Oxo-indolinyl amide derivatives for inhibiting NLRP3 and uses thereof

Abstract

The present disclosure relates to compounds of formula (I), or pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotope derivatives, prodrugs, or polymorphs thereof. Further provided are pharmaceutical compositions comprising the compounds, methods of making and methods of use and treatment thereof, for example, as NLRP3 inhibitors useful in the treatment of diseases and conditions inhibited by the proteins. # imgabs0 #

Description

Related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 341,614, filed May 13, 2022, the entire contents of which are incorporated herein by reference. Background Technology

[0002] The innate immune response is mediated by different types of receptors called pattern recognition receptors (PRRs). PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once involved, these receptors trigger activation of downstream inflammatory pathways, which help resolve damage. However, in many cases, this activation can be uncontrolled and lead to disease.

[0003] Inflammasomes represent a class of proton pump inhibitors (PRRs) that are key components of the innate immune response. Activation of inflammasomes triggers a cascade of events that release IL-1β and IL-18 and promote an inflammatory form of cell death induced by Gasdermin activation, known as pyroptosis. Pyroptosis is a unique form of inflammatory cell death that not only leads to the release of cytokines but also to the release of other intracellular components that promote a broader immune response that supports both the innate and adaptive immune systems. Therefore, inflammasome activation is a major regulator of the inflammatory cascade.

[0004] NLRP3 is the most frequently characterized inflammasome and has been shown to be crucial in innate immunity and inflammatory responses. While several other NLR complexes, such as NLRC4, are activated under very specific conditions, NLRP3 can be activated by many stimuli and should be considered a sensor of intracellular homeostasis imbalances. Therefore, its accurate function is essential. In addition to its role in host immune defense, NLRP3 dysregulation is also associated with the pathogenesis of many inflammatory conditions. These include genetic disorders, such as cryopyrin-associated periodic syndrome (CAPS) caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, NLRP3 overactivation has been preclinically demonstrated to play a critical role in a wide range of inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and many other autoinflammatory diseases. Therefore, the need in this field for small molecules to modulate NLRP3 activity to treat a wide range of diseases and conditions remains unmet. Summary of the Invention

[0005] In one aspect, this disclosure provides oxoindololinylamide compounds of formula (I): Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, or prodrug, wherein: R 1 It is halogenated, –CN, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups; R 4 It is a –C1–C6 alkyl–, –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10 heteroaryl)–, where each instance of L1 is independently –(C(R L1 )2)–, further where R L1 Each instance is independently H, halogenated, C1–C3 alkyl, or two Rs. L1 Groups together with the atoms they are attached to form C 3-4 Cycloalkyl; and wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl; Z is –(L2) n –(carboxylic acid) or –(L2) n – tetrazolium, where each instance of L2 is independently – (C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, C1–C3 alkyl, or two Rs. L2 Groups together with the atoms they are attached to form C 3-4 Cycloalkyl; and wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups; Each R 5 Independently, it is a halogenated or C1–C6 alkyl group, wherein the alkyl group is optionally substituted with one or more halogenated, -CN, -OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6 It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6” It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 7 Independently H or C1–C4 alkyl; n is an integer of 0, 1, 2, or 3; and p is an integer of 0, 1, or 2.

[0006] In some aspects, pharmaceutical compositions are provided that include a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more pharmaceutically acceptable excipients.

[0007] In some respects, methods for preparing compounds of formula (I) are provided. In other respects, intermediates suitable for use in the methods for preparing compounds of formula (I) are provided.

[0008] In other respects, methods for treating a disease or condition in a subject in need are provided, including administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof.

[0009] In other respects, methods for inhibiting NLRP3 activity in cells are provided, comprising exposing the cells to an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. definition

[0010] Unless otherwise stated, the following terms used in this specification and claims have the meanings set forth below.

[0011] "Aliphatic hydrocarbons" refer to acyclic hydrocarbon groups that contain carbon atoms in their skeleton and may also contain one or more double or triple bonds within the hydrocarbon skeleton. Such groups include alkyl, alkenyl, and alkynyl groups as defined herein.

[0012] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1–C6 alkyl” is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups, each of which does not contain double or triple bonds in its backbone. For example, C1–C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include portions having one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, straight-chain or branched alkyl groups have six or fewer carbon atoms in their backbone (e.g., C1–C6 for straight-chain and C3–C6 for branched-chain), and in another embodiment, straight-chain or branched alkyl groups have four or fewer carbon atoms in their backbone.

[0013] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or a substituted alkyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbons of the hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkyloxy carbonyloxy, aryloxy carbonyloxy, carboxyl ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thio carbonyl, alkoxy, phosphate ester, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarboxylic ester, sulfate, alkyl sulfinyl, sulfonyl, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic or heteroaromatic moieties.

[0014] As used herein, “alkenyl,” “C2, C3, C4, C5, or C6 alkenyl,” or “C2–C6 alkenyl” is intended to include unsaturated aliphatic hydrocarbon groups having two to six carbon atoms and at least one double bond in their backbone, and includes C2, C3, C4, C5, or C6 straight-chain (linear) alkenyl groups and C3, C4, C5, or C6 branched alkenyl groups. For example, the term “alkenyl” includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl) and branched alkenyl groups. In some embodiments, the straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2–C6 for straight-chain and C3–C6 for branched). The term “C2–C6” includes alkenyl groups having two to six carbon atoms in their backbone, while the term “C3–C6” includes alkenyl groups having three to six carbon atoms in their backbone.

[0015] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or a substituted alkenyl as described above with a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkyloxy carbonyloxy, aryloxy carbonyloxy, carboxylate, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amidin, imino, mercapto, alkyl thio, aryl thio, thiocarboxylate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclic, alkyl aryl, or aromatic or heteroaromatic moieties.

[0016] As used herein, the terms “alkynyl,” “C2, C3, C4, C5, or C6 alkynyl,” or “C2–C6 alkynyl” are intended to include unsaturated aliphatic hydrocarbon groups having two to six carbon atoms and at least one triple bond in their skeleton, including C2, C3, C4, C5, or C6 straight-chain (linear) unsaturated alkynyl groups and C3, C4, C5, or C6 branched unsaturated alkynyl groups. For example, “alkynyl” includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, penynyl, hexynyl) and branched alkynyl groups. In some embodiments, the straight-chain or branched alkynyl group has six or fewer carbon atoms in its skeleton (e.g., C2–C6 for straight chains and C3–C6 for branched chains). The term “C2–C6” includes alkynyl groups having two to six carbon atoms in their skeleton, while the term “C3–C6” includes alkynyl groups having three to six carbon atoms in their skeleton.

[0017] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or a substituted alkynyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylate, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amidin, imino, mercapto, alkyl thio, aryl thio, thiocarboxylate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic or heteroaromatic moieties.

[0018] Other optional substituted portions (such as optional substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups) include both unsubstituted portions and portions having one or more specified substituents. For example, substituted heterocycloalkyl groups include heterocycloalkyl groups substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0019] As used herein, the term "cycloalkyl" refers to a non-aromatic saturated or partially unsaturated cyclic hydrocarbon that is a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 12 carbon atoms (e.g., C3–C4). 12 C3–C 10 (Or C3–C8). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cycloalkyl groups, only one ring in the cycloalkyl group needs to be non-aromatic.

[0020] As used herein, the term "optionally substituted cycloalkyl" refers to an unsubstituted cycloalkyl or a substituted cycloalkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbons or heteroatoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylate, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarboxylate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic hydrocarbon moiety or heteroaromatic moiety.

[0021] As used herein, the term "heterocyclic" or "heterocyclic alkyl" refers to a non-aromatic saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic), or 11-14 membered tricyclic (fused, bridged, or spirocyclic) ring system having one or more cyclic heteroatoms (such as O, N, S, P, or Se) independently selected from nitrogen, oxygen, and sulfur in the ring skeleton, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example 1, 2, 3, 4, 5, or 6 heteroatoms, unless otherwise specified. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, dioxyl, tetrahydrofuranyl, isoindolinyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazaheptanyl, 1,4-oxacycloheptanyl, and 2-oxa-5-azaheptanyl. Bicyclic [2.2.1]heptyl, 2,5-diazabicyclic [2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'- [furano[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7 ,8-Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, 5,6-dihydro-4H-cyclopentano[b]thiophene, etc. In the case of polycyclic heterocyclic groups, only one ring in the heterocyclic group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0022] As used herein, the term "optionally substituted heterocyclic group" refers to an unsubstituted heterocyclic group or a substituted heterocyclic group having a specified substituent that replaces one or more hydrogen atoms on one or more carbon or heteroatoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylate, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarboxylate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic hydrocarbon moiety or heteroaromatic moiety.

[0023] Unless otherwise specifically defined, the term "aryl" or "aromatic hydrocarbon" part or group refers to a cyclic C6–C group having one to three aromatic hydrocarbon rings. 14 Aromatic hydrocarbon groups (including carbons in the ring skeleton), including monocyclic or bicyclic groups, such as phenyl (C6), biphenyl (C6 aryl substituted with C6 aryl), or naphthyl (C6 aryl substituted with C6 aryl). 10 In cases containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted at any position on the aryl ring by one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, –H, –halogen, –O–(C1–C6)alkyl, (C1–C6)alkyl, –O–(C2–C6)alkenyl, –O–(C2–C6)ynyl, (C2–C6)alkenyl, (C2–C6)ynyl, –OH, –OP(O)(OH)2, –OC(O)(C1–C6)alkyl, –C(O)(C1–C6)alkyl, –OC(O)O(C1–C6)alkyl, –NH2, NH((C1–C6)alkyl), N((C1–C6)alkyl)2, –S(O)2–(C1–C6)alkyl, –S(O)NH(C1–C6)alkyl, and –S(O)N((C1–C6)alkyl)2. The substituent itself may optionally be substituted. Furthermore, when containing two or more fused aromatic hydrocarbon rings, the aryl group defined herein may have a saturated or partially unsaturated cycloalkyl or heterocyclic ring fused to a fully unsaturated aromatic hydrocarbon ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, phenatenyl, phenanthyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannullenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annullenyl, etc.

[0024] Unless otherwise specifically defined, "heteroaryl" or "heteroaromatic" part or group refers to a monocyclic or polycyclic aromatic group of 5 to 14 ring atoms, containing one or more cyclic heteroatoms selected from N, O, S, P, Se, or B within an aromatic ring system, with the remaining ring atoms being C. As defined herein, heteroaryl also means a bicyclic heteroaromatic group, wherein the cyclic heteroatoms are selected from N, O, S, P, Se, or B. As defined herein, heteroaryl also means a tricyclic heteroaromatic group containing one or more cyclic heteroatoms selected from N, O, S, P, Se, or B. The aromatic group may optionally be independently substituted by one or more substituents as described herein. Examples include, but are not limited to, furanyl, thiophene, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazoleyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophene-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazole[1,2-b]pyridine Azolyl, furano[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazole, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indoleyl Indololinyl, indololinone, dihydrobenzothiophene, dihydrobenzofuran, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthidyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazo[1,5-] a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, isoydinolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, furano[2,3-b]pyridyl, benzothiophene, 1,5-naphthidyl, furano[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidyl, [1, [2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, triazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl and their derivatives. Furthermore, when containing two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings fused to a fully unsaturated heteroaromatic ring, such as a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms, wherein the saturated or partially unsaturated cycloalkyl or heterocyclic ring comprises 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted by one or more oxo groups (i.e., C=O groups). In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated cycloalkyl or heterocyclic ring may be further fused to the saturated or partially unsaturated cycloalkyl or heterocyclic rings described herein. Exemplary ring systems of these heteroaryl groups include, for example, indololinyl, indololinone, dihydrobenzothiophene, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranone, indololinyl, oxoindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 7,8-dihydro-6H-pyrido[3 [2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopentano[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin, pyrazolo[1,5-a]pyrimidin-7(4H)-keto, 3,4-dihydropyrazolo[1,2-a]indole-1(2H)-keto or benzo[c][1,2]oxaboranecyclopentano-1(3H)-ol.

[0025] "Arylalkyl" or "arylalkyl" refers to an optionally substituted C6-C1 alkyl group attached to a C1-C6 alkyl group. 10 An aryl group, or an optionally substituted 5- to 6-membered heteroaryl group linked to a C1-C6 alkyl group, wherein the linking point to the parent molecule is located on the alkyl group. In some embodiments, the arylalkyl group is an aryl-C 1-6 alkyl.

[0026] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings may be substituted at one or more ring positions (e.g., cyclic carbon or heteroatom, such as N) with such substituents as described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl ester, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl The group can be alkylthiocarbonyl, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkylsulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties. Aryyl and heteroaromatic groups can also be fused or bridged with non-aromatic cycloalkyl or heterocyclic groups to form polycyclic systems (e.g., tetrahydronaphthalene, methylenedioxyphenyl, such as benzo[d][1,3]dioxacyclopenten-5-yl), provided that the connection point with the parent molecule is located on the aromatic or heteroaromatic ring.

[0027] As used herein, the term "divalent group" refers to a group having two connection points, such as alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups as defined herein.

[0028] As used herein, the terms “nitrile” and “cyano” are used interchangeably and each refers to –CN.

[0029] As used in this article, the term "carboxylic acid" refers to the group –CO2H.

[0030] As used in this article, the term "tetraazole" refers to the following tautomers:

[0031] As used herein, the term "hydroxyl" or "hydroxyl group" refers to the –OH group.

[0032] As used herein, the term "amino" refers to a primary, secondary, or tertiary amine. In some embodiments, the amino group is –NH2, C1–C6 alkylamino, C… 1– C6 dialkylamino-, C6–C 10 arylamino-, C6–C 10 Diarylamino-or (C1–C6 alkyl) (C6–C 10 (Aryl)amino-.

