 16D, 16B-OMe, 16C-OMe, and 16D-OMe [ka] [ka]

[0626] Example 16 follows Protocol A. Step 1: A solution of 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (1000 mg, 3.921 mmol, 1 equivalent), 1-(bromodinthio)-3-(tert-butoxy)propan-2-one (3228.51 mg, 11.763 mmol, 3 equivalents), and bis(tri-tert-butylphosphine)palladium(0)(Pd[(t-Bu)3P]2)(601.16 mg, 1.176 mmol, 0.3 equivalents) in tetrahydrofuran (THF) was stirred for 2 hours under a nitrogen atmosphere at 60°C. The resulting mixture was extracted with ethyl acetate (SiO) (3 × 10 mL). The combined organic layers were washed with water (3 × 10 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 (8:1) to obtain tert-butyl 2-[2-methoxy-4-(trifluoromethyl)phenyl]acetate (800 mg, yield 70%). LCMS (ES, m / z): RT=0.576 min, m / z=290.0 [M+H] + .

[0627] Step 2: A solution of tert-butyl 2-[2-methoxy-4-(trifluoromethyl)phenyl]acetate (800 mg, 2.756 mmol, 1 equivalent), ethenyldiphenylsulfanium (764.27 mg, 3.583 mmol, 1.3 equivalents), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (1258.70 mg, 8.268 mmol, 3 equivalents) in dimethyl sulfoxide (DMSO) was stirred for 1 hour under a nitrogen atmosphere at 25°C. The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 60% to 70% gradient over 10 minutes, detector, UV254 nm) to obtain tert-butyl 1-[2-methoxy-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate (600 mg, yield 69%). LCMS(ES,m / z): RT=1.025 min, m / z=316[M+H] + .

[0628] Step 3: A solution of tert-butyl 1-(2-methoxy-4-methylphenyl)cyclopropane-1-carboxylate (600 mg, 2.287 mmol, 1 equivalent) and trifluoroacetic acid (TFA) (5215.48 mg, 45.740 mmol, 20 equivalents) in dichloromethane (DCM) was stirred for 2 hours under an air atmosphere at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water (0.1% FA), 40% to 50% gradient over 10 mins, detector, UV 254 nm) to obtain 1-[2-methoxy-4-(trifluoromethyl)phenyl]cyclopropane-1carboxylic acid (500 mg, yield 84%). LCMS (ES, m / z): RT=0.607 min, m / z=260 [M+H] + .

[0629] Step 4: A solution of 1-[2-methoxy-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (200 mg, 0.769 mmol, 1 equivalent), (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine ("Amine(i) Reagent") (280.13 mg, 1.538 mmol, 2 equivalents), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (150.96 mg, 0.538 mmol, 0.7 equivalents), and N-methylimidazole (NMI) (252.43 mg, 3.076 mmol, 4 equivalents) in acetonitrile (MeCN) was stirred for 2 hours under a nitrogen atmosphere at room temperature. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 20%-30% gradient over 10 mins, detector, UV 254 nm) to obtain 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 16A-OMe). LCMS (ES, m / z): RT=0.519 min, m / z=425 [M+H] + .

[0630] Step 5: A solution of compound 16-OMe (50 mg, 0.118 mmol, 1 equivalent) and sodium (ethylsulfanyl) (297.26 mg, 3.540 mmol, 30 equivalents) in dimethyl sulfoxide (DMSO) was stirred at 120°C under a nitrogen atmosphere for 2 hours. The resulting mixture was extracted with ethyl acetate (siRNA) (3 × 100 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous sodium SiO₂. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 20%-30% gradient over 10 minutes, detector, UV 254 nm) to obtain the crude product (50 mg). This was further purified by preparative HPLC (30% acetonitrile in water, isocratic) to obtain 1-(2-hydroxy-4-(trifluoromethyl)phenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 16A) (9.8 mg, yield 20%). LCMS (ES, m / z): RT=1.381 min, m / z=410 [M+H] + .

[0631] Compounds 16B-OMe and 16B can be synthesized from (3S,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 16.

[0632] Compounds 16C-OMe and 16C can be synthesized from (3R,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 16.

[0633] Compounds 16D-OMe and 16D can be synthesized from (3S,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 16. Example 17. Synthesis of 1-(2-methoxy-4-(trifluoromethoxy)phenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 17A-OMe), 1-(2-hydroxy-4-(trifluoromethoxy)phenyl)-N-(((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 17A), and compounds 17B, 17C, 17D, 17B-OMe, 17C-OMe, and 17D-OMe [ka] [ka]

[0634] Example 17 follows Protocol A. Step 1: 2-bromo-5-(trifluoromethoxy)phenol (500 mg, 1.945 mmol, 1 equivalent), K2CO3 (806.63 mg, 5.835 mmol, 3 equivalents), methyl iodide (MeI) (552.28 mg, 3.890 mmol, 2 equivalents), and acetonitrile (MeCN) (5 mL) were added to a 20 mL vial at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 1 hour. The aqueous layer was extracted with ethyl acetate (Â) (3 × 50 mL). The residue was purified by silica gel column chromatography eluted with petroleum ether:ethyl acetate (8:1) to obtain 1-bromo-2-methoxy-4-(trifluoromethoxy)benzene (400 mg, yield 76%).

[0635] Step 2: 1-Bromo-2-methoxy-4-(trifluoromethoxy)benzene (500 mg, 1.845 mmol, 1 equivalent), tert-butyl 2-(bromodinthio)acetate (960.92 mg, 3.690 mmol, 2 equivalents), tetrahydrofuran (THF) (5 mL), 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (655.55 mg, 0.922 mmol, 0.5 equivalents), and tert-butyl 2-[2-methoxy-4-(trifluoromethoxy)phenyl]acetate (400 mg) were added to a 20 mL vial at room temperature. The resulting mixture was stirred overnight under a nitrogen atmosphere at 70°C. The aqueous layer was extracted with ethyl acetate (siRNA) (3 × 50 mL). The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (12:1) to obtain tert-butyl 2-[2-methoxy-4-(trifluoromethoxy)phenyl]acetate (400 mg, yield 71%).

[0636] Step 3: In an 8 mL vial, tert-butyl 2-[2-methoxy-4-(trifluoromethoxy)phenyl]acetate (200 mg, 0.653 mmol, 1 equivalent), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (298.24 mg, 1.959 mmol, 3 equivalents), dimethyl sulfoxide (DMSO) (5 mL), and diphenylvinylsulfonium triflate (354.95 mg, 0.980 mmol, 1.5 equivalents) were added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water (0.1% NH3 in water), 50% to 80% gradient over 10 minutes, detector, UV 254 nm) to obtain tert-butyl 1-[2-methoxy-4-(trifluoromethoxy)phenyl]cyclopropane-1-carboxylate (150 mg, yield 69%).

[0637] Step 4: In an 8 mL vial, tert-butyl 1-[2-methoxy-4-(trifluoromethoxy)phenyl]cyclopropane-1-carboxylate (200 mg, 0.602 mmol, 1 equivalent), dichloromethane (DCM) (2 mL), and trifluoroacetic acid (TFA) (0.5 mL) were added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours, and then concentrated under vacuum to obtain 1-[2-methoxy-4-(trifluoromethoxy)phenyl]cyclopropane-1-carboxylic acid (150 mg, 90% yield).

[0638] Step 5: 1-[2-hydroxy-4-(trifluoromethoxy)phenyl]cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (100 mg, 0.381 mmol, 1 equivalent), (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine ("Amine(i) Reagent") (72.57 mg, 0.398 mmol, 1.1 equivalents), triethylamine (TEA) (109.91 mg, 1.086 mmol, 3 equivalents), and dimethylformamide (DMF) (2 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water (0.1% NH3 in water), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain 1-(2-methoxy-4-(trifluoromethoxy)phenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 17A-OMe).

[0639] Step 6: Compound 17A-OMe (50 mg, 0.114 mmol, 1 equivalent), tetrahydrofuran (DMSO) (2 mL), and sodium (ethylsulfanyl) (95.49 mg, 1.140 mmol, 10 equivalents) were added to an 8 mL vial. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acteonitrile (MeCN) in water (0.1% NH3 in water), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain 1-(2-hydroxy-4-(trifluoromethoxy)phenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 17A) (19.1 mg). LCMS(ESI): RT=1.537min, m / z=427[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 7.32(d,J=9.0Hz,1H),6.79-6.73(m,2H),3.99-3.83(m,2H),3.79(dd,J=12.6,4.2Hz,1H),2.73(dd,J=12.0,10.7Hz,1H),2.56(dd,J=1 2.8,11.3Hz,1H),1.90(d,J=12.9Hz,1H),1.53(q,J=3.3Hz,2H),1.18-1.07(m,1H),1.05(tt,J=4.7,2.6Hz,2H),0.97(d,J=6.6Hz,3H).

[0640] Compounds 17B-OMe and 17B can be synthesized from (3S,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 5 of Example 17.

[0641] Compounds 17C-OMe and 17C can be synthesized from (3R,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 17.

[0642] Compounds 17D-OMe and 17D can be synthesized from (3S,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 17. Example 18. Synthesis of 1-(4-chloro-3-fluoro-2-methoxyphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 18-OMe, rac-18-OMe), 1-(4-chloro-3-fluoro-2-hydroxyphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 18, rac-18), compounds 18A-OMe*, 18B-OMe*, 18C-OMe*, and 18D-OMe*, and compounds 18A*, 18B*, 18C*, and 18D*. Scheme 18A. [ka] Scheme 18B. [ka] Scheme 18C. [ka] Scheme 18D. [ka]

[0643] Example 18 follows Protocol A. Step 1: Allylamine hydrochloride (25.0 g, 267.23 mmol, 1 equivalent), ethanol (EtOH) (400 mL), ethyl acrylate (32.10 g, 320.68 mmol, 1.2 equivalents), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (81.36 g, 534.47 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. The resulting mixture was concentrated under reduced pressure. The reaction was quenched at room temperature by adding water (100 mL), the aqueous layer was extracted with ethyl acetate (RINKAN) (3 × 500 mL), the organic layer was dried over anhydrous Na₂SO₄, and the resulting mixture was concentrated under reduced pressure to obtain ethyl 3-(propa-2-en-1-ylamino)propanoate (26 g, yield 62%), which was used in the next step without further purification. LCMS (ES, m / z): RT = 0.236 min, m / z = 158[M+1]+.

[0644] Step 2: Ethyl 3-(propa-2-en-1-ylamino)propanoate (25.0 g, 159.02 mmol, 1 equivalent), di-tert-butyl dicarbonate (69.41 g, 318.04 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 then the reaction was quenched by adding ice water (200 mL) at 0°C. The aqueous layer was extracted with ethyl acetate (siRNA) (3 × 500 mL), and the organic layer was dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under reduced pressure, and the residue 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 g, 56% yield). LCMS (ES, m / z): RT=0.993 min, m / z=258[M+1]+.

[0645] Step 3: To a stirred solution of ethyl 3-[(tert-butoxycarbonyl)(propa-2-en-1-yl)amino]propanoate (20 g, 77.72 mmol, 1 equivalent) in tetrahydrofuran (THF) (300 mL), bis(trimethylsilyl)amide (LiHMDS) (15.61 g, 93.26 mmol, 1.2 equivalents) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at -78°C under a nitrogen atmosphere. Then, 3-bromo-2-methylprop-1-ene (20.82 g, 155.44 mmol, 2 equivalents) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0°C under a nitrogen atmosphere. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (500 mL) at 0°C. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 500 mL). The combined organic layers were dried over anhydrous sodium 2SO4. The resulting mixture was concentrated under reduced pressure. The residue 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}pento-4-enoate (15 g, yield 65%). LCMS (ES, m / z): RT = 1.097 min, m / z = 312[M+1]+.

[0646] Step 4: Ethyl 2-{[(tert-butoxycarbonyl)(propa-2-en-1-yl)amino]methyl}-4-methylpenta-4-enoate (40 g, 128.44 mmol, 1 equivalent), tetrahydrofuran (4000 mL), and (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (Grubbs second-generation catalyst) (16.36 g, 19.26 mmol, 0.15 equivalents) were added to a 5000 mL three-necked round-bottom flask at room temperature. The resulting mixture was stirred at 55 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water (500 mL). The aqueous layer was extracted with ethyl acetate (ELISA) (3 × 300 mL). The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (12:1) to obtain 1-tert-butyl3-ethyl5-methyl-2,3,4,7-tetrahydroazepine-1,3-dicarboxylate) (30 g, yield 82%).

[0647] Step 5: 1-tert-butyl 3-ethyl 5-methyl-2,3,4,7-tetrahydroazepine-1,3-dicarboxylate (20.0 g, 70.58 mmol, 1 equivalent), methanol (MeOH) (100 mL), NaOH (14.11 g, 352.90 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 acidified to pH=6 with HCl (aqueous solution) (2 M) at 0°C. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 200 mL). The organic layer was dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under reduced pressure to obtain the crude product 1-(tert-butoxycarbonyl)-5-methyl-2,3,4,7-tetrahydro-1H-azepine-3-carboxylic acid, which was used directly in the next step without further purification.