[0033] As used herein, the terms “halogenated” or “halogen” are used interchangeably and refer to fluorine, chlorine, bromine, and iodine.

[0034] The terms “halogenated alkyl” or “halogenated alkoxy” refer to an alkyl or alkoxy group that has been substituted by one or more halogen atoms.

[0035] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl or a haloalkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylate, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amidin, imino, mercapto, alkyl thio, aryl thio, thiocarboxylate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic or heteroaromatic moieties.

[0036] As used herein, the term "alkoxy" or "alkoxy group" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxyl ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thio carbonyl, alkoxy, phosphate ester, phosphonate ester, hypophosphonate ester, amino (including alkyl amino, dialkyl amino, aryl amino, diaryl amino and alkyl aryl amino), acyl amino (including alkyl carbonyl amino, aryl carbonyl amino, carbamoyl and urea), amidin, imino, mercapto, alkyl thio, aryl thio, thiocarboxylic ester, sulfate ester, alkyl sulfinyl, sulfonate ester, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0037] As used herein, the term “substituted” means that any one or more hydrogen atoms on a specified atom are replaced by an option selected from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. When the substituent is an oxo group (i.e., a C=O group), two hydrogen atoms on that atom are replaced. Oxosubstituents are not present on aromatic moieties. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). “Stable compound” and “stable structure” are intended to indicate a compound that is robust enough to remain intact after being isolated from the reaction mixture to a useful level of purity and formulated into an effective therapeutic agent.

[0038] When the bond to a substituent shows a cross bond with two atoms in the linking ring, the substituent may bond to any atom in that ring. When a substituent is listed but not specified via which atom it bonds to the remainder of a compound of a given general formula, the substituent may bond via any atom in that general formula. Combinations of substituents and / or variables are permitted, but only if such combinations produce stable compounds.

[0039] When any variable (e.g., R) 1 R 2 R 3 R 4 R 5 R 6 R6’ R 6” R 7 When a group (L1, L2, L3, L4, L5) appears more than once in any component or general formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a group shows to be substituted by 0-3 R moieties, the group may optionally be substituted by at most two R moieties, and R is chosen independently from the definition of R for each occurrence. Furthermore, combinations of substituents and / or variables are permitted, but only if such combinations produce a stable compound.

[0040] Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." Compounds with more than one chiral (asymmetric) center can exist as individual diastereomers or as mixtures of diastereomers, and are called "diasteremeric mixtures." Similarly, compounds with only one chiral (asymmetric) center can exist as individual enantiomers or as mixtures of enantiomers. Mixtures containing diastereomers or mixtures of enantiomers (in approximately equal proportions) are called "racemic mixtures." Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ordered according to the Cahn, Ingold, and Prelog ordering rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). Methods for determining stereochemistry and resolving stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution in racemic forms.

[0041] As used herein, the term "geometric isomer" refers to diastereomers whose existence is attributable to rotational hindering around a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by their names using the prefixes cis and trans, or Z and E, indicating whether the groups are located on the same or opposite sides of the double bond in the molecule, according to the Cahn–Ingold–Prelog rule. Some compounds of this disclosure may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure covers all geometric isomers and mixtures thereof.

[0042] “Salt” includes any and all salts, including pharmaceutically acceptable salts.

[0043] As used herein, the term "pharmaceutically acceptable salt" refers to compounds of this disclosure, wherein the parent compound is modified by preparing its acidic or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and basic or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids selected from: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, formic acid, glucoheponic acid, gluconic acid, glutamic acid, glycolylaminobenzoic acid, hexylresorcinolic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, mesylic acid, and naphthylsulfonic acid. The following are listed: acid), nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphorous acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, hypoacetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, trifluoroacetic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0044] Other pharmaceutically acceptable examples of salts include hexanoic acid, cyclopentylpropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[0045] Salts can be formed between an anion and a positively charged group (e.g., amino group) on the substituted compounds disclosed herein. As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). Similarly, salts can also be formed between a cation and a negatively charged group (e.g., carboxyl group) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom. In the salt form, it should be understood that the ratio of the compound to the salt's cation or anion can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0046] In some implementation schemes, pharmaceutically acceptable salts are sodium, potassium, calcium, magnesium, diethylamine, choline, meglumine, benzathine, tromethamine, ammonium, arginine, or lysine salts.

[0047] It should be understood that all references to pharmaceutically acceptable salts include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0048] The compounds are also provided herein in the form of “neutral” compounds. “Neutral” and “free base” are used interchangeably herein and refer to non-salt compounds. It should be understood that all references to neutral (free base) forms include the same neutral (free base) compound in its solvation form (solvent) or crystalline form (polymorph) as defined herein. For illustrative purposes, neutral compounds can be converted into their corresponding pharmaceutically acceptable salts using conventional techniques in the art (e.g., by saponifying esters to carboxylates, or by hydrolyzing amides to form the corresponding carboxylic acid, and then converting that carboxylic acid to a carboxylate). In some embodiments, the solvation or crystalline form has different properties compared to the neutral compound.

[0049] As used herein, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap solvent molecules in a fixed molar ratio in a crystalline solid state, thereby forming a solvate. If the solvent is water, the formed solvate is a "hydrate"; and if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by the combination of one or more molecules of water with one molecule of a substance, wherein the water retains its molecular state as H₂O, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that the compounds of this disclosure may exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0050] "Inclusion compound" is a host molecule in which the guest molecule (i.e., compound of formula (I)) is located in a cage formed by the host molecule or by the lattice of the host molecule.

[0051] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and readily transform from one isomer to another. This transformation results in the migration of hydrogen atoms, accompanied by a switching of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomer groups. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept that tautomers can interconvert through tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, electrons and hydrogen atoms shift simultaneously. Ring-chain tautomerism occurs when the aldehyde group (-CHO) in a sugar molecule reacts with a hydroxyl group (-OH) in the same molecule, giving it a cyclic (ring-like) form, as exhibited by glucose. Examples of tautomer forms include ketone, enol, and enolate forms, for example, in the following tautomer pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0052] It should be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer. It should be understood that some tautomers may have higher levels of activity than others.

[0053] It should also be understood that certain compounds of any of the general formulas disclosed herein may exhibit polymorphism (“polymorphs”), and this disclosure covers all such forms, or mixtures thereof. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis. In some embodiments, polymorphs may have different properties compared to neutral compounds.

[0054] Compounds of any of the general formulas disclosed herein can be administered as prodrugs, which decompose in the human or animal body to release the disclosed compounds. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the disclosed compounds. Examples of prodrugs include derivatives containing alkyl or acyl substituents at the ester or amide group in any of the general formulas disclosed herein that can be cleaved in vivo. A suitable prodrug for a compound of any of the general formulas disclosed herein is based on reasonable medical judgment that it is suitable for administration to humans or animals without undesirable pharmacological activity and without excessive toxicity. Various forms of prodrugs have been described, for example in the following literature: a) Methods in Enzymology, Vol. 42, pp. 309–396 (Academic Press, 1985), edited by K. Widder et al.; b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, Chapter 5, “Design and Application of Pro-drugs,” edited by Krogsgaard–Larsen and H. Bundgaard, H. Bundgaard, pp. 113–191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1–38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro–Drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987.

[0055] Suitable prodrugs of compounds of any of the general formulas disclosed herein that contain a hydroxyl group are, for example, esters or ethers that can be cleaved in vivo. Esters or ethers of compounds of any of the general formulas disclosed herein that contain a hydroxyl group that can be cleaved in vivo are, for example, pharmaceutically acceptable esters or ethers that, upon cleavage in a human or animal body, produce a parent hydroxyl compound. Pharmaceutically acceptable ester-forming groups suitable for the hydroxyl group include inorganic esters, such as phosphate esters (including cyclic aminophosphates). Other pharmaceutically acceptable ester-forming groups suitable for the hydroxyl group include C1–C1… 10 Alkyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups; C1–C 10 Alkoxycarbonyl groups, such as ethoxycarbonyl, N,N–(C1–C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4–(C1–C4 alkyl)piperazine-1-ylmethyl. Pharmaceutically acceptable ether-forming groups suitable for the hydroxyl group include α-acyloxyalkyl groups, such as acetoxymethyl and neopentyloxymethyl.

[0056] Suitable pharmaceutically acceptable prodrugs of compounds having a carboxyl group of any of the general formulas disclosed herein are, for example, amides that can be cleaved in vivo, such as amides formed with amines such as ammonia, C1–4 alkylamines such as methylamine, (C1–4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1–4 alkoxy-C2–C4 alkylamines such as 2-methoxyethylamine, phenyl-C1–C4 alkylamines such as benzylamine and amino acids such as glycine or their esters.

[0057] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group of any of the general formulas disclosed herein are, for example, amide derivatives that can be cleaved in vivo. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, those with C1–C 10 Amides formed from alkyl acyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1–C4 alkyl)piperazine-1-ylmethyl.

[0058] The in vivo effects of compounds of any general formula disclosed herein can be partially exerted by one or more metabolites formed in a human or animal body following administration of a compound of any general formula disclosed herein. As described above, the in vivo effects of compounds of any general formula disclosed herein can also be exerted through metabolism via a prodrug.

[0059] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are enriched or labeled with an isotope. For example, an isotope derivative of a compound of formula (I) is isotopically enriched or labeled with one or more isotopes, compared to the corresponding compound of formula (I).

[0060] As used herein, the terms "pharmaceutical composition" or "pharmaceutical formulation" are used interchangeably and refer to a formulation containing a compound of formula (I) in a form suitable for administration to a subject and a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, or a combination thereof. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. Unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, a single pump or vial on an aerosol inhaler. The amount of active ingredient in a unit dose of the composition may vary depending on the specific treatment involved. Various routes of administration are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms of the compounds disclosed herein for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any desired preservative, buffer, or propellant.

[0061] As used herein, the term “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, those compounds, anions, cations, materials, compositions, carriers and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0062] As used herein, the terms "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" are used interchangeably and refer to excipients that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, including excipients acceptable for both veterinary and human pharmaceutical applications. As used in this specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

[0063] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of compounds (e.g., compounds of formula (I)) as described herein to provide such treatment. It should be further understood that, unless otherwise stated, any description of a treatment method includes the use of compounds to prepare a medicament for treating such conditions. Treatment includes treating human or non-human animals, including rodents and other disease models. As used herein, the term “subject” is interchangeable with the term “subject in need,” both referring to a subject who has a disease or condition or is at increased risk of developing such a disease or condition.

[0064] As used herein, “subject” is a mammal. A mammal can be, for example, a human or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. In one embodiment, the mammal is a human. The subject in need can be a subject who has been previously diagnosed or identified as having a disease or condition disclosed herein. The subject in need can also be a subject suffering from a disease or condition disclosed herein. Alternatively, the subject in need can be a subject with an increased risk of developing such a disease or condition relative to the majority of the population (i.e., a subject susceptible to such a condition relative to the majority of the population). The subject in need can have a treatment-resistant or resistant disease or condition disclosed herein (i.e., a disease or condition disclosed herein that is unresponsive to treatment or has not yet responded to treatment). A subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need has received all known effective therapies for the disease or condition disclosed herein but has failed. In some embodiments, the subject in need has received at least one prior therapy. The terms “subject” and “patient” are used interchangeably herein.

[0065] As used herein, the terms “treatment” or “treatment” describe the management and care of a subject for the purpose of combating a disease, condition, or symptom, and include the administration of compounds of this disclosure, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, tautomers, isotope derivatives, prodrugs, or polymorphs thereof, to alleviate symptoms or complications of a disease, condition, or symptom, or to eliminate a disease, condition, or symptom suffered by the subject (“therapeutic treatment”; “therapeutic treatment”), or may be used to prevent a disease, condition, or symptom that has been diagnosed in the subject or that the subject is susceptible to but has not yet shown symptoms (“preventive treatment”; “preventive treatment”). The term “treatment” may also include treatment of cells or animal models in vitro. Therefore, “treatment” or “management” of a state, symptom or condition includes: (1) preventing the occurrence of the state, symptom or condition in persons who may have or are susceptible to it, or delaying the onset of its clinical symptoms; (2) suppressing the state, symptom or condition, i.e. preventing, reducing or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or weakening the disease, i.e. causing the disappearance of the state, symptom or condition or at least one of its clinical or subclinical symptoms.

[0066] In some implementation schemes, treating a disease or condition is not the same as preventing a disease or condition.

[0067] As used herein, the term “therapeutic effective amount” refers to the amount of a compound used to treat or improve an identified disease or condition suffered by a subject, or to exhibit a detectable therapeutic or inhibitory effect, while “preventive effective amount” refers to the amount of a compound used to prevent an identified disease or condition that a subject has been diagnosed with or is susceptible to but has not yet shown symptoms. “Therapeutic effective” and “preventive effective” are collectively referred to as “effective amount,” which is sufficient to treat or prevent the inflammasome-related conditions mentioned herein, slow their progression, and / or alleviate symptoms associated with the condition. Based on well-known medical principles, the dosage of a compound of formula (I) used for therapeutic or preventive purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration. The effect can be detected by any assay known in the art. The accurate effective amount for a subject will depend on the subject’s weight, body size, and health status; the nature and severity of the symptom; and the choice of therapeutic agent or combination of therapeutic agents for administration. The therapeutic or preventive effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0068] "Inhibition" refers to the ability of a compound to reduce, slow down, stop, or prevent the activity of a specific biological process in a cell (e.g., NLRP3 activity) relative to a mediator.

[0069] The phrase "at least one" refers to one or more cases.

[0070] As used herein, the term "about" means a quantity, value, or duration listed ± 10% or less of said quantity, value, or duration. In some embodiments, "about" means a quantity, value, or duration listed ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 2%, ± 1%, or ± 0.5%. In some embodiments, "about" means a quantity, value, or duration listed ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, or ± 2%. In some embodiments, "about" means a quantity, value, or duration listed ± 5%. In some embodiments, "about" means a quantity, value, or duration listed ± 2% or ± 1%. For example, in some embodiments, when the term "about" is used when listing temperatures or temperature ranges, these terms mean a temperature or temperature range listed ± 5°C, ± 2°C, or ± 1°C. In some embodiments, the term "about" means a temperature or temperature range listed ± 2°C.

[0071] The words “a” and “a kind” are used in this disclosure to mean one or more (i.e., at least one) grammatical object of the word.

[0072] The term “and / or” is used in this disclosure to mean “and” or “or”, unless otherwise stated.

[0073] Unless otherwise stated, all percentages and ratios used in this document are by weight. Detailed Implementation

[0074] This disclosure relates to oxoindololinylamide derivatives, pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, single stereoisomers, mixtures of stereoisomers, or racemic mixtures of stereoisomers, their tautomers, isotopic derivatives, prodrugs, and polymorphs, which inhibit NLRP3 activity and are therefore useful in methods of treating human or animal bodies. This disclosure also relates to methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and their use in treating NLRP3-related conditions, such as inflammation, autoimmune diseases, cancer, infections, diseases or disorders of the central nervous system, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, mental illnesses, graft-versus-host disease, abnormal pain, or NLRP3-related diseases in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3. (1) Compound

[0075] In one aspect, this disclosure provides oxoindololinylamide compounds of formula (I): Or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, tautomers, isotope derivatives, prodrugs, and / or polymorphs thereof, wherein: R 1 It is halogenated, –CN, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups; R 4 It is a –C1–C6 alkyl–, –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10 heteroaryl)–, where each instance of L1 is independently –(C(R L1 )2)–, further where R L1 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L1 Groups together with the atoms they are attached to form C 3-4Cycloalkyl; and wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl; Z is –(L2) n –(carboxylic acid) or –(L2) n – tetrazolium, where each instance of L2 is independently –(C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L2 Groups together with the atoms they are attached to form C 3-4 Cycloalkyl; and wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups; Each R 5 Independently, it is a halogenated or C1–C6 alkyl group, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6 It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6” It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 7 Independently H or C1–C4 alkyl; n is an integer of 0, 1, 2, or 3; and p is an integer of 0, 1, or 2.

[0076] In some implementations of equation (I): R 1 It is brominated, chlorinated, –CN, C1–C6 alkyl, C1–C6 haloalkyl or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C1–C6 haloalkyl, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 Cycloning together to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups; R 4 For –(n-propyl)–, –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10 heteroaryl)–, where R L1 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L1 The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the n-propyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups; Z is –(L2) n –(carboxylic acid) or –(L2) n – tetrazolium, where each instance of L2 is independently –(C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L2The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups. Each R 5 Independently, it is a halogenated or C1–C6 alkyl group, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6 It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 6” It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 7 Independently H or C1–C4 alkyl; n is an integer of 0, 1, 2, or 3; and p is an integer of 0, 1, or 2.

[0077] In some implementations of equation (I): R 1 It is brominated, chlorinated, –CN, C1–C6 alkyl, C1–C6 haloalkyl or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C1–C6 haloalkyl, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 Cycloning together to form C3–C 12Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups; R 4 For –(n-propyl)–, –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10 heteroaryl)–, where R L1 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L1 The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the n-propyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups; Z is –(L2) n –(carboxylic acid) or –(L2) n – tetrazolium, where each instance of L2 is independently –(C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L2 The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups. Each R 5 Independently fluorinated or C1–C6 alkyl, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 6” It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 7 Independently H or C1–C4 alkyl; n is an integer of 0, 1, 2, or 3; and p is an integer of 0, 1, or 2.

[0078] In some implementations, each R 5 Independently fluorinated or C1–C6 alkyl, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 Cycloalkyl.

[0079] In some embodiments, the compound of formula (I) is a compound of formula (IA): Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, wherein: R 1 It is halogenated, –CN, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups; R 4 It is a –C1–C6 alkyl–, –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10-membered heteroaryl)–, R L1 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L1 The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally substituted by one or more halogroups, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups; Z is –(L2) n –(carboxylic acid) or –(L2) n – tetrazolium, where each instance of L2 is independently –(C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L2 The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups. Each R 5 Independently fluorinated or C1–C6 alkyl, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.12 cycloalkyl; R 6 It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6” It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; n is an integer of 0, 1, 2, or 3; and p is an integer of 0, 1, or 2.

[0080] In some implementations of formula (IA): R 1 It is brominated, chlorinated, –CN, C1–C6 alkyl, C1–C6 haloalkyl or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C1–C6 haloalkyl, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 Cycloning together to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups; R 4 For –(n-propyl)–, –(L1) p –(C3–C 12 cycloalkyl), –(L1) p –(3 to 12-membered heterocyclic groups), –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10 heteroaryl)–, where R L1Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L1 The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the n-propyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups; Z is –(L2) n –(carboxylic acid) or –(L2) n – tetrazolium, where each instance of L2 is independently –(C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L2 The groups together with the atoms to which they are attached form a C3 cycloalkyl group; and wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups. Each R 5 Independently fluorinated or C1–C6 alkyl, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6 It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; R 6” It can be H, halogenated, –OH, C1–C6 alkyl, or C1–C6 alkoxy; n is an integer of 0, 1, 2, or 3; and p is an integer of 0, 1, or 2.

[0081] This paper further considers alternative implementation schemes. (a) Group R 2 and R 3

[0082] As generally defined in this article, each R 2 and R 3 Independently H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0083] In some implementations, each R 2 and R 3 Independently H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 The aryl or 5- to 10-membered heteroaryl group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0084] In some implementations, each R 2 and R 3 H stands for H independently.

[0085] In some implementations, each R 2 and R 3 Independently C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10The aryl or 5- to 10-membered heteroaryl group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0086] In some implementation schemes, R 2 H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 The aryl or 5- to 10-membered heteroaryl group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0087] In some implementation schemes, R 2 For H.

[0088] In some implementation schemes, R 2 It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 The aryl or 5- to 10-membered heteroaryl group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0089] In some implementation schemes, R 2 It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 Aryl or 5 to 10 heteroaryl compounds.

[0090] In some implementation schemes, R 2It is a C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy.

[0091] In some implementation schemes, R 2 It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0092] In some implementation schemes, R 2 It is C1–C6 alkyl, C2–C6 alkenyl or C2–C6 alkynyl.

[0093] In some implementation schemes, R 2 C1–C6 alkyl groups optionally substituted with one or more of the following: halogen, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy.

[0094] In some implementation schemes, R 2 It is a C1–C6 alkyl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0095] In some implementation schemes, R 2 It is a C1–C6 alkyl group.

[0096] In some implementation schemes, R 2 It is methyl. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is propyl. In some embodiments, R 2 For butyl. In some implementations, R 2 It is pentyl. In some implementations, R 2 For its own foundation. In some implementation schemes, R 2 It is isopropyl. In some embodiments, R 2 It is isobutyl. In some embodiments, R 2 It is isopentyl. In some embodiments, R 2 It is an allotropic group. In some implementations, R 2 It is sec-butyl. In some implementations, R 2 It is sec-amyl. In some implementations, R 2For Zhongjiji. In some implementations, R 2 It is tert-butyl.

[0097] In some implementation schemes, R 2 C2–C6 alkenyl groups are optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0098] In some implementation schemes, R 2 It is a C2–C6 alkenyl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0099] In some implementation schemes, R 2 It is a C2–C6 alkenyl group.

[0100] In some implementation schemes, R 2 It is C2-olefinic. In some embodiments, R 2 It is a C3 alkenyl group. In some embodiments, R 2 It is a C4 alkenyl group. In some embodiments, R 2 It is a C5 alkenyl group. In some embodiments, R 2 It is a C6 alkenyl group.

[0101] In some implementation schemes, R 2 C2–C6 alkynyl is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0102] In some implementation schemes, R 2 It is a C2–C6 alkynyl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0103] In some implementation schemes, R 2 It is a C2–C6 ynyl group.

[0104] In some implementation schemes, R 2 It is a C2 acetylene group. In some embodiments, R 2 It is a C3 acetyl group. In some embodiments, R 2 It is a C4 acetylene group. In some embodiments, R 2 It is a C5 acetyl group. In some embodiments, R 2 It is a C6 acetylene group.

[0105] In some implementation schemes, R 2 It is a C1–C6 haloalkyl or C1–C6 alkoxy.

[0106] In some implementation schemes, R 2 It is a C1–C6 haloalkyl that is optionally substituted with one or more of a halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0107] In some implementation schemes, R 2 It is a C1–C6 haloalkyl group substituted with one or more of the following: halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy.

[0108] In some implementation schemes, R 2 It is a C1–C6 haloalkyl group.

[0109] In some implementation schemes, R 2 It is a halomethyl group. In some embodiments, R 2 It is a haloethyl. In some embodiments, R 2 It is a halogenated propyl group. In some embodiments, R 2 It is a halogenated butyl group. In some implementations, R 2 It is a halopentyl group. In some embodiments, R 2 It is a halogenated hexyl group.

[0110] In some implementation schemes, R 2 C1–C6 alkoxy groups optionally substituted with one or more of the following: halogen, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0111] In some implementation schemes, R 2 It is a C1–C6 alkoxy group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0112] In some implementation schemes, R 2 It is a C1–C6 alkoxy group.

[0113] In some implementation schemes, R 2 It is methoxylated. In some embodiments, R 2 It is ethoxylated. In some embodiments, R 2It is propoxylated. In some embodiments, R 2 It is butoxylated. In some embodiments, R 2 It is pentoxygenated. In some embodiments, R 2 It is an hexoxy group.

[0114] In some implementation schemes, R 2 For C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 Aryl or 5 to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0115] In some implementation schemes, R 2 For C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 Aryl or 5 to 10 heteroaryl compounds.

[0116] In some implementation schemes, R 2 C3–C alkyl group optionally substituted with one or more of the following: –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy group. 12 Cycloalkyl.

[0117] In some implementation schemes, R 2 C3–C substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups 12 Cycloalkyl.

[0118] In some implementation schemes, R 2 For C3–C 12 Cycloalkyl.

[0119] In some implementation schemes, R 2 It is a C3–C6 cycloalkyl group.

[0120] In some implementation schemes, R 2 It is a C3 cycloalkyl group. In some embodiments, R 2 It is a C4 cycloalkyl group. In some embodiments, R 2 It is a C5 cycloalkyl group. In some embodiments, R 2 It is a C6 cycloalkyl group.

[0121] In some implementation schemes, R 2It is a C7 cycloalkyl group. In some embodiments, R 2 It is a C8 cycloalkyl group. In some embodiments, R 2 It is a C9 cycloalkyl group. In some embodiments, R 2 C 10 Cycloalkyl. In some embodiments, R 2 C 11 Cycloalkyl. In some embodiments, R 2 C 12 Cycloalkyl.

[0122] In some implementation schemes, R 2 It is a 3- to 12-membered heterocyclic group optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0123] In some implementation schemes, R 2 It is a 3- to 12-membered heterocyclic group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0124] In some implementation schemes, R 2 It consists of 3 to 12-membered heterocyclic groups.

[0125] In some implementation schemes, R 2 It is a 3-membered heterocyclic group. In some implementations, R 2 It is a 4-membered heterocyclic group. In some implementations, R 2 It is a 5-membered heterocyclic group. In some implementations, R 2 It is a 6-membered heterocyclic group. In some implementations, R 2 It is a 7-membered heterocyclic group. In some implementations, R 2 It is an 8-membered heterocyclic group. In some implementations, R 2 It is a 9-membered heterocyclic group. In some implementations, R 2 It is a 10-membered heterocyclic group. In some implementations, R 2 It is an 11-membered heterocyclic group. In some implementations, R 2 It is a 12-membered heterocyclic group.

[0126] In some implementation schemes, R 2 C6–C6 alkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy group optionally substituted with one or more of the following: 10 Aryl.

[0127] In some implementation schemes, R 2 C6–C6 alkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy group are substituted with one or more of these groups. 10 Aryl.

[0128] In some implementation schemes, R 2 For C6–C 10 Aryl.

[0129] In some implementation schemes, R 2 It is C6 aryl. In some embodiments, R 2 It is C8 aryl. In some embodiments, R 2 C 10 Aryl.

[0130] In some implementation schemes, R 2 It is a 5- to 10-membered heteroaryl group optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0131] In some implementation schemes, R 2 It is a 5- to 10-membered heteroaryl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0132] In some implementation schemes, R 2 It consists of 5 to 10 heteroaryl groups.

[0133] In some implementation schemes, R 2 It is a 5-membered heteroaryl group. In some implementations, R 2 It is a 6-membered heteroaryl group. In some implementations, R 2 It is a 7-membered heteroaryl group. In some implementations, R 2 It is an 8-membered heteroaryl group. In some implementations, R 2 It is a 9-membered heteroaryl group. In some implementations, R 2 It is a 10-membered heteroaryl group.

[0134] In some implementation schemes, R 3 H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10The aryl or 5- to 10-membered heteroaryl group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0135] In some implementation schemes, R 3 For H.

[0136] In some implementation schemes, R 3 It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 The aryl or 5- to 10-membered heteroaryl group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0137] In some implementation schemes, R 3 It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 Aryl or 5 to 10 heteroaryl compounds.

[0138] In some implementation schemes, R 3 It is a C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy.