[0648] Step 6: 1-(tert-butoxycarbonyl)-5-methyl-2,3,4,7-tetrahydroazepine-3-carboxylic acid (20.0 g, 78.33 mmol, 1 equivalent), toluene (250 mL), benzyl alcohol (25.41 g, 235.01 mmol, 3 equivalents), diphenyl phosphoryl azide (DPPA) (64.67 g, 235.01 mmol, 3 equivalents), and triethylamine (TEA) (23.78 g, 235.01 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. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate (RINKAN) (3 × 500 mL). The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 50%-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]+.

[0649] 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, 27.74 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 resulting mixture was concentrated under reduced pressure. This yielded (5-methyl-2,3,4,7-tetrahydro-1H-azepine-3-yl)carbamate (8 g), which was used directly in the next step without further purification. LCMS (ES, m / z): RT = 0.563 min, m / z = 261 [M+1] + .

[0650] Step 8: Benzyl N-(5-methyl-2,3,4,7-tetrahydro-1H-azepine-3-yl)carbamate (8.0 g, 30.72 mmol, 1 equivalent), acetonitrile (MeCN) (50 mL), K2CO3 (12.74 g, 92.18 mmol, 3 equivalents), and BrCN (3.91 g, 36.87 mmol, 1.20 equivalents) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The aqueous layer was extracted with ethyl acetate (RINKAN) (3 × 200 mL). The resulting mixture was concentrated under reduced pressure. The residue 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 g, yield 80%). LCMS(ES,m / z): RT=0.837 min, m / z=286[M+1]+.

[0651] Step 9: Benzyl N-(1-cyano-5-methyl-2,3,4,7-tetrahydroazepin-3-yl)carbamate (5 g, 17.52 mmol, 1 equivalent), NH4Cl (2.81 g, 52.56 mmol, 3 equivalents), and azidotrimethylsilane (6.06 g, 52.56 mmol, 3 equivalents) were added to a 50 mL round-bottom flask at room temperature. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature. The residue was purified by reverse flash chromatography (C18 column, mobile phase: acetonitrile (MeCN) in water, gradient of 40% to 60% over 10 minutes, detector: UV 254 nm) to obtain benzyl (5-methyl-1-(1H-tetrazole-5-yl)-2,3,4,7-tetrahydro-1H-azepine-3-yl)carbamate (4 g, yield 70%). LC-MS (ES, m / z): RT=0.773 min, m / z=329[M+1]+.

[0652] 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, 12.18 mmol, 1 equivalent), methanol (MeOH) (100 mL), and Pd / C (1.30 g, 12.18 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 filtered, and the filter cake was washed with methanol (MeOH) (3 × 20 mL). The filtrate was concentrated under reduced pressure to obtain 5-methyl-1-(1H-tetrazole-5-yl)azepan-3-amine (2.5 g). LCMS (ES, m / z): RT = 0.101 min, 0.289, m / z = 197 [M+1]+.

[0653] Step 11: 1-Bromo-4-chloro-3-fluoro-2-methoxybenzene (400 mg, 1.044 mmol, 1 equivalent), tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3) (265.20 mg, 0.209 mmol, 0.2 equivalents), and tetrahydrofuran (THF) (15 mL) were added to a 40 mL sealed tube at room temperature. The resulting mixture was stirred at 80°C for 10 hours under a nitrogen atmosphere. The resulting mixture was extracted with ethyl acetate (siRNA) (3 × 250 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 (10:1) to obtain tert-butyl 2-(4-chloro-3-fluoro-2-methoxyphenyl)acetate (400 mg, yield 79%). GCMS(ESI): RT=8.5 min, m / z=274.

[0654] Step 12: In a 40 mL sealed tube, tert-butyl 2-(4-chloro-3-fluoro-2-methoxyphenyl) acetate (400 mg, 0.728 mmol, 1 equivalent), ethenyl diphenyl sulfanium (400.95 mg, 1.092 mmol, 1.5 equivalents), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (660.06 mg, 2.184 mmol, 3 equivalents), and dimethyl sulfoxide (DMSO) (4 mL, 56.318 mmol, 77.36 equivalents) were added at room temperature. The resulting mixture was stirred for 1 hour under an air atmosphere at room temperature. The resulting mixture was extracted with ethyl acetate (siRNA) (3 × 250 mL), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (water:acetonitrile (MeCN) = 2:8) to obtain tert-butyl 1-(4-chloro-3-fluoro-2-methoxyphenyl)cyclopropane-1-carboxylate (200 mg, 55% yield). GC-MS (ESI): RT = 8.7 min, m / z = 300.

[0655] Step 13: In an 8 mL sealed tube, tert-butyl 1-(4-chloro-3-fluoro-2-methoxyphenyl)cyclopropane-1-carboxylate (400 mg, 0.399 mmol, 1 equivalent) and dichloromethane (DCM) (5 mL, 78.653 mmol, 197.12 equivalents) were added at room temperature. The resulting mixture was stirred for 1 hour under an air atmosphere at room temperature, then concentrated to obtain crude 1-(4-chloro-3-fluoro-2-methoxyphenyl)cyclopropane-1-carboxylic acid, which was used directly in the next step without further purification. LCMS (ESI): RT=0.84 min, m / z=245 [M+H] + .

[0656] Step 14: 1-(4-chloro-3-fluoro-2-methoxyphenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (120 mg, 0.490 mmol, 1 equivalent), 5-methyl-1-(1H-tetrazole-5-yl)azepan-3-amine ("Amine(i) Reagent") (96 mg, 0.490 mmol, 1 equivalent), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (137.62 mg, 0.490 mmol, 1 equivalent), N-methylimidazole (NMI) (201.36 mg, 2.450 mmol, 5 equivalents), and acetonitrile (MeCN) (6.67 mL, 126.699 mmol, 258.57 equivalents) were added to a 20 mL sealed tube at room temperature. The resulting mixture was stirred for 1 hour under room temperature air. The mixture was concentrated under vacuum. The residue product was purified by reverse-phase flash chromatography (water:acetonitrile (MeCN) = 6:4) to obtain 1-(4-chloro-3-fluoro-2-methoxyphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 18-OMe, rac-18-OMe) (70 mg, yield 37%). LCMS (ESI): RT = 0.74 min, m / z = 423 [M + H] + .