[0139] In some implementation schemes, R 3 It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0140] In some implementation schemes, R 3 It is C1–C6 alkyl, C2–C6 alkenyl or C2–C6 alkynyl.

[0141] In some implementation schemes, R 3C1–C6 alkyl groups optionally substituted with one or more of the following: halogen, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy.

[0142] In some implementation schemes, R 3 It is a C1–C6 alkyl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0143] In some implementation schemes, R 3 It is a C1–C6 alkyl group.

[0144] In some implementation schemes, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is propyl. In some embodiments, R 3 For butyl. In some implementations, R 3 It is pentyl. In some implementations, R 3 For its own foundation. In some implementation schemes, R 3 It is isopropyl. In some embodiments, R 3 It is isobutyl. In some embodiments, R 3 It is isopentyl. In some embodiments, R 3 It is an allotropic group. In some implementations, R 3 It is sec-butyl. In some implementations, R 3 It is sec-amyl. In some implementations, R 3 For Zhongjiji. In some implementations, R 3 It is tert-butyl.

[0145] In some implementation schemes, R 3 C2–C6 alkenyl groups are optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0146] In some implementation schemes, R 3 It is a C2–C6 alkenyl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0147] In some implementation schemes, R 3 It is a C2–C6 alkenyl group.

[0148] In some implementation schemes, R 3 It is C2-olefinic. In some embodiments, R 3 It is a C3 alkenyl group. In some embodiments, R 3 It is a C4 alkenyl group. In some embodiments, R 3 It is a C5 alkenyl group. In some embodiments, R 3 It is a C6 alkenyl group.

[0149] In some implementation schemes, R 3 C2–C6 alkynyl is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0150] In some implementation schemes, R 3 It is a C2–C6 alkynyl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0151] In some implementation schemes, R 3 It is a C2–C6 ynyl group.

[0152] In some implementation schemes, R 3 It is a C2 acetylene group. In some embodiments, R 3 It is a C3 acetyl group. In some embodiments, R 3 It is a C4 acetylene group. In some embodiments, R 3 It is a C5 acetyl group. In some embodiments, R 3 It is a C6 acetylene group.

[0153] In some implementation schemes, R 3 It is a C1–C6 haloalkyl or C1–C6 alkoxy.

[0154] In some implementation schemes, R 3 It is a C1–C6 haloalkyl that is optionally substituted with one or more of a halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0155] In some implementation schemes, R 3 It is a C1–C6 haloalkyl group substituted with one or more of the following: halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy.

[0156] In some implementation schemes, R3 It is a C1–C6 haloalkyl group.

[0157] In some implementation schemes, R 3 It is a halomethyl group. In some embodiments, R 3 It is a haloethyl. In some embodiments, R 3 It is a halogenated propyl group. In some embodiments, R 3 It is a halogenated butyl group. In some implementations, R 3 It is a halopentyl group. In some embodiments, R 3 It is a halogenated hexyl group.

[0158] In some implementation schemes, R 3 C1–C6 alkoxy groups optionally substituted with one or more of the following: halogen, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0159] In some implementation schemes, R 3 It is a C1–C6 alkoxy group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0160] In some implementation schemes, R 3 It is a C1–C6 alkoxy group.

[0161] In some implementation schemes, R 3 It is methoxylated. In some embodiments, R 3 It is ethoxylated. In some embodiments, R 3 It is propoxylated. In some embodiments, R 3 It is butoxylated. In some embodiments, R 3 It is pentoxygenated. In some embodiments, R 3 It is an hexoxy group.

[0162] In some implementation schemes, R 3 For C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 Aryl or 5 to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0163] In some implementation schemes, R 3 For C3–C 12Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 Aryl or 5 to 10 heteroaryl compounds.

[0164] In some implementation schemes, R 3 C3–C alkyl group optionally substituted with one or more of the following: –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy group. 12 Cycloalkyl.

[0165] In some implementation schemes, R 3 C3–C substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups 12 Cycloalkyl.

[0166] In some implementation schemes, R 3 For C3–C 12 Cycloalkyl.

[0167] In some implementation schemes, R 3 It is a C3–C6 cycloalkyl group.

[0168] In some implementation schemes, R 3 It is a C3 cycloalkyl group. In some embodiments, R 3 It is a C4 cycloalkyl group. In some embodiments, R 3 It is a C5 cycloalkyl group. In some embodiments, R 3 It is a C6 cycloalkyl group.

[0169] In some implementation schemes, R 3 It is a C7 cycloalkyl group. In some embodiments, R 3 It is a C8 cycloalkyl group. In some embodiments, R 3 It is a C9 cycloalkyl group. In some embodiments, R 3 C 10 Cycloalkyl. In some embodiments, R 3 C 11 Cycloalkyl. In some embodiments, R 3 C 12 Cycloalkyl.

[0170] In some implementation schemes, R 3 It is a 3- to 12-membered heterocyclic group optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0171] In some implementation schemes, R3 It is a 3- to 12-membered heterocyclic group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0172] In some implementation schemes, R 3 It consists of 3 to 12-membered heterocyclic groups.

[0173] In some implementation schemes, R 3 It is a 3-membered heterocyclic group. In some implementations, R 3 It is a 4-membered heterocyclic group. In some implementations, R 3 It is a 5-membered heterocyclic group. In some implementations, R 3 It is a 6-membered heterocyclic group. In some implementations, R 3 It is a 7-membered heterocyclic group. In some implementations, R 3 It is an 8-membered heterocyclic group. In some implementations, R 3 It is a 9-membered heterocyclic group. In some implementations, R 3 It is a 10-membered heterocyclic group. In some implementations, R 3 It is an 11-membered heterocyclic group. In some implementations, R 3 It is a 12-membered heterocyclic group.

[0174] In some implementation schemes, R 3 C6–C6 alkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy group optionally substituted with one or more of the following: 10 Aryl.

[0175] In some implementation schemes, R 3 C6–C6 alkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy group are substituted with one or more of these groups. 10 Aryl.

[0176] In some implementation schemes, R 3 For C6–C 10 Aryl.

[0177] In some implementation schemes, R 3 It is C6 aryl. In some embodiments, R 3 It is C8 aryl. In some embodiments, R 3 C 10 Aryl.

[0178] In some implementation schemes, R 3It is a 5- to 10-membered heteroaryl group optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0179] In some implementation schemes, R 3 It is a 5- to 10-membered heteroaryl group substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0180] In some implementation schemes, R 3 It consists of 5 to 10 heteroaryl groups.

[0181] In some implementation schemes, R 3 It is a 5-membered heteroaryl group. In some implementations, R 3 It is a 6-membered heteroaryl group. In some implementations, R 3 It is a 7-membered heteroaryl group. In some implementations, R 3 It is an 8-membered heteroaryl group. In some implementations, R 3 It is a 9-membered heteroaryl group. In some implementations, R 3 It is a 10-membered heteroaryl group.

[0182] In some implementation schemes, R 2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0183] In some implementation schemes, R 2 and R 3 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 Cycloalkyl.

[0184] In some implementation schemes, R 2 and R 3 Cyclization with the atoms they are attached to forms C3–C atoms substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 Cycloalkyl.

[0185] In some implementation schemes, R 2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl.

[0186] In some implementation schemes, R 2 and R 3 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C4 cycloalkyl groups. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C5 cycloalkyl groups. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C6 cycloalkyl groups. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C7 cycloalkyl groups. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C8 cycloalkyl groups. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C9 cycloalkyl groups. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C 10 Cycloalkyl. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C 11 Cycloalkyl. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form C 12 Cycloalkyl.

[0187] In some implementation schemes, R 2 and R 3 Cyclization with the atoms to which they are attached forms a C3 cycloalkyl group optionally substituted with one or more halogens, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0188] In some implementation schemes, R 2 and R 3Cyclization with the atoms to which they are attached forms a C3 cycloalkyl group substituted with one or more halogens, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0189] In some implementation schemes, R 2 and R 3 Cyclization with the atoms to which they are attached forms a 3- to 12-membered heterocyclic group optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0190] In some implementation schemes, R 2 and R 3 Cyclization with the atoms to which they are attached forms a 3- to 12-membered heterocyclic group substituted with one or more halogens, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0191] In some implementation schemes, R 2 and R 3 They cyclize together with the atoms they are attached to to form 3 to 12-membered heterocyclic groups.

[0192] In some implementation schemes, R 2 and R 3 They cyclize together with the atoms they are attached to to form a 3-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form a 4-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form a 5-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form a 6-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form a 7-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form an 8-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form a 9-membered heterocyclic group. In some embodiments, R 2 and R 3They cyclize together with the atoms they are attached to to form a 10-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form an 11-membered heterocyclic group. In some embodiments, R 2 and R 3 They cyclize together with the atoms they are attached to to form 12-membered heterocyclic groups.

[0193] In some implementation schemes, R 2 and R 3 Each instance is independently H, C1–C3 alkyl, C1–C3 haloalkyl, or R 2 and R 3 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups. In some embodiments, R 2 and R 3 Each instance is H. In some implementations, R 2 and R 3 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups. (b) Groups L1, L2, R 4 R 7 Z, p and n

[0194] As generally defined in this article, R 4 It is a –C1–C6 alkyl–, –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10 heteroaryl)–, where each instance of L1 is independently –(C(R L1 )2)–, further where R L1 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L1 Groups together with the atoms they are attached to form C 3-4 Cycloalkyl; wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; and p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0195] As further generally defined in this paper, Z is –(L2). n–(carboxylic acid) or –(L2) n –Tetraazole, each instance of L2 is independently –(C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L2 The groups, together with the atoms to which they are attached, form a C3 cycloalkyl group; wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; and n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0196] As further generally defined in this article, R 7 Independently, it is H or C1–C4 alkyl. In some embodiments, R 7 For H. In some implementations, R 7 It is a C1–C4 alkyl group. In some embodiments, R 7 It is methyl. In some embodiments, R 7 It is ethyl. In some embodiments, R 7 It is propyl. In some embodiments, R 7 It is isopropyl. In some embodiments, R 7 It is n-butyl. In some implementations, R 7 It is sec-butyl. In some implementations, R 7 It is tert-butyl.

[0197] In some implementation schemes, R 7 It is H or methyl.

[0198] It should be understood that R 4 For a binary part with two connection points, one connection point is connected to NR. 7 Amide nitrogen, while another connection point is attached to the Z portion. The groups listed in this text are read from left to right, with the left-hand description corresponding to NR. 7 The amide nitrogen is bonded, while the description on the right is bonded to Z. For example, for the group –(L1). p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)– and –(L1) p –(5 to 10-membered heteroaryl)–, left side –(L1) p – Groups and NR 7 Amide-nitrogen bonding. It should be further understood that a portion of the Z group, namely –(L2).n – where n is 0, 1, 2, or 3, and also includes NR 7 The amide nitrogen is part of the linker to the terminal carboxylic acid or tetrazolium group.

[0199] Each instance of L1 is independently –(C(R) L1 )2)–of–(L1) p In some implementations, R L1 At least one example is a -C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L1 At least one instance is H. In some implementations, R L1 Each instance of L1 is H, i.e., each instance of L1 is –(CH2)–.

[0200] Each instance of L2 is independently –(C(R) L2 )2)–of–(L2) n In some implementations, R L2 At least one example is a -C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L2 At least one instance is H. In some implementations, R L2 Each instance of is H, that is, each instance of L2 is –(CH2)–.

[0201] In some implementations, each instance of L1 is –(CH2)– and each instance of L2 is –(CH2)–. In some implementations, p is 1, L1 is –(CH(CH3))–, and each instance of L2 is –(CH2)–.

[0202] In some implementation schemes, R 4 It is a –C1–C6 alkyl– or –(CH2) p –(C3–C 12 cycloalkyl)–, –(3 to 12-membered heterocyclic)–, –C6–C 10 Aryl – or – (CH2) p –(5 to 10-membered heteroaryl)–, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0203] In some implementation schemes, R 4–C1–C6 alkyl–, optionally substituted with one or more of the following: –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0204] In some implementation schemes, R 4 –C1–C6 alkyl– is substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0205] In some implementation schemes, R 4 For –(CH2) p –(C3–C 12 cycloalkyl)–, –(3 to 12-membered heterocyclic)–, –C6–C 10 Aryl – or – (CH2) p –(5 to 10-membered heteroaryl)–, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0206] In some implementation schemes, R 4 For –(CH2) p –(C3–C 12 (cycloalkyl) –. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0207] In some implementation schemes, R 4 For –(CH2) p –(C3–C 12 (Cycloalkyl)–, wherein the cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0208] In some implementation schemes, R 4 For –(CH2) p –(3 to 12-membered heterocyclic group)–. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0209] In some implementation schemes, R 4For –(CH2) p –(3 to 12-membered heterocyclic group)–, wherein the heterocyclic group is optionally substituted with one or more halogroups, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0210] In some implementation schemes, R 4 For –(3 to 12-membered heterocyclic groups) –.

[0211] In some implementation schemes, R 4 It is –(3 to 12-membered heterocyclic group)–, wherein the heterocyclic group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0212] In some implementation schemes, R 4 For –C6–C 10 Aryl–.

[0213] In some implementation schemes, R 4 For –C6–C 10 aryl-, wherein the aryl group is optionally substituted by one or more halogenated, -CN, -OH, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl or C1-C6 alkoxy groups.

[0214] In some implementation schemes, R 4 It is –C6 aryl–.

[0215] In some implementation schemes, R 4 It is –C6 aryl–, wherein the aryl group is optionally substituted by one or more halogen, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0216] In some implementation schemes, R 4 For –(CH2) p –(5 to 10-membered heteroaryl)–. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0217] In some implementation schemes, R 4 For –(CH2) p–(5 to 10-membered heteroaryl)–, wherein the heteroaryl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0218] In some implementation schemes, R 4 For –(CH2) p –(6-membered heteroaryl)–. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0219] In some implementation schemes, R 4 For –(CH2) p –(6-membered heteroaryl)–, wherein the heteroaryl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0220] In some implementation schemes, R 4 It is –(n-propyl)–, –(CH2) p –(C3–C 12 cycloalkyl)–, –(3 to 12-membered heterocyclic)–, –C6–C 10 Aryl – or – (CH2) p –(5 to 10-membered heteroaryl)–, wherein the n-propyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0221] In some implementation schemes, R 4 –(n-propyl)-, optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0222] In some implementation schemes, R 4 –(n-propyl)– is substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0223] In some implementation schemes, R 4 It is –(n-propyl)–.

[0224] In some implementations, Z is –(CH2). n –(carboxylic acid) or tetrazolium. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0225] In some implementations, Z is –(CH2). n – (carboxylic acid). In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0226] In some implementations, n is 0 and Z is a carboxylic acid.

[0227] In some implementations, Z is –(CH2). n – Tetrazol. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0228] In some implementations, n is 0 and Z is tetrazolium.

[0229] As described in this article, R 4 The combination is a divalent moiety, and the group Z has –(L2). n – Forming NR 7 The amide nitrogen is linked to a linker group of a terminal carboxylic acid or tetrazolium group. In some embodiments, NR 7 The minimum number of atoms in which the amide nitrogen is continuously covalently bonded to the terminal carboxylic acid or tetrazolium group is 3.

[0230] In some implementation schemes, R 4 For –(L1) p –(C3–C 12 Cycloalkyl) – or – (L1) p –(3 to 12-membered heterocyclic group)–, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; p is 0; n is 2; and Z is –(L2). n –(carboxylic acid) or –(L2) n -Tetraazole; making NR 7 The minimum number of atoms in a continuous covalent bond between the amide nitrogen and the terminal carboxylic acid or tetrazolium group is three consecutive covalently bonded atoms. For example, in some embodiments, –R4 –Z is a group of formula (i): Where Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl group or a 4- to 5-membered heterocyclic group; each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl; and x is 0, 1, 2, or 3. In some embodiments, R L2 At least one example is a -C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L2 Each instance is H.

[0231] In some implementations, the group of formula (i) is: Z' represents a tetrazolium or a carboxylic acid.

[0232] In some implementations, the group of formula (i) is:

[0233] In some implementation schemes, R 4 For –(L1) p –(C3–C 12 Cycloalkyl) – or – (L1) p –(3 to 12-membered heterocyclic group)–, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; p is 1; n is 1; and Z is –(L2). n –(carboxylic acid) or –(L2) n -Tetraazole; making NR 7 The minimum number of atoms in a continuous covalent bond between the amide nitrogen and the terminal carboxylic acid or tetrazolium group is three consecutive covalently bonded atoms. For example, in some embodiments, –R 4 –Z is a group of formula (ii): Where Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl group or a 4- to 5-membered heterocyclic group; each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl; and x is 0, 1, 2, or 3. In some embodiments, R L1 At least one example is a -C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L2At least one example is a -C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L1 Each instance is H. In some implementations, R L2 Each instance is H. In some implementations, R L1 and R L2 Each instance is H.

[0234] In some implementations, the group of formula (ii) is: Z' represents a tetrazolium or a carboxylic acid.

[0235] In some embodiments, the group of formula (ii-a) is:

[0236] In some implementation schemes, R 4 For –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L2) p –(C6–C 10 Aryl)–or–(L2) p –(5 to 10-membered heteroaryl)–, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more haloalkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; p is 0; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n -Tetraazole; making NR 7 The minimum number of atoms in a continuous covalent bond between the amide nitrogen and the terminal carboxylic acid or tetrazolium group is three consecutive covalently bonded atoms. For example, in some embodiments, –R 4 –Z is a group of formula (iii): Where Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl group or a 4- to 5-membered heterocyclic group; each R 4a It is independently a halogenated, C1–C3 alkyl, C1–C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

[0237] In some embodiments, the group of formula (iii) is: Z' represents a tetrazolium or a carboxylic acid.

[0238] In some embodiments, the group of formula (iii-a) is:

[0239] In some implementation schemes, R 4 –(n-propyl)–, optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n -Tetraazole; making NR 7 The number of atoms in the amide nitrogen group that are sequentially covalently bonded to the terminal carboxylic acid or tetrazolium group is three. In some embodiments, R 4 –(n-propyl)–, independently substituted with 0, 1, 2, or 3 halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl groups; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n – Tetrazol. In some implementations, R 4 –(n-propyl)–, independently substituted with 0, 1, 2, or 3 fluorinated, –CH3, -CF3, or C3 cycloalkyl groups; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n –Tetraazole. In some implementations, –R 4 –Z is a group of formula (iv): Where Z' is a tetrazolium or a carboxylic acid; each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl; and x is 0, 1, 2, or 3. In some embodiments, each R 4a Independently –CH3, -CF3, C3 cycloalkyl, or fluorinated. In some embodiments, each R 4a It can be independently bonded to any carbon atom of formula (iv).

[0240] In some embodiments, the groups of formula (iv) have the following formula: Where Z' is a tetrazolium or a carboxylic acid; and each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl. In some embodiments, each R4a It can be independently –CH3, -CF3, C3 cycloalkyl or fluorinated.

[0241] In some embodiments, the groups of formula (iv) have the following formula: Where Z' is a tetrazolium or a carboxylic acid; and each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl. In some embodiments, each R 4a It can be independently –CH3, -CF3, C3 cycloalkyl or fluorinated.

[0242] In some embodiments, the groups of formula (iv) have the following formula:

[0243] In some implementations, p is 1; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n – tetrazolium; and R 4 For –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; such that NR 7 The minimum number of atoms in a continuous covalent bond between the amide nitrogen and the terminal carboxylic acid or tetrazolium group is three consecutive covalently bonded atoms. In some embodiments, –R of formula (v) is provided. 4 –Z group: Where Z' is a tetrazolium or a carboxylic acid; each R 4a Independently, it is halogenated, C1–C3 alkyl, or C1–C3 haloalkyl; and x is 0, 1, 2, or 3. In some embodiments, R L2 At least one example is a C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L2 Each instance is H.

[0244] In some implementations, R of formula (va) 4 –Z group is:

[0245] In some implementation schemes, NR 7 The minimum number of atoms in a continuous covalent bond between the amide nitrogen and the terminal carboxylic acid or tetrazolium group is two consecutively covalently bonded atoms. For example, in some embodiments, p is 0; n is 0; Z is –(L2). n –(carboxylic acid) or –(L2) n – tetrazolium; and R 4 For –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10-membered heteroaryl), wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more haloalkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; such that NR 7 The minimum number of atoms in a continuous covalent bond between the amide nitrogen and the terminal carboxylic acid or tetrazolium group is two consecutively covalently bonded atoms. In some embodiments, –R of formula (vi) is provided. 4 –Z group: Where Z' is a tetrazolium or a carboxylic acid; each R 4a It is independently a halogenated, C1–C3 alkyl, or C1–C3 haloalkyl; and x is 0, 1, 2, or 3.

[0246] In some implementations, R of formula (vi) 4 –Z group is:

[0247] In some implementation schemes, NR 7 The minimum number of atoms in which the amide nitrogen is sequentially covalently bonded to the terminal carboxylic acid or tetrazolium group is four consecutively covalently bonded atoms (e.g., carbon atoms). For example, in some embodiments, p is 0; n is 0; Z is –(L2). n –(carboxylic acid) or –(L2) n – tetrazolium; and R 4 For –(L1) p –(C6–C 10 Aryl) – or – (L1) p–(5 to 10-membered heteroaryl)–, wherein the aryl or heteroaryl group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; such that NR 7 The minimum number of atoms in which the amide nitrogen is sequentially covalently bonded to the terminal carboxylic acid or tetrazolium group is four. In some embodiments, –R of formula (vii) is provided. 4 –Z group: Where Z' is a tetrazolium or a carboxylic acid; and each R 4a It is independently a halogenated, C1–C3 alkyl, or C1–C3 haloalkyl, and x is 0, 1, 2, or 3.

[0248] In some implementations, R of formula (vii) 4 –Z group is: (c) Group R 1 R 5 R 6 R 6’ R 6”

[0249] As generally defined in this article, each R 5 Independently fluorinated or C1–C6 alkyl, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 Cycloalkyl.

[0250] In some implementation schemes, R 5 Each instance of R is the same group. In some implementations, R 5 Each instance is halogenated. For example, in some implementations, R 5 Each instance is fluorinated. In some implementations, R 5 Each instance is the same optionally substituted C1–C6 alkyl group, for example, –CH3. In some embodiments, R 5 Each instance is different.

[0251] In some implementation schemes, R5 Each instance is independently a C1–C6 alkyl group, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0252] In some implementation schemes, R 5 Each instance is independently a C1–C6 alkyl group, wherein the alkyl group is substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups.

[0253] In some implementation schemes, R 5 Each instance is independently a C1–C6 alkyl group.

[0254] In some implementation schemes, R 5 At least one instance of R is methyl. In some embodiments, R 5 At least one instance is ethyl. In some embodiments, R 5 At least one instance is propyl. In some embodiments, R 5 At least one instance is butyl. In some implementations, R 5 At least one instance is pentyl. In some implementations, R 5 At least one instance of R is hexadi. In some implementations, R 5 At least one instance is isopropyl. In some embodiments, R 5 At least one instance is isobutyl. In some implementations, R 5 At least one instance is isopentyl. In some embodiments, R 5 At least one instance of R is an isohystery. In some implementations, R 5 At least one instance is sec-butyl. In some implementations, R 5 At least one instance is sec-pentyl. In some implementations, R 5 At least one instance is methyl ethyl ... 5 At least one instance is tert-butyl.

[0255] In some implementations, two R 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 Cycloalkyl.

[0256] In some implementations, two R 5 Cyclization with the atoms they are attached to forms C3–C atoms substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 Cycloalkyl.

[0257] In some implementations, two R 5 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl.

[0258] In some implementations, two R 5 They cyclize together with the atoms they are attached to to form a C3 cycloalkyl group. In some embodiments, the two R atoms... 5 They cyclize together with the atoms they are attached to to form C4 cycloalkyl groups. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C5 cycloalkyl groups. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form a C6 cycloalkyl group. In some embodiments, the two R atoms... 5 They cyclize together with the atoms they are attached to to form C7 cycloalkyl groups. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C8 cycloalkyl groups. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form a C9 cycloalkyl group. In some embodiments, the two R atoms... 5 They cyclize together with the atoms they are attached to to form C 10 Cycloalkyl. In some embodiments, the two Rs 5 They cyclize together with the atoms they are attached to to form C 11 Cycloalkyl. In some embodiments, the two Rs 5 They cyclize together with the atoms they are attached to to form C 12 Cycloalkyl.

[0259] In some implementation schemes, R 5 Each instance is selected from fluorinated and C1–C6 alkyl groups, or two R groups. 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0260] In some implementation schemes, R 5 Each instance is selected from fluorinated and C1–C6 alkyl groups, or two R groups. 5 They cyclize together with the atoms they are attached to to form C3 or C5 cycloalkyl groups.

[0261] In some implementation schemes, R5 Each instance is identical, selected from fluorinated and C1–C6 alkyl groups, or two R groups. 5 They cyclize together with the atoms they are attached to to form C3 or C5 cycloalkyl groups. In some embodiments, R 5 Each instance is identical, selected from fluorinated and –CH3, or both R 5 They cyclize together with the atoms they are attached to to form C3 or C5 cycloalkyl groups. In some embodiments, R 5 Each instance is fluorinated. In some implementations, R 5 Each instance is –CH3. In some implementations, two R 5 They cyclize together with the atoms they are attached to to form C3 or C5 cycloalkyl groups.

[0262] In some implementation schemes, R 5 Each instance is identical, selected from fluorinated and C1–C6 alkyl groups, or two R groups. 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups. In some embodiments, R 5 Each instance is identical, selected from fluorinated and –CH3, or both R 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups. In some embodiments, R 5 Each instance is fluorinated. In some implementations, R 5 Each instance is –CH3. In some implementations, two R 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0263] As generally defined in this article, R 1 It is halogenated, –CN, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 Cycloalkyl.

[0264] In some implementation schemes, R 1 It is either halogenated or –CN.

[0265] In some implementation schemes, R 1 Halogenation. In some implementations, R 1 It can be F, Br, Cl, or I. In some implementations, R 1 It is F, Br, or Cl. In some implementations, R 1 For F. In some implementations, R 1 For Br. In some implementations, R 1 For Cl. In some implementations, R 1 For I.

[0266] In some implementation schemes, R 1 For –CN.

[0267] In some implementation schemes, R 1 It is a C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 Cycloalkyl.

[0268] In some implementation schemes, R 1 It is C1–C6 alkyl, C2–C6 alkenyl or C2–C6 alkynyl.

[0269] In some implementation schemes, R 1 It is a C1–C6 alkyl group.

[0270] In some implementation schemes, R 1 It is methyl. In some embodiments, R 1 It is ethyl. In some embodiments, R 1 It is propyl. In some embodiments, R 1 For butyl. In some implementations, R 1 It is pentyl. In some implementations, R 1 For its own foundation. In some implementation schemes, R 1 It is isopropyl. In some embodiments, R 1 It is isobutyl. In some embodiments, R 1 It is isopentyl. In some embodiments, R 1 It is an allotropic group. In some implementations, R 1 It is sec-butyl. In some implementations, R 1 It is sec-amyl. In some implementations, R 1 For Zhongjiji. In some implementations, R 1 It is tert-butyl.

[0271] In some implementation schemes, R 1 It is a C2–C6 alkenyl group.