[0657] Step 15: rac-18-OMe (70.0 mg, 0.170 mmol, 1 equivalent), sodium ethanethiolate (EtSNa) (216 mg, 2.56 mmol, 15 equivalents), and dimethylformamide (DMF) (2 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at 120 °C for 1 hour. The reaction was monitored by LC-MS. The reaction was quenched with water at room temperature (2 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 20% to 35% gradient over 10 minutes, detector, UV 220 nm) to obtain 1-(4-chloro-3-fluoro-2-hydroxyphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 18, rac-18) (55 mg, purity 73%).

[0658] Step 16: Crude rac-18 (55 mg) was purified by preparative HPLC (XBridge preparative phenyl OBD column, 19 × 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%B at 8 min, wavelength: 254 nm, RT (min): 8.5 to 10.5) to obtain a cis mixture (26 mg, yield 36%) which is assumed to be the first elution peak, and a trans mixture (16 mg, yield 23%) which is assumed to be the second elution peak, and the stereochemistry was arbitrarily assigned.

[0659] Step 17: The assumed transform mixture was separated using the following conditions (CHIRALPAK ID, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: ethanol, flow rate: 20 mL / min, gradient: 12%B to 12%B over 16 mins, wavelength: 220 / 254 nm) to obtain compound 18B* (RT(min): 13.09, 10.6 mg) and compound 18C* (RT(min): 15.32, 10.4 mg). Stereochemistry was arbitrarily assigned.

[0660] Compound 18B*: LCMS (ESI): RT = 0.74 min, m / z = 409 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.22 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.16 (q, J = 6.4 Hz, 1H), 3.61 - 3.47 (m, 3H), 3.18 (ddd, J = 13.8, 9.7, 4.4 Hz, 1H), 1.77 (s, 1H), 1.68 (d, J = 15.0 Hz, 1H), 1.60 - 1.52 (m, 1H), 1.45 (dtd, J = 15.8, 7.9, 6.4, 3.6 Hz, 1H), 1.42 - 1.30 (m, 1H), 1.31 (t, J = 4.5 Hz, 1H), 1.27 (dd, J = 9.6, 5.0 Hz, 1H), 0.95 (ddd, J = 10.2, 6.6, 3.7 Hz, 1H), 0.87 (d, J = 6.8 Hz, 3H), 0.82 (ddd, J = 9.6, 6.6, 3.5 Hz, 1H).

[0661] Compound 18C*: LCMS (ESI): RT = 0.74 min, m / z = 409.1 [M+H] + , 1H NMR(400MHz,DMSO-d6) δ 14.64(s,1H),10.22(s,1H),6.91(d,J=8.6Hz,1H),6.84(dd,J=8.4,6.6Hz,1H),6.58(d,J=8.1Hz,1H),4.16(q,J=6.9,6.5Hz,1H),3.61-3.47(m,3H),3.18(d,J=13.9Hz,1H),1.76(d,J=8.0Hz,1H),1.67(d,J=14.6Hz,1H),1.61-1.21(m,5H),0.95(d,J=10.1Hz,1H),0.90-0.77(m,4H).

[0662] Step 18: The expected cis-compound mixture product was purified by preparative chiral HPLC (CHIRAL ART cellulose-SB, 2 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: ethanol, flow rate: 20 mL / min, gradient: 8%B~8%B at 18 min, wavelength: 220 / 254 nm) to obtain compound 18A* (RT(min): 15.63, 4.4 mg) and compound 18D* (RT(min): 17.71, 4.9 mg). Stereochemistry was arbitrarily assigned.

[0663] Compound 18A*:LCMS(ESI): RT=0.83 min, m / z=409[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 10.13 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.98 - 6.90 (m, 1H), 3.97 (s, 1H), 3.61 - 3.38 (m, 4H), 1.74 (d, J = 13.5 Hz, 1H), 1.52 (d, J = 12.2 Hz, 1H), 1.38 (s, 2H), 1.31 (s, 2H), 1.30 - 1.23 (m, 1H), 0.88 (d, J = 6.6 Hz, 5H).

[0664] Compound 18D*:LCMS(ESI): RT=0.74 min, m / z=409[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 10.22 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.84 (dd, J = 8.4, 6.6 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 4.16 (q, J = 6.9, 6.5 Hz, 1H), 3.61 - 3.47 (m, 3H), 3.18 (ddd, J = 13.9, 9.7, 4.4 Hz, 1H), 1.76 (d, J = 8.0 Hz, 1H), 1.67 (d, J = 14.6Hz, 1H), 1.61 - 1.21 (m, 5H), 0.95 (ddd, J = 10.1, 6.6, 3.7 Hz, 1H), 0.90 - 0.77 (m, 4H).

[0665] Compounds 18A-OMe, 18B-OMe, 18C-OMe, and 18D-OMe can be separated from rac-18-OMe in step 14 by chiral HPLC. Example 19. Synthesis of 1-(4-(difluoromethoxy)-2-methoxyphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 19A-OMe), 1-(4-(difluoromethoxy)-2-hydroxyphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 19A), and compounds 19B, 19C, 19D, 19B-OMe, 19C-OMe, and 19D-OMe [ka] [ka]

[0666] Example 19 follows Protocol A. Step 1: 1-Bromo-4-(difluoromethoxy)-2-methoxybenzene (600 mg, 2.371 mmol, 1 equivalent), tert-butyl 2-(bromodinthio)acetic acid (1852.62 mg, 7.113 mmol, 3 equivalents), bis(tri-tert-butylphosphine)palladium(0)(Pd[(t-Bu)3P]2) (242.36 mg, 0.474 mmol, 0.2 equivalents), and tetrahydrofuran (5 mL) were added to a 20 mL sealed tube at 60°C. The resulting mixture was stirred under a nitrogen atmosphere at 60°C for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate (SiO) (2 × 10 mL). The combined organic layers were washed with water (4 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane (DCM) / petroleum ether 1:1) to obtain tert-butyl 2-[4-(difluoromethoxy)-2-methoxyphenyl]acetate (600 mg, yield 88%). LCMS (ES, m / z): RT=1.03 min, m / z=289.2 [M+1] + .