[0272] In some implementation schemes, R 1 It is C2-olefinic. In some embodiments, R 1 It is a C3 alkenyl group. In some embodiments, R 1 It is a C4 alkenyl group. In some embodiments, R 1 It is a C5 alkenyl group. In some embodiments, R 1 It is a C6 alkenyl group.

[0273] In some implementation schemes, R 1 It is a C2–C6 ynyl group.

[0274] In some implementation schemes, R 1 It is a C2 acetylene group. In some embodiments, R 1 It is a C3 acetyl group. In some embodiments, R 1 It is a C4 acetylene group. In some embodiments, R 1 It is a C5 acetyl group. In some embodiments, R 1 It is a C6 acetylene group.

[0275] In some implementation schemes, R 1 It is a C1–C6 haloalkyl or C1–C6 alkoxy.

[0276] In some implementation schemes, R 1 It is a C1–C6 haloalkyl group.

[0277] In some implementation schemes, R 1 It is a halomethyl group. In some embodiments, R 1 It is a haloethyl. In some embodiments, R 1 It is a halogenated propyl group. In some embodiments, R 1 It is a halogenated butyl group. In some implementations, R 1 It is a halopentyl group. In some embodiments, R 1 It is a halogenated hexyl group.

[0278] In some implementation schemes, R 1 It is a C1–C6 alkoxy group.

[0279] In some implementation schemes, R 1 It is methoxylated. In some embodiments, R 1 It is ethoxylated. In some embodiments, R 1 It is propoxylated. In some embodiments, R 1 It is butoxylated. In some embodiments, R 1 It is pentoxygenated. In some embodiments, R 1 It is an hexoxy group.

[0280] In some implementation schemes, R 1 For C3–C 12 Cycloalkyl.

[0281] In some implementation schemes, R 1 It is a C3–C6 cycloalkyl group.

[0282] In some implementation schemes, R 1 It is a C3 cycloalkyl group. In some embodiments, R 1 It is a C4 cycloalkyl group. In some embodiments, R 1 It is a C5 cycloalkyl group. In some embodiments, R1 It is a C6 cycloalkyl group.

[0283] In some implementation schemes, R 1 It is a C7 cycloalkyl group. In some embodiments, R 1 It is a C8 cycloalkyl group. In some embodiments, R 1 It is a C9 cycloalkyl group. In some embodiments, R 1 C 10 Cycloalkyl. In some embodiments, R 1 C 11 Cycloalkyl. In some embodiments, R 1 C 12 Cycloalkyl.

[0284] In some implementation schemes, R 1 The derivatives are Cl, Br, I, CF3, cyclopropyl, methyl, isopropyl, or cyclopentyl.

[0285] As generally defined in this article, R 6 It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0286] In some implementation schemes, R 6 For H.

[0287] In some implementation schemes, R 6 It can be halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0288] In some implementation schemes, R 6 It is halogenated or –OH.

[0289] In some implementation schemes, R 6 Halogenated.

[0290] In some implementation schemes, R 6 It can be F, Cl, Br, or I. In some implementations, R 6 It can be F, Cl, or Br.

[0291] In some implementation schemes, R 6 For F. In some implementations, R 6 For Cl. In some implementations, R 6 For Br. In some implementations, R 6 For I.

[0292] In some implementation schemes, R 6 It is –OH.

[0293] In some implementation schemes, R 6 It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0294] In some implementation schemes, R 6 It is C1–C6 alkyl, C2–C6 alkenyl or C2–C6 alkynyl.

[0295] In some implementation schemes, R 6 It is a C1–C6 alkyl group.

[0296] In some implementation schemes, R 6 It is methyl. In some embodiments, R 6 It is ethyl. In some embodiments, R 6 It is propyl. In some embodiments, R 6 For butyl. In some implementations, R 6 It is pentyl. In some implementations, R 6 For its own foundation. In some implementation schemes, R 6 It is isopropyl. In some embodiments, R 6 It is isobutyl. In some embodiments, R 6 It is isopentyl. In some embodiments, R 6 It is an allotropic group. In some implementations, R 6 It is sec-butyl. In some implementations, R 6 It is sec-amyl. In some implementations, R 6 For Zhongjiji. In some implementations, R 6 It is tert-butyl.

[0297] In some implementation schemes, R 6 It is a C2–C6 alkenyl group.

[0298] In some implementation schemes, R 6 It is C2-olefinic. In some embodiments, R 6 It is a C3 alkenyl group. In some embodiments, R 6 It is a C4 alkenyl group. In some embodiments, R 6 It is a C5 alkenyl group. In some embodiments, R 6 It is a C6 alkenyl group.

[0299] In some implementation schemes, R 6 It is a C2–C6 ynyl group.

[0300] In some implementation schemes, R 6 It is a C2 acetylene group. In some embodiments, R 6It is a C3 acetyl group. In some embodiments, R 6 It is a C4 acetylene group. In some embodiments, R 6 It is a C5 acetyl group. In some embodiments, R 6 It is a C6 acetylene group.

[0301] In some implementation schemes, R 6 It is a C1–C6 haloalkyl or C1–C6 alkoxy.

[0302] In some implementation schemes, R 6 It is a C1–C6 haloalkyl group.

[0303] In some implementation schemes, R 6 It is a halomethyl group. In some embodiments, R 6 It is a haloethyl. In some embodiments, R 6 It is a halogenated propyl group. In some embodiments, R 6 It is a halogenated butyl group. In some implementations, R 6 It is a halopentyl group. In some embodiments, R 6 It is a halogenated hexyl group.

[0304] In some implementation schemes, R 6 It is a C1–C6 alkoxy group.

[0305] In some implementation schemes, R 6 It is methoxylated. In some embodiments, R 6 It is ethoxylated. In some embodiments, R 6 It is propoxylated. In some embodiments, R 6 It is butoxylated. In some embodiments, R 6 It is pentoxygenated. In some embodiments, R 6 It is an hexoxy group.

[0306] In some implementation schemes, R 6 It can be H, F, or –OH.

[0307] As generally defined in this article, R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0308] In some implementation schemes, R 6’ For H.

[0309] In some implementation schemes, R 6’ It can be halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0310] In some implementation schemes, R 6’ It is halogenated or –OH.

[0311] In some implementation schemes, R 6’ Halogenated.

[0312] In some implementation schemes, R 6’ It can be F, Cl, Br, or I. In some implementations, R 6’ It can be F, Cl, or Br.

[0313] In some implementation schemes, R 6’ For F. In some implementations, R 6’ For Cl. In some implementations, R 6’ For Br. In some implementations, R 6’ For I.

[0314] In some implementation schemes, R 6’ It is –OH.

[0315] In some implementation schemes, R 6’ It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0316] In some implementation schemes, R 6’ It is C1–C6 alkyl, C2–C6 alkenyl or C2–C6 alkynyl.

[0317] In some implementation schemes, R 6’ It is a C1–C6 alkyl group.

[0318] In some implementation schemes, R 6’ It is methyl. In some embodiments, R 6’ It is ethyl. In some embodiments, R 6’ It is propyl. In some embodiments, R 6’ For butyl. In some implementations, R 6’ It is pentyl. In some implementations, R 6’ For its own foundation. In some implementation schemes, R 6’ It is isopropyl. In some embodiments, R 6’ It is isobutyl. In some embodiments, R 6’ It is isopentyl. In some embodiments, R 6’ It is an allotropic group. In some implementations, R 6’ It is sec-butyl. In some implementations, R 6’ It is sec-amyl. In some implementations, R 6’ For Zhongjiji. In some implementations, R6’ It is tert-butyl.

[0319] In some implementation schemes, R 6’ It is a C2–C6 alkenyl group.

[0320] In some implementation schemes, R 6’ It is C2-olefinic. In some embodiments, R 6’ It is a C3 alkenyl group. In some embodiments, R 6’ It is a C4 alkenyl group. In some embodiments, R 6’ It is a C5 alkenyl group. In some embodiments, R 6’ It is a C6 alkenyl group.

[0321] In some implementation schemes, R 6’ It is a C2–C6 ynyl group.

[0322] In some implementation schemes, R 6’ It is a C2 acetylene group. In some embodiments, R 6’ It is a C3 acetyl group. In some embodiments, R 6’ It is a C4 acetylene group. In some embodiments, R 6’ It is a C5 acetyl group. In some embodiments, R 6’ It is a C6 acetylene group.

[0323] In some implementation schemes, R 6’ It is a C1–C6 haloalkyl or C1–C6 alkoxy.

[0324] In some implementation schemes, R 6’ It is a C1–C6 haloalkyl group.

[0325] In some implementation schemes, R 6’ It is a halomethyl group. In some embodiments, R 6’ It is a haloethyl. In some embodiments, R 6’ It is a halogenated propyl group. In some embodiments, R 6’ It is a halogenated butyl group. In some implementations, R 6’ It is a halopentyl group. In some embodiments, R 6’ It is a halogenated hexyl group.

[0326] In some implementation schemes, R 6’ It is a C1–C6 alkoxy group.

[0327] In some implementation schemes, R 6’ It is methoxylated. In some embodiments, R 6’ It is ethoxylated. In some embodiments, R 6’ It is propoxylated. In some embodiments, R 6’It is butoxylated. In some embodiments, R 6’ It is pentoxygenated. In some embodiments, R 6’ It is an hexoxy group.

[0328] In some implementation schemes, R 6’ It can be H, F, CF3, methoxy, or –OH.

[0329] As generally defined in this article, R 6” It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0330] In some implementation schemes, R 6” For H.

[0331] In some implementation schemes, R 6” It can be halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0332] In some implementation schemes, R 6” It is halogenated or –OH.

[0333] In some implementation schemes, R 6” Halogenated.

[0334] In some implementation schemes, R 6” It can be F, Cl, Br, or I. In some implementations, R 6” It can be F, Cl, or Br.

[0335] In some implementation schemes, R 6” For F. In some implementations, R 6” For Cl. In some implementations, R 6” For Br. In some implementations, R 6” For I.

[0336] In some implementation schemes, R 6” It is –OH.

[0337] In some implementation schemes, R 6” It is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0338] In some implementation schemes, R 6” It is C1–C6 alkyl, C2–C6 alkenyl or C2–C6 alkynyl.

[0339] In some implementation schemes, R 6” It is a C1–C6 alkyl group.

[0340] In some implementation schemes, R 6” It is methyl. In some embodiments, R 6” It is ethyl. In some embodiments, R 6” It is propyl. In some embodiments, R 6” For butyl. In some implementations, R 6” It is pentyl. In some implementations, R 6” For its own foundation. In some implementation schemes, R 6” It is isopropyl. In some embodiments, R 6” It is isobutyl. In some embodiments, R 6” It is isopentyl. In some embodiments, R 6” It is an allotropic group. In some implementations, R 6” It is sec-butyl. In some implementations, R 6” It is sec-amyl. In some implementations, R 6” For Zhongjiji. In some implementations, R 6” It is tert-butyl.

[0341] In some implementation schemes, R 6” It is a C2–C6 alkenyl group.

[0342] In some implementation schemes, R 6” It is C2-olefinic. In some embodiments, R 6” It is a C3 alkenyl group. In some embodiments, R 6” It is a C4 alkenyl group. In some embodiments, R 6” It is a C5 alkenyl group. In some embodiments, R 6” It is a C6 alkenyl group.

[0343] In some implementation schemes, R 6” It is a C2–C6 ynyl group.

[0344] In some implementation schemes, R 6” It is a C2 acetylene group. In some embodiments, R 6” It is a C3 acetyl group. In some embodiments, R 6” It is a C4 acetylene group. In some embodiments, R 6” It is a C5 acetyl group. In some embodiments, R 6” It is a C6 acetylene group.

[0345] In some implementation schemes, R 6” It is a C1–C6 haloalkyl or C1–C6 alkoxy.

[0346] In some implementation schemes, R 6” It is a C1–C6 haloalkyl group.

[0347] In some implementation schemes, R 6” It is a halomethyl group. In some embodiments, R 6” It is a haloethyl. In some embodiments, R 6” It is a halogenated propyl group. In some embodiments, R 6” It is a halogenated butyl group. In some implementations, R 6” It is a halopentyl group. In some embodiments, R 6” It is a halogenated hexyl group.

[0348] In some implementation schemes, R 6” It is a C1–C6 alkoxy group.

[0349] In some implementation schemes, R 6” It is methoxylated. In some embodiments, R 6” It is ethoxylated. In some embodiments, R 6” It is propoxylated. In some embodiments, R 6” It is butoxylated. In some embodiments, R 6” It is pentoxygenated. In some embodiments, R 6” It is an hexoxy group.

[0350] In some implementation schemes, R 6” It can be H or F.

[0351] In some implementation schemes, R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl; R 6 H, halogenated, or –OH; R 6’ It is H, halo, –OH, C1–C3 alkyl, C1–C3 haloalkyl, or C1–C3 alkoxy; and R 6” It is H or halogenated.

[0352] In some implementations, the 6,5-double-ring core of formula (viii) is: It has the following formula: Where R 6 R 6’ and R 6” At least one of them is not H. In some embodiments of equation (viii), R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl; R 6 Halogenated or –OH; R 6’ It is a halogenated, –OH, C1–C3 alkyl, C1–C3 haloalkyl, or C1–C3 alkoxy group; R6” Halogenation. In some implementations, R 5 Each instance is independently identical or different, selected from fluorinated or C-type compounds. 1–3 Alkyl, or two R 5 They cyclize together with the atoms they are attached to to form C3–C5 cycloalkyl groups.