[0667] Step 2: In a 20 mL sealed tube, tert-butyl 2-(4-(difluoromethoxy)-2-methoxyphenyl) acetate (600 mg, 2.08 mmol, 1 equivalent), diphenyl(vinyl)sulfonium trifluoromethanesulfonate (2.26 g, 6.24 mmol, 3 equivalents), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (379 mg, 2.49 mmol, 1.2 equivalents), and DMSO (5 mL) were added at room temperature. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / petroleum ether = 1:1) to obtain tert-butyl 2-[4-(difluoromethoxy)-2-methoxyphenyl]acetate (400 mg, yield 59%) as a pale yellow oil. LCMS (ES, m / z): RT = 1.02 min, m / z = 314.2 [M + H] + .

[0668] Step 3: In an 8 mL vial, tert-butyl 1-[4-(difluoromethoxy)-2-methoxyphenyl]cyclopropane-1-carboxylate (200 mg, 0.636 mmol, 1 equivalent), dichloromethane (DCM) (2 mL), and trifluoroacetaldehyde (2 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. The resulting mixture was extracted with ethyl acetate ( Depositphotos) (2 × 20 mL). The combined organic layers were washed with water (4 × 5 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 1-[4-(difluoromethoxy)-2-methoxyphenyl]cyclopropane-1-carboxylic acid (150 mg, 91% yield). LC-MS (ES, m / z): RT = 1.12 min, m / z = 257.0 [M-1] - .

[0669] Step 4: 1-[4-(difluoromethoxy)-2-methoxyphenyl]cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (50 mg, 0.194 mmol, 1 equivalent), (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine ("Amine(i) Reagent") (70.5 mg, 0.388 mmol, 2 equivalents), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (65.20 mg, 0.233 mmol, 1.2 equivalents), N-methylimidazole (NMI) (47.70 mg, 0.582 mmol, 3 equivalents), and acetonitrile (MeCN) (0.5 mL, 0.019 mmol) were added to an 8 L vial at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. The residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile in water, gradient from 0% to 100% over 30 minutes, detector, UV 254 nm) to obtain 1-(4-(difluoromethoxy)-2-methoxyphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 19A-OMe) (50 mg, yield 65%). LC-MS (ES, m / z): RT=0.83 min, m / z=423.0 [M-1] - .

[0670] Step 5: Compound 19A-OMe (30 mg, 0.071 mmol, 1 equivalent), sodium (ethylsulfanyl) (89.60 mg, 1.065 mmol, 15 equivalents), and dimethylformamide (DMF) (1 mL) were added to an 8 mL vial at 120 °C. The resulting mixture was stirred at 80 °C for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with methanol (MeOH) (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase: acetonitrile in water, gradient from 0% to 100% over 10 minutes, detector: UV 254 nm) to obtain the crude product (30 mg), which was then purified by preparative HPLC (XBridge preparative phenyl OBD column, 19 × 250 mm, 5 μm, mobile phase A: water (0.05% trifluoroacetic acid (TFA)), mobile phase B: acetonitrile (MeCN), flow rate: 25 mL / min, gradient: 40%B to 50%B, 50%B over 10 minutes, wavelength: 254 nm, RT (min): 9) to obtain 1-(4-(difluoromethoxy)-2-hydroxyphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 19A) (10.7 mg). LCMS(ES,m / z): RT=0.69 min, m / z=409.2[M+1] + . 1 H NMR (400MHz, methanol-d4) δ 7.29-7.21(m,1H),7.00-6.57(m,3H),3.97-3.69(m,3H),2.76-2.65(m,1H),2.56(m,J =12.7,11.3Hz,1H),1.96-1.75(m,2H),1.51(q,J=3.3,2.9Hz,2H),1.14-0.90(m,6H).

[0671] Compounds 19B-OMe and 19B can be synthesized from (3S,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 19.

[0672] Compounds 19C-OMe and 19C can be synthesized from (3R,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 19.

[0673] Compounds 19D-OMe and 19D can be synthesized from (3S,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 4 of Example 19. Example 20. Synthesis of 1-(2-methoxy-4-methylphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 20A-OMe), 1-(2-hydroxy-4-methylphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 20A), and compounds 20B, 20C, 20D, 20B-OMe, 20C-OMe, and 20D-OMe [ka] [ka]

[0674] Example 20 follows Protocol A. Step 1: Methyl 1-(4-chloro-2-methoxyphenyl)cyclopropane-1-carboxylate (220 mg, 0.914 mmol, 1 equivalent), trimethyl-1,3,5,2,4,6-trioxatriborinane (137.69 mg, 1.097 mmol, 1.2 equivalents), K3PO4 (582.08 mg, 2.742 mmol, 3 equivalents), bis(tri-tert-butylphosphine)palladium(0)(Pd[(t-Bu)3P]2) (140.14 mg, 0.274 mmol, 0.3 equivalents), and dioxane (4 mL) were added to an 8 mL vial. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The desired product could be detected by LC-MS. The resulting mixture was filtered, and the filtrate was washed with ethyl acetate (siRNA) (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 8:1) to obtain methyl 1-(2-methoxy-4-methylphenyl)cyclopropane-1-carboxylate (159 mg, yield 79%).

[0675] Step 2: Methyl 1-(2-methoxy-4-methylphenyl)cyclopropane-1-carboxylate (140 mg, 0.636 mmol, 1 equivalent), NaOH (76.27 mg, 1.908 mmol, 3 equivalents), methanol (MeOH) (3 mL), and water (0.6 mL) were added to an 8 mL vial. The resulting mixture was stirred overnight under an air atmosphere at 40°C. The desired product could be detected by LC-MS. The mixture was acidified to pH 2 with concentrated HCl. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 10 mL), and the resulting mixture was washed with brine (10 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 2:1) to obtain 1-(2-methoxy-4-methylphenyl)cyclopropane-1-carboxylic acid (106 mg, yield 81%).

[0676] Step 3: In an 8 mL vial, add 1-(2-methoxy-4-methylphenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (100 mg, 0.485 mmol, 1 equivalent), (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine ("Amine(i) Reagent") (106.03 mg, 0.582 mmol, 1.2 equivalents), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (184.36 mg, 0.485 mmol, 1 equivalent), triethylamine (TEA) (147.20 mg, 1.455 mmol, 3 equivalents), and dimethylamine. 2.5 mL of ioformudine (DMF) was added. The resulting mixture was stirred for 2 hours under an air atmosphere at room temperature. The desired product could be detected by LC-MS. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 10 mL). The resulting mixture was washed with brine (10 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (dichloromethane (DCM) / methanol (MeOH) 20:1) to obtain 1-(2-methoxy-4-methylphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 20A-OMe) (200 mg, yield 89%).