[0353] In some embodiments of equation (viii-a), the 6,5–double-ring core has the following formula:

[0354] In some embodiments of formula (viii-c), the 6,5-double-ring core has the following formula:

[0355] In some embodiments of equation (viii-d), the 6,5–double-ring core has the following formula:

[0356] In some embodiments of equation (viii-e), the 6,5–double-ring core has the following formula: (d) Alternative implementation schemes

[0357] It should be understood that, for the compounds disclosed herein, the variable R... 1 R 2 R 3 R 4 R 5 R 6 R 6’ R 6” R 7 Z, L1, L2, n, and p can each be selected from the groups described herein, and this document refers to the variable R. 1 R 2 R 3 R 4 R 5 R 6 R 6’ R 6” R 7 Any group described by any of Z, L1, L2, n, and p can be used in conjunction with the variable R described in this paper, where applicable. 1 R 2 R 3 R 4 R 5 R 6 R 6’ R6” R 7 Any combination of one or more of the remaining groups described in Z, L1, L2, n and p.

[0358] For example, when –R 4 In some embodiments where –Z is a group of formula (i), compounds of formula (IB) are provided: Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, wherein Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl or a 4- to 5-membered heterocyclic group; each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl; and x is 0, 1, 2, or 3. In some embodiments, each R 4a Independently –CH3, -CF3, C3 cycloalkyl, or fluorinated. In some embodiments, n is 0 and R 4a It does not exist. In some implementations, n is 1, 2, or 3, and R 4a Each instance is independently –CH3, -CF3, C3 cycloalkyl, or fluorinated. In some embodiments, R 2 and R 3 Each instance is H. In some embodiments, Z' is a carboxylic acid. In some embodiments, R L2 At least one example is a -C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L2 Each instance is H. In some implementations, –R of equation (i) 4 –Z group has the formula (ic). In some embodiments, R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl. In some embodiments, R 6 It can be H, halogenated, or –OH. In some embodiments, R 6’ It can be H, halogenated, –OH, C1–C3 alkyl, C1–C3 haloalkyl, or C1–C3 alkoxy. In some embodiments, R 6” It is H or halogenated. In some embodiments, the 6,5-bicyclic core of formula (viii) has formula (viii-c), (viii-d), or (viii-e). In some embodiments, R 5 Each instance is independently identical or different, selected from fluorinated or C-type compounds. 1–3 Alkyl group. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0359] When –R 4 In some embodiments where –Z is a group of formula (ii), compounds of formula (IC) are provided: Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, wherein Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl or a 4- to 5-membered heterocyclic group; each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl; and x is 0, 1, 2, or 3. In some embodiments, each R 4a Independently –CH3, -CF3, C3 cycloalkyl, or fluorinated. In some embodiments, n is 0 and R 4a It does not exist. In some implementations, n is 1, 2, or 3, and R 4a Each instance is independently –CH3, -CF3, C3 cycloalkyl, or fluorinated. In some embodiments, R 2 and R 3 Each instance is H. In some embodiments, Z' is a carboxylic acid. In some embodiments, R L2 At least one example is a -C1–C3 alkyl group optionally substituted with one or more halogens. In some embodiments, R L2 Each instance is H. In some implementations, –R of equation (ii) 4 –Z group has formula (ii-a). In some embodiments, R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl. In some embodiments, R 6 It can be H, halogenated, or –OH. In some embodiments, R 6’ It can be H, halogenated, –OH, C1–C3 alkyl, C1–C3 haloalkyl, or C1–C3 alkoxy. In some embodiments, R 6” H or halogenated. In some embodiments, the 6,5-bicyclic core of formula (viii) has formula (viii-c), (viii-d), or (viii-e). In some embodiments, R 5 Each instance is independently identical or different, selected from fluorinated or C-type compounds. 1–3 Alkyl group. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0360] When –R 4 In some embodiments where –Z is a group of formula (iv), compounds of formula (ID) are provided: Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, wherein Z' is a tetrazolium or carboxylic acid; each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl; and x is 0, 1, 2, or 3. In some embodiments, each R 4a Independently –CH3, -CF3, C3 cycloalkyl, or fluorinated. In some embodiments, n is 0 and R 4a It does not exist. In some implementations, n is 1, 2, or 3, and R 4a Each instance is independently –CH3, -CF3, C3 cycloalkyl, or fluorinated. In some embodiments, R 2 and R 3 Each instance is H. In some embodiments, Z' is a carboxylic acid. In some embodiments, –R of formula (iv) 4 –Z groups have the formula (iv-a), (iv-b), (iv-c), or (iv-h). In some embodiments, the –R group of formula (iv-b) 4 –Z group has the formula (iv-b-2). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-1). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-2). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-1). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-2). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-3). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-4). In some embodiments, R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl. In some embodiments, R 6 It can be H, halogenated, or –OH. In some embodiments, R 6’ It can be H, halogenated, –OH, C1–C3 alkyl, C1–C3 haloalkyl, or C1–C3 alkoxy. In some embodiments, R 6” H or halogenated. In some embodiments, the 6,5-bicyclic core of formula (viii) has formula (viii-c), (viii-d), or (viii-e). In some embodiments, R 5Each instance is independently identical or different, selected from fluorinated or C-type compounds. 1–3 Alkyl group. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0361] In some embodiments where the 6,5-bicyclic core of formula (viii) has formula (viii-c), compounds of formula (IE) are provided: Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. In some embodiments, R 6’ It is H or halogenated, and R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl. In some embodiments, R 6’ Halogenated and R 1 It is a C3–C5 cycloalkyl group. In some embodiments, R 6’ It is fluorinated and R 1 It is a C3–C5 cycloalkyl group. In some embodiments, R 6’ Halogenated and R 1 It is a C3 cycloalkyl group. In some embodiments, R 2 and R 3 Each instance is H. In some implementations, Z is –(L2). n -Carboxylic acid. In some implementations, –R 4 –Z group has formula (iv). In some embodiments, –R 4 –Z groups have the formula (iv-a), (iv-b), (iv-c), or (iv-h). In some embodiments, the –R group of formula (iv-b) 4 –Z group has the formula (iv-b-2). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-1). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-2). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-1). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-2). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-3). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-4). In some embodiments, R5 Each instance is independently identical or different, selected from fluorinated or C-type compounds. 1–3 Alkyl group. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0362] In some embodiments where the 6,5-bicyclic core of formula (viii) has formula (viii-d), compounds of formula (IF) are provided: Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. In some embodiments, R 6” It is H or halogenated, and R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl. In some embodiments, R 6” Halogenated and R 1 It is a C3–C5 cycloalkyl group. In some embodiments, R 6” It is fluorinated and R 1 It is a C3–C5 cycloalkyl group. In some embodiments, R 6” Halogenated and R 1 It is a C3 cycloalkyl group. In some embodiments, R 2 and R 3 Each instance is H. In some implementations, Z is –(L2). n -Carboxylic acid. In some implementations, –R 4 –Z group has formula (iv). In some embodiments, –R 4 –Z groups have the formula (iv-a), (iv-b), (iv-c), or (iv-h). In some embodiments, the –R group of formula (iv-b) 4 –Z group has the formula (iv-b-2). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-1). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-2). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-1). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-2). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-3). In some embodiments, the –R group of formula (iv-h) 4–Z group has the formula (iv-h-4). In some embodiments, R 5 Each instance is independently identical or different, selected from fluorinated or C-type compounds. 1–3 Alkyl group. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0363] In some embodiments where the 6,5-bicyclic core of formula (viii) has formula (viii-e), compounds of formula (IG) are provided: Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. In some embodiments, R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl, R 6’ It is a halogenated, –OH, C1–C3 alkyl, C1–C3 haloalkyl, or C1–C3 alkoxy group, and R 6” Halogenation. In some implementations, R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3–C5 cycloalkyl, R 6’ It is halogenated, and R 6” Halogenation. In some implementations, R 1 It is a C3 cycloalkyl group, R 6’ It is halogenated, and R 6” Halogenation. In some implementations, R 1 It is a C3 cycloalkyl group, R 6’ It is fluorinated, and R 6” It is fluorinated. In some implementations, R 2 and R 3 Each instance is H. In some implementations, Z is –(L2). n -Carboxylic acid. In some implementations, –R 4 –Z group has formula (iv). In some embodiments, –R 4 –Z groups have the formula (iv-a), (iv-b), (iv-c), or (iv-h). In some embodiments, the –R group of formula (iv-b) 4 –Z group has the formula (iv-b-2). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-1). In some embodiments, the –R group of formula (iv-c) 4 –Z group has the formula (iv-c-2). In some embodiments, the –R group of formula (iv-h) 4–Z group has the formula (iv-h-1). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-2). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-3). In some embodiments, the –R group of formula (iv-h) 4 –Z group has the formula (iv-h-4). In some embodiments, R 5 Each instance is independently identical or different, selected from fluorinated or C-type compounds. 1–3 Alkyl group. In some embodiments, the two R groups... 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0364] In some embodiments, the compound is selected from the compounds in Table 1 or 2, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, tautomers, isotopic derivatives, prodrugs, or polymorphs thereof. Compounds containing a tetrazolium (Z) group may comprise a mixture of tetrazolium tautomers. In some embodiments, the compound is a compound in Table 1 or 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a neutral (free base) compound in Table 1 or 2. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound in Table 1 or 2. Tables 1 and 2 provide the position of the compound in the Examples (Ex) according to the Example number, or as provided in Table A (TA) of the Examples. An asterisk (*) next to the compound number (#) indicates that any stereochemistry has been specified.

[0365] In some embodiments, the compound is compound 58 (e.g., compound 58A*), compound 59A, compound 60A*, compound 61A, compound 61B, compound 62A, compound 63A, compound 64A, compound 66, compound 67C*, or compound 67D*, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof.

[0366] In some embodiments, the compound is compound 58 (e.g., compound 58A*), compound 59A, compound 60A*, compound 61A, compound 61B, compound 62A, compound 63A, compound 64A, compound 66, compound 67C*, or compound 67D*, or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the compound is a free base of compound 58 (e.g., compound 58A*), compound 59A, compound 60A*, compound 61A, compound 61B, compound 62A, compound 63A, compound 64A, compound 66, compound 67C*, or compound 67D*.

[0368] In some embodiments, the compound is an isotopic derivative of a compound of formula (I) or any compound provided in Table 1 or Table 2. In some embodiments, the isotopic derivative is selected from... 2 H, 13 C 14 C 15 N、 18 O、 29 Si、 31 P and 34 The isotope derivative is enriched with or labeled with one or more atoms of S. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., rich in one or more atoms of S). 2 H). In some embodiments, the compound is 18 An F-labeled compound. In some embodiments, the compound is... 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compounds or any combination thereof. In some embodiments, the compound is...33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds or any combination thereof.

[0369] It should be understood that any of the various techniques recognized in the art can be used to prepare... 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S-labeled compounds. For example, they can typically be obtained by performing the schemes described herein and / or the procedures disclosed in the examples, by using... 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S-labeled reagents are used to replace non-isotope-labeled reagents to prepare deuterium-labeled compounds. Compounds containing one or more of the aforementioned... 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and 36 Compounds containing the sulfur atom are within the scope of this disclosure. Furthermore, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S) substitution can provide certain therapeutic benefits due to greater metabolic stability, such as a longer half-life in vivo or a reduced dose required.

[0370] In some embodiments, the isotope derivative is a deuterium-labeled compound of any of the general formulas disclosed herein.

[0371] It should be understood that any of the various techniques recognized in the art can be used to prepare isotope derivatives. For example, isotope derivatives can typically be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents by performing the schemes described herein and / or the procedures disclosed in the examples. (2) Preparation method

[0372] It should be understood that the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, employing standard synthetic methods and procedures known to those skilled in the art or understood by those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for functional group transformations and manipulations are available from relevant scientific literature or from standard textbooks in the field. Although not limited to any one or more sources, classic textbooks such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are known and recognized as useful reference textbooks for those skilled in the art in organic synthesis.

[0373] Those skilled in the art will notice that the order of certain steps, such as the introduction and removal of protecting groups, can be altered during the reaction sequence and synthetic scheme described herein. Those skilled in the art will recognize that certain groups may need to be protected from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999. For example, a carboxylic acid protecting group (PG) may include C 1-6 Alkyl, C6 aryl or aryl C 1-6 Alkyl group, wherein the alkyl and aryl groups are optionally substituted with halogen, alkyl or alkoxy groups. In some embodiments, the carboxylic acid protecting group (PG) is methyl (-CH3, Me), ethyl (-CH2CH3, Et) or tert-butyl (-C(CH3)3, tBu).

[0374] In the synthetic schemes described herein, for simplicity, compounds may be drawn to have a specific configuration. Such a specific configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regio isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regio isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regio isomer, or stereoisomer.

[0375] Suitable general methods for preparing compounds of formula (I), as well as intermediates that can be used to synthesize said compounds, are provided in the following general schemes 1-12. Examples also describe non-limiting procedures for preparing such compounds. General Solution 1 (1A) (1B)

[0376] Compound of formula (I), where Z is –(L2). n –Tetraazole, which can be prepared as shown in General Scheme 1, by amide coupling of a substituted indolinone (acetic acid) (i) or a salt thereof with an aminotetrazole (ii) or a salt thereof to provide a target tetraazole analog (iii) or (iii-a) or a salt thereof, wherein the indolinone (acetic acid) (i) and the aminotetrazole (ii) are commercially available or known in the chemical literature unless otherwise stated, and the dashed line corresponds to an optional spirofused cycloalkyl group. General Solution 2 (2A) (2B)

[0377] Compound of formula (I), where Z is –(L2). n –Carboxylic acids can be prepared by the two-step method shown in General Scheme 2, which involves amide coupling of a substituted indololinone (acetic acid) (i) or its salt with an amino ester (iv) or its salt, wherein PG is a protecting group, such as C 1-6 Alkyl, C6 aryl or aryl-C 1-6 Alkyl group, wherein the alkyl group and aryl group are optionally halogenated, C-terminated ... 1-6 Alkyl or C 1-6 The alkoxy group is substituted and then hydrolyzed to provide the target carboxylic acid analog (v) or (va) or a salt thereof, wherein the indolinone (acetic acid) (i) and the amino ester (iv) are commercially available or known in the chemical literature unless otherwise stated, and the dashed line corresponds to an optional spirofused cycloalkyl group.