[0677] Step 4: Compound 20A-OMe (170 mg, 0.459 mmol, 1 equivalent), sodium (ethylsulfanyl) (385.97 mg, 4.590 mmol, 10 equivalents), and dimethylformamide (DMF) (3.5 mL) were added to an 8 mL vial. The resulting mixture was stirred at 120°C under an air atmosphere for 2 hours. The desired product could be detected by LC-MS. The resulting mixture was filtered, and the filtrate cake was washed with dimethylformamide (DMF) (3 × 3 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD 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: 19%B~29%B, 29%B at 10 min, wavelength: 254 nm, RT (min): 7.78) to obtain 1-(2-hydroxy-4-methylphenyl)-N-((3R,5S)-5-methyl-1-(1H-tetrazole-5-yl)piperidine-3-yl)cyclopropane-1-carboxamide (compound 20A) (29.6 mg). LCMS (ES, m / z): RT = 0.67 min, m / z = 357.2 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.05 (d, J = 7.7 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.61 - 6.57 (m, 1H), 6.13 (d, J = 8.3 Hz, 1H), 3.86 - 3.63 (m, 3H), 2.34 - 2.24 (m, 1H), 2.22 (s, 3H), 2.20 - 2.10 (m, 1H), 1.74 - 1.59 (m, 2H), 1.38 - 1.26 (m, 2H), 0.93 - 0.77 (m, 6H).

[0678] Compounds 20B-OMe and 20B can be synthesized from (3S,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 3 of Example 20.

[0679] Compounds 20C-OMe and 20C can be synthesized from (3R,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 3 of Example 20.

[0680] Compounds 20D-OMe and 20D can be synthesized from (3S,5R)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine instead of (3R,5S)-5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)piperidine-3-amine in step 3 of Example 20. Example 21. Synthesis of 1-(4-chloro-2-hydroxy-3-methylphenyl)-N-(5-methyl-1-(1H-tetrazol-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 21, rac-21), 1-(4-chloro-2-methoxy-3-methylphenyl)-N-(5-methyl-1-(1H-tetrazol-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 21-OMe, rac-21-OMe), compounds 21A*, 21B*, 21C*, and 21D*, and compounds 21A-OMe*, 21B-OMe*, 21C-OMe*, and 21D-OMe*. Scheme 21A. [ka] Scheme 21B. [ka] Scheme 21C. [ka]

[0681] Example 21 follows Protocol A. Step 1: 6-bromo-3-chloro-2-methylphenol (1.00 g, 4.52 mmol, 1 equivalent), acetonitrile (MeCN) (10 mL), K2CO3 (1.87 g, 13.55 mmol, 3 equivalents), and methyl iodide (1.28 g, 9.03 mmol, 2 equivalents) were added to a 50 mL vial at room temperature. The resulting mixture was stirred for 2 hours under an air atmosphere at 80°C. The desired product could be detected by GC-MS. The resulting mixture was extracted with ethyl acetate (Â) (3 × 50 mL). The combined organic layers were washed with water (3 × 10 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 (5:1) to obtain 1-bromo-4-chloro-2-methoxy-3-methylbenzene (800 mg, yield 68%). GCMS:(ES,m / z):RT=4.65 min, m / z=234.0.

[0682] Step 2: 1-Bromo-4-chloro-2-methoxy-3-methylbenzene (800 mg, 3.40 mmol, 1 equivalent), tert-butyl 2-(bromodinthio)acetate (2654.05 mg, 10.19 mmol, 3 equivalents), tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3) (622.13 mg, 0.68 mmol, 0.2 equivalents), and tetrahydrofuran (THF) (16 mL) were added to a 40 mL sealed tube at room temperature. The resulting mixture was stirred at 70°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by TLC. The resulting mixture was extracted with ethyl acetate (siRNA) (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (petroleum ether:ethyl acetate 8:1, Rf=0.4) to obtain tert-butyl 2-(4-chloro-2-methoxy-3-methylphenyl) acetate (400 mg, yield 39%).

[0683] Step 3: In a 30 mL sealed tube, tert-butyl 2-(4-chloro-2-methoxy-3-methylphenyl) acetate (400 mg, 1.48 mmol, 1 equivalent), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (1.12 g, 7.38 mmol, 5 equivalents), ethenyldiphenylsulfanium triflate (1.61 g, 4.43 mmol, 3 equivalents), and dimethyl sulfoxide (DMSO) (4 mL) were added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction was monitored by GC-MS. The resulting mixture was extracted with ethyl acetate (siRNA) (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by reverse-phase flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain tert-butyl 1-(4-chloro-2-methoxy-3-methylphenyl)cyclopropane-1-carboxylate (220 mg, yield 50%). LCMS (ES, m / z): RT = 0.87 min.

[0684] Step 4: In a 20 mL vial, tert-butyl 1-(4-chloro-2-methoxy-3-methylphenyl)cyclopropane-1-carboxylate (220 mg, 0.74 mmol, 1 equivalent), dichloromethane (DCM) (2 mL), and trifluoroacetic acid (TFA) (0.4 mL) were added at room temperature. The resulting mixture was stirred for 1 hour under an air atmosphere at room temperature. The reaction was monitored by LC-MS. Upon completion, the resulting mixture was concentrated under reduced pressure to obtain 1-(4-chloro-2-methoxy-3-methylphenyl)cyclopropane-1-carboxylic acid (180 mg, 91% yield). LC-MS (ES, m / z): RT = 0.67 min, m / z = 241.0 [M+1] + .

[0685] Step 5: In a 20 mL vial, combine 1-(4-chloro-2-methoxy-3-methylphenyl)cyclopropane-1-carboxylic acid ("Carboxyl(ii) Reagent") (170 mg, 0.71 mmol, 1 equivalent), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (295.43 mg, 0.78 mmol, 1.1 equivalents), dimethylformamide (DMF) (6 mL), triethylamine (TEA) (357.38 mg, 3.53 mmol, 5 equivalents), and 5-methyl-1-(1H-1,2,3,4-tetrazole-5-yl)azepan-3-amine ("Amine(i) Reagent"). 277.25 mg (1.412 mmol, 2 equivalents) of compound 21-OMe was added at room temperature. The resulting mixture was stirred for 2 hours under an air atmosphere at room temperature. The reaction was monitored by LC-MS. After completion, the residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 10% to 40% gradient over 20 minutes, detector, UV 254 nm) to obtain 1-(4-chloro-2-methoxy-3-methylphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 21-OMe, rac-21-OMe) (160 mg, yield 49%). LC-MS (ES, m / z): RT = 0.84 min, m / z = 419.0 [M+1] + .

[0686] Step 6: rac-21-OMe (150 mg, 0.36 mmol, 1 equivalent), dimethyl sulfoxide (DMSO) (10 mL), and sodium (ethylsulfanyl) (451.77 mg, 5.37 mmol, 15 equivalents) were added to a 40 mL vial at room temperature. The resulting mixture was stirred for 2 hours under an air atmosphere at 120 °C. The reaction was monitored by LC-MS. Upon completion, the reaction product was concentrated, and the residue was purified by reverse flash chromatography (C18 silica gel, mobile phase, acetonitrile (MeCN) in water, 30% to 50% gradient over 10 mins, detector, UV 254 nm) to obtain 1-(4-chloro-2-hydroxy-3-methylphenyl)-N-(5-methyl-1-(1H-tetrazole-5-yl)azepan-3-yl)cyclopropane-1-carboxamide (compound 21, rac-21) (30 mg, yield 19%) as a mixture of cis and trans isomers. LCMS (ES, m / z): RT=1.30 min, m / z=405.0 [M+1] + .

[0687] Step 7: The crude product rac-21 (30 mg) was purified by 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: 22%B to 32%B at 8 min, wavelength: 254 nm, RT (min): 7 to 10.5) to obtain a cis mixture (30 mg, yield 19 percent), which is expected to be the first elution peak, and a trans mixture (30 mg, yield 19 percent), which is expected to be the second elution peak.

[0688] Step 8: The expected trans mixture (30 mg) was separated by chiral HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: isopropanol, flow rate: 20 mL / min, gradient: 30%B to 30%B at 19 min, wavelength: 220 / 254 nm) to obtain compound 21B* (RT(min): 10.75, 10.1 mg) and compound 21C* (RT(min): 15.88, 14.9 mg). Arbitrarily assigned stereochemistry.

[0689] Compound 21B*: LCMS (ES, m / z): RT = 1.30 min, m / z = 405.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.59 (s, 1H), 6.97-6.87 (m, 2H), 6.80 (d, J = 8.3 Hz, 1H), 4.21-4.10 (m, 1H), 3.64 - 3.46 (m, 3H), 3.22-3.11 (m, 1H), 2.20 (s, 3H), 1.81 - 1.72 (m, 1H), 1.67 (d, J = 14.5 Hz, 1H), 1.59 - 1.41 (m, 2H), 1.40-1.34 (m, 1H), 1.31-1.21 (m, 2H), 0.97-0.89 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H), 0.83-0.75 (m, 1H).

[0690] Compound 21C*: LCMS (ES, m / z): RT = 1.43 min, m / z = 405.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.59 (s, 1H), 6.98-6.87 (m, 2H), 6.80 (d, J = 8.2 Hz, 1H), 4.21 - 4.08 (m, 1H), 3.63-3.46 (m, 3H), 3.22-3.10 (m, 1H), 2.20 (s, 3H), 1.83 - 1.71 (m, 1H), 1.68 (d, J = 14.3 Hz, 1H), 1.60 - 1.41 (m, 2H), 1.41-1.32 (m, 1H), 1.32-1.21 (m, 2H), 0.96-0.90 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H), 0.83-0.76 (m, 1H).

[0691] Step 9: The expected cis mixture (30 mg) was separated by chiral HPLC (Lux 5 μm cellulose-4, 2.12 × 25 cm, 5 μm, mobile phase A: hexane (0.1% trifluoroacetic acid (TFA), mobile phase B: isopropanol, flow rate: 20 mL / min, gradient: 20%B to 20%B at 28 min, wavelength: 220 / 254 nm) to obtain compound 21D* (RT(min): 20.08, 4.2 mg) and compound 21A* (RT(min): 25.04, 2.2 mg). Arbitrarily assigned stereochemistry.

[0692] Compound 21A*:LCMS(ES,m / z): RT=1.513 min, m / z=405.1[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 3.93 (d, J = 8.6 Hz, 1H), 3.63-3.52 (m, 2H), 3.47-3.40 (m, 1H), 3.26 - 3.20 (m, 1H), 2.24 (s, 2H), 1.74 - 1.64 (m, 1H), 1.58 - 1.46 (m, 2H), 1.43 - 1.28 (m, 3H), 1.19-1.06 (m, 1H), 0.88 (t, J = 7.7 Hz, 5H).

[0693] Compound 21D*:LCMS(ES,m / z): RT=1.503 min, m / z=405.1[M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.99-3.90 (m, 1H), 3.70-3.64 (m, 1H), 3.56 - 3.43 (m, 2H), 3.20-3.11 (m, 1H), 2.25 (s, 3H), 1.70-1.60 (m, 1H), 1.58-1.46 (m, 2H), 1.44-1.29 (m, 3H), 1.14-1.01 (m, 1H), 0.95-0.89 (m, 1H), 0.86 (d, J = 6.7 Hz, 4H).

[0694] Compounds 21A-OMe, 21B-OMe, 21C-OMe, and ...

Claims

1. A compound of formula (I-A): 【Chemistry 1】 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, and G １ , G ２ , G ３ , and G ４ are two or less of 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 to which they bond, 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 The compound, or a pharmaceutically acceptable salt or tautomer thereof, that forms a haloalkylene crosslinking 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 following formula: 【Transformation 5】 And in the formula, L is C １－３ Alkylene crosslinking group or C １－３ A compound according to claim 4, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

6. The compound in question is one of the following formulas: 【Chemistry 6-1】 【Chemistry 6-2】 The compound according to claim 4, 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 Alkyl, C １－６ Haloalkyl, -OR Ｇ５ , -SR Ｇ５ , 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 Replaced by, R Ｇ１ , R Ｇ２ , R Ｇ３ , and R Ｇ４ However, each is independent of hydrogen, halo, and C. １－６ Alkyl 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, 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 is Cl, Br, methyl, isopropyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, OCF ２ H, OCF ３ CF ２ H, CF ３ SCF ３ or SCF ２ H, and R Ｇ１ , R Ｇ２ , R Ｇ３ , and R Ｇ４ However, each is independent of hydrogen, F, Cl, methyl, OH, and OCH. ３ , 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, halo, and C. １－６ Alkyl, C １－６ Haloalkyl, or C ３ -C ４ It is carbocyclyl, R ３ Each case is independent of C １－６ Alkyl or two R ３ The bases are linked together, C １－３ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or tautomer thereof, that forms an alkylene crosslinking group.

10. Ring B is a ring system, and in the formula, R ２ａ and R ２ｂ Each of these cases independently involves hydrogen, F, and CF. ３ , methyl, or cyclopropyl, R ３ Each of these cases is independently either methyl or two R ３ The compound according to claim 9, or a pharmaceutically acceptable salt or tautomer thereof, wherein groups are linked to form an ethylene crosslinking group.

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, CR Ｇ１ G ２ However, it is CH, G ３ However, it is CH, G ４ But is it CH? G １ However, CR Ｇ１ G ２ However, CR Ｇ２ G ３ However, it is CH, G ４ But is it CH? G １ However, CR Ｇ１ G ２ However, it is CH, G ３ However, CR Ｇ３ G ４ But is it CH? 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, N is G ３ However, it is CH, G ４ But is it CH? 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, it is CH, G ３ However, N is G ４ But is it CH? G １ However, CR Ｇ１ G ２ However, it is CH, G ３ However, N is G ４ But is it CH? G １ However, CR Ｇ１ G ２ However, CR Ｇ２ G ３ However, CR Ｇ３ G ４ However, is N, or G １ However, CR Ｇ１ G ２ However, it is CH, G ３ However, it is CH, 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 However, is it CH or G １ However, it is CH, G ２ However, CR Ｇ２ G ３ However, it is CH, G ４ The compound according to claim 11, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is CH.

13. R １ However, Cl, Br, methyl, isopropyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, OCF ２ H, OCF ３ CF ２ H, CF ３ SCF ３ , or SCF ２ A compound according to any one of claims 1 to 12, wherein H is present, or a pharmaceutically acceptable salt or tautomer thereof.

14. R Ｇ１ , R Ｇ２ , R Ｇ３ , and R Ｇ４ However, each is independent of hydrogen, F, Cl, methyl, OH, and OCH. ３ , and OCF ２ A compound according to any one of claims 1 to 13, selected from the group consisting of H, or a pharmaceutically acceptable salt or tautomer thereof.

15. R Ｇ５ and R Ｇ６ However, each independently, hydrogen, C １－６ Alkyl, or C １－６ A compound according to any one of claims 1 to 14, which is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

16. R Ｇ５ However, CF ２ H or CF ３ And R Ｇ６ However, hydrogen, methyl, or CF ２ The compound according to claim 15, wherein H is present, or a pharmaceutically acceptable salt or tautomer thereof.

17. R ２ａ and R ２ｂ Each of these cases independently involved hydrogen, halo, and C. １－６ Alkyl, C １－６ Haloalkyl, or C ３ -C ４ A compound according to any one of claims 1 to 16, which is a carbocyclyl, or a pharmaceutically acceptable salt or tautomer thereof.

18. R ２ａ and R ２ｂ Each of these examples involves hydrogen, F, and CF. ３ The compound according to claim 17, which is methyl, or cyclopropyl, or a pharmaceutically acceptable salt or tautomer thereof.

19. R ３ Each case is independent of C １－６ A compound according to any one of claims 1 to 18, which is alkyl, or a pharmaceutically acceptable salt or tautomer thereof.

20. R ３ The compound according to claim 19, or a pharmaceutically acceptable salt or tautomer thereof, wherein each of the cases is independently methyl.

21. Two R's ３ A compound according to any one of claims 1 to 20, wherein the groups are linked to form an ethylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

22. Ring A of the equation: 【Transformation 7】 However, the basis of the following equation: 【Transformation 8】 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 21, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

23. Ring A of equation (a-2), (a-4), (a-5), or (a-6) is the basis of the following equation: 【Chemistry 9】 The compound according to claim 22, or a pharmaceutically acceptable salt or tautomer thereof.

24. Ring A of the equation: 【Chemistry 10】 However, the basis of the following equation: 【Chemistry 11】 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 23, or a pharmaceutically acceptable salt or tautomer thereof.

25. Ring A of formula (a-7N), (a-8N), or (a-9N) is the one with the following formula: 【Chemistry 12】 The compound according to claim 24, or a pharmaceutically acceptable salt or tautomer thereof.

26. Ring A of the equation: 【Chemistry 13】 R １ and G ２ However, they are linked together with the atoms to which they bond, forming a five-membered heteroaryl ring, where rings A, R1, and G2 are the bases of the following formula: 【Chemistry 14】 Provided, During the ceremony, X is O, S, NH, or NR Ｇ７ And, Y is N, CH, or CR Ｇ７ And, z is 0 or 1, 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 to 21, which is a haloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

27. Ring A is R １ and G ２ However, when they are linked together with the atoms to which they bond, forming a five-membered heteroaryl ring, the base of the following formula: 【Chemistry 15】 The compound according to claim 26, or a pharmaceutically acceptable salt or tautomer thereof.

28. Ring A is the basis of the following equation: 【Chemistry 16】 The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or tautomer thereof.

29. Ring A is the basis of the following equation: 【Chemistry 17-1】 【Chemistry 17-2】 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or tautomer thereof.

30. Ring B of the equation: [Chemistry 18] However, the basis of the following equation: 【Chemistry 19】 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or tautomer thereof.

31. Ring B is the basis of the following equation: 【Chemistry 20】 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 30, which is a carbocyclyl or a 3-4 membered heterocyclyl, or a pharmaceutically acceptable salt or tautomer thereof.

32. Ring B of equation (b-1), (b-2), (b-3), or (b-4) is two R ３ The bases are linked together to form 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 21】 And, In the formula, L is C １－３ Alkylene crosslinking group or C １－３ A compound according to claim 30, which is a haloalkylene crosslinking group, or a pharmaceutically acceptable salt or tautomer thereof.

33. Ring B is the basis of the following equation: 【Chemistry 22】 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 32, which is a carbocyclyl or a 3-4 membered heterocyclyl, or a pharmaceutically acceptable salt or tautomer thereof.

34. Ring B is the basis of the following equation: 【Chemistry 23】 The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt or tautomer thereof.

35. Ring B is the basis of the following equation: 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt or tautomer thereof.

36. The compound is selected from the compounds listed in Table 1, 2, or 3, and is a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt or tautomer thereof.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.

38. A method for adjusting NLRP3, comprising administering to a subject a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 37.

39. 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 36, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 37.

40. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 37, for use in treating or preventing a disease or disorder.

41. Use of a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for the treatment or prevention of a disease or disorder.

42. Use of a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment or prevention of a disease or disorder.

43. The method, compound, or use according to any one of claims 38 to 42, 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.

44. A process for preparing a compound of formula (I-A) according to any one of claims 1 to 36, or a salt or tautomer thereof, wherein the compound is synthesized according to general scheme A, B, or C.

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