[0378] In some embodiments, the compounds disclosed herein are: Or its salt.

[0379] In some implementations, PG is C 1-6 Alkyl, C6 aryl or aryl-C 1-6 Alkyl group, wherein the alkyl group and aryl group are optionally halogenated, C-terminated ... 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0380] In some implementations, PG is C 1-6 Alkyl, C6 aryl or aryl-C 1-6 alkyl.

[0381] In some implementations, PG is optionally halogenated, C 1-6 Alkyl or C 1-6 alkoxy-substituted C 1-6 alkyl.

[0382] In some implementations, PG is C 1-6 alkyl.

[0383] In some implementations, PG is optionally halogenated, C 1-6 Alkyl or C 1-6 C6 aryl groups substituted with alkoxy groups.

[0384] In some implementations, PG is C6 aryl.

[0385] In some implementations, PG is aryl-C 1-6 Alkyl group, wherein the alkyl group and aryl group are optionally halogenated, C-terminated ... 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0386] In some implementations, PG is aryl-C 1-6 alkyl.

[0387] Exemplary compounds of formula (vo) include any of the compounds provided in Table 3 or their salts, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, tautomers, isotopic derivatives, or polymorphs thereof. In some embodiments, the compound of formula (vo) is a prodrug. General Solution 3 (3A) (3B)

[0388] Compound (I) can be prepared as shown in General Scheme 3 by alkylation of indolinone (vi) or a salt thereof, followed by hydrolysis, to provide indolinone (acetic acid) (i) or a salt thereof. Then, amide coupling (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) provides a target carboxylic acid analog (v) or (va) or a salt thereof, or a target tetrazolium analog (iii-a) or a salt thereof, wherein the starting materials indolinone (vi), amino ester (iv), and aminotetrazole (ii) are commercially available or known in the chemical literature, unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 4 (4A) (4B)

[0389] Compound (I) can be prepared as shown in General Scheme 4 via halogen transfer of bromoindolone (vii) or its salt, wherein PG is a protecting group, such as C 1-6 Alkyl, C6 aryl or aryl-C 1-6 Alkyl group, wherein the alkyl group and aryl group are optionally halogenated, C-terminated ... 1-6 Alkyl or C 1-6 The alkoxy group is substituted to form an iodoindolone (viii) or a salt thereof, which is then copper-coupled to give a –CF3 analog (ix) or a salt thereof, followed by ester hydrolysis to provide a carboxylic acid intermediate (x) or a salt thereof, which is then amide-coupled with (iv) or (ii) or a salt thereof (and, when the target is a carboxylic acid rather than a tetrazolium, the subsequent hydrolysis) to provide a carboxylic acid target analog (xi) or (vb) or a salt thereof, or a tetrazolium target analog (iii-b) or a salt thereof, wherein the starting materials indolone (vii), amino ester (iv) and aminotetrazole (ii) are commercially available, known in the chemical literature or prepared by the aforementioned schemes herein, unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 5 (5A) (5B)

[0390] Compound (I) can be prepared according to the method shown in General Scheme 5, by reacting an indolinone (vii) or a salt thereof with a coupling coupler (xii) or a salt thereof such as R″′–X or R 1 –X palladium cross-coupling, where X is a leaving group and R″′ or R 1 It is a C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12Cycloalkyl groups are used to provide alkylated ester products (xiii) or salts thereof, which are then hydrolyzed to carboxylic acid intermediates (xiv) or salts thereof. As used herein, “leaving group” is a term understood in the art as referring to a molecular fragment that leaves with a pair of electrons during heterolytic bond cleavage, wherein the molecular fragment is an anionic or neutral molecule. In some embodiments, X is boric acid or a borate ester. See, for example, Smith, March Advanced Organic Chemistry, 6th edition (501–502). Exemplary leaving groups include, but are not limited to, halogens (e.g., chlorine, bromine, iodine) and sulfonyl-substituted hydroxyl groups (e.g., toluenesulfonyl, methanesulfonyl, benzenesulfonyl). Then, amide coupling with an amino ester (iv) or its salt or aminotetrazole (ii) or its salt (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) provides a target analog, a carboxylic acid target analog (xv) or (vc) or its salt, and a tetrazolium target analog (iii-c) or its salt, wherein the starting material bromoindololinone (vii), the coupling coupler (xii), the amino ester (iv), and the aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the aforementioned schemes herein, unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 6 (6A) (6B)

[0391] Compound of formula (I), wherein R 2 and R 3 The linkage to form a C3 cycloalkyl group can be prepared according to the method shown in General Scheme 6, which involves replacing indolinone (vi) or its salt with an alkyl (e.g., methyl)propynate, wherein PG is C 1-6 Alkyl, C6 aryl or aryl-C 1-6 Alkyl group, wherein the alkyl group and aryl group are optionally halogenated, C-terminated ... 1-6 Alkyl or C 1-6Alkoxy groups are substituted to provide α, β-unsaturated esters (xvi) or salts thereof, followed by cyclopropanation of the alkenyl moiety (e.g., via Corey–Chaykovsky cyclopropanation) to provide a cyclopropanated intermediate (xvii) or a salt thereof. This is then hydrolyzed to a carboxylic acid intermediate (xviii) or a salt thereof, followed by amide coupling with an amino ester (iv) or a salt thereof or an aminotetrazole (ii) or a salt thereof (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) to provide the target analogue, wherein the indolinone (vi), amino ester (iv), and aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the methods described above, unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 7 (7A) (7B)

[0392] Compound of formula (I), wherein R 6 ′ is –OH and R 1 For –Br or –Cl, it can be prepared according to the method shown in General Scheme 7, which involves iodination of indolinone (xx) or a salt thereof, followed by alkylation to provide (xxii) or a salt thereof. This is then oxidized to phenol (xxiii) or a salt thereof, followed by hydrolysis to a carboxylic acid intermediate (xxiv) or a salt thereof, and amide coupling (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium), providing a carboxylic acid target analog (xxv) or (ve) or a salt thereof, and a tetrazolium target analog (iii-e) or a salt thereof, wherein the indolinone (xx), amino ester (iv), and aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the aforementioned scheme herein, and X and R 1 The substituted form is chlorinated or brominated unless otherwise specified, and the dashed line corresponds to an optional spirofused cycloalkyl group. General Solution 8 (8A) (8B)

[0393] Compound of formula (I), wherein R 6 ′ is –F and R 1 For –Br or –Cl, it can be prepared according to the method shown in General Scheme 8, which involves alkylation of indolinone (xxvi) or its salt to provide (xxvii) or its salt, followed by halogenation (e.g., bromination or chlorination), where X or R 1For –Br or –Cl), a halogenated intermediate (xxviii) or a salt thereof is provided. N-alkylation provides an ester (xxix) or a salt thereof, followed by hydrolysis to give a carboxylic acid intermediate (xxx) or a salt thereof, then amide coupling (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) to provide a carboxylic acid target analog (xxxi) or (vf) or a salt thereof, and a tetrazolium target analog (iii-f) or a salt thereof, wherein the indolinone (xxvi), amino ester (iv), and aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the aforementioned schemes herein, unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 9 (9A) (9B)

[0394] Compound of formula (I), wherein R 1 For –Br and R 6 ′ is a C1–C6 alkoxy group (e.g., –OR) 6a , where R 6a The alkyl group (C1–C6 alkyl) can be prepared according to the method shown in General Scheme 9, which involves alkylation of a hydroxyindolinone carboxylic acid (xxiv) or a salt thereof, followed by ester hydrolysis to provide a carboxylic acid intermediate (xxxiii) or a salt thereof. Amide coupling (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) then provides the target carboxylic acid analog (xxxiv) and (vg) or a salt thereof, and the target tetrazolium analog (iii-g) or a salt thereof, wherein the indolinone (xxiv), amino ester (iv), and aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the aforementioned schemes unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 10 (10A) (10B)

[0395] Compound of formula (I), wherein R 1 For –I or –Br and R 6 The ' is –OH, and can be prepared according to the method shown in General Scheme 10, which provides an ester intermediate (xxxv) or a salt thereof by amide coupling of (xxiv) or its salt, wherein PG is a protecting group, such as C 1-6Alkyl, C6 aryl or aryl-C 1-6 Alkyl group, wherein the alkyl group and aryl group are optionally halogenated, C-terminated ... 1-6 Alkyl or C 1-6 The alkoxy group is substituted, followed by copper-mediated halogen transfer (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) to provide a carboxylic acid target analog (xxxvii) or (vh) or a salt thereof, and a tetrazolium target analog (iii-ha) and (iii-hb) or a salt thereof, wherein the indolinone (xxiv), amino ester (iv), and aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the aforementioned schemes, unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 11 (11A) (11B)

[0396] Compound of formula (I), wherein R 6 The ' is –OH, which can be prepared according to the method shown in General Scheme 11, by esterification of a carboxylic acid (xxiv) or its salt to provide an ester intermediate (xxxviii) or its salt, followed by coupling with a coupling partner (xii) or its salt such as R″′–X or R 1 –X undergoes palladium coupling, where X is a leaving group and R″′ or R 1 It is a C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 Cycloalkyl groups, which may optionally be substituted as described herein, provide alkylated ester products (xxxix) or salts thereof. Hydrolysis and amide coupling (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) then provide a carboxylic acid target analog (xli) or (vi) or a salt thereof, and a tetrazolium target analog (iii-i) or a salt thereof, wherein the indolinone (xxiv), amino ester (iv), and aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the aforementioned schemes unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. General Solution 12 (12A) (12B)

[0397] Compound of formula (I), wherein R 6C1–C6 alkoxy groups (e.g., –OR) 6b , where R 6b (C1–C6 alkyl) and R 1 The –Br group can be prepared according to the method shown in General Scheme 12, which involves alkylation of (xlii) or its salt to provide a dialkylated product (xliii) or its salt, followed by bromination to provide a brominated intermediate (xliv) or its salt, and N-alkylation to provide an ester intermediate (xlv) or its salt. Hydrolysis and amide coupling (and subsequent hydrolysis when the target is a carboxylic acid rather than a tetrazolium) then provide a carboxylic acid target analog (xlvii) or (vh) or its salt, and a tetrazolium target analog (iii-i) or its salt, wherein the indolinone (xlii), amino ester (iv), and aminotetrazole (ii) are commercially available, known in the chemical literature, or prepared by the aforementioned schemes unless otherwise stated, and the dashed lines correspond to optional spirofused cycloalkyl groups. (3) Bioassay

[0398] Once compounds designed, selected, and / or optimized using the methods described above are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compound possesses biological activity. For example, molecules can be characterized by routine assays, including but not limited to those described below, to determine whether they possess predicted activity, binding activity, and / or binding specificity. The effectiveness of the compounds disclosed herein can be determined based on industry-accepted assays / disease models, according to standard practices as elucidated in the art and found in present general knowledge.

[0399] Furthermore, high-throughput screening can be used to accelerate analyses using such assays. As a result, molecules described herein can be rapidly screened for activity using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays can employ one or more different assay techniques, including, but not limited to, those described below.

[0400] Various in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility change assays, reporter gene assays, binding assays, cell assays (cell lines, primary cells, and whole blood), in vitro cell viability assays, and assays for determining NLRP3 potency, unbound clearance, solubility, and permeability.

[0401] In some embodiments, the human-NLRP3 inhibitory activity of the compounds disclosed herein can be tested using known procedures, such as those reported in Coll et al. Nat Med. (2015) 21(3):248–255. See also the Bioassays section of the Examples.

[0402] In some embodiments, the unbound clearance (Clu) of the disclosed compounds can be tested according to known procedures, such as those described in Miller et al., J. Med. Chem. (2020) 63:12156-12170. For example, the 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.

[0403] In some embodiments, the solubility of the compounds disclosed herein can be determined according to 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, kinetic solubility in physiologically relevant media can be measured using serial dilutions and a two-hour incubation period, followed by filtration, and reported in mM by LC-MS / MS. Thermodynamic solubility in physiologically relevant media can be measured by LC-MS / MS after a twenty-four-hour incubation period, followed by filtration, and reported in mg / mL. (4) Pharmaceutical Composition

[0404] In some aspects, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, as an active ingredient, and one or more pharmaceutically acceptable diluents, carriers, or excipients. In some embodiments, this disclosure provides pharmaceutical compositions comprising a compound of formula (I) selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more pharmaceutically acceptable diluents, carriers, or excipients. In some embodiments, this disclosure provides pharmaceutical compositions comprising a compound of formula (I) selected from Table 1, or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more pharmaceutically acceptable diluents, carriers, or excipients. In some embodiments, this disclosure provides pharmaceutical compositions comprising a compound selected from the formula (I) of Table 2, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more pharmaceutically acceptable diluents, carriers, or excipients.

[0405] The pharmaceutical composition can be administered orally, nasally, transdermally, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the pharmaceutical composition is administered orally.

[0406] For example, compounds of formula (I) can be formulated for oral use, such as as tablets, pills, hard capsules or soft capsules (each including sustained-release or timed-release formulations), lozenges, suspensions (e.g., aqueous or oily suspensions), emulsions, powders (e.g., dispersible powders), granules, syrups, elixirs and tinctures; for topical use (e.g. as creams, ointments, gels or aqueous or oily solutions or suspensions); for inhalation (e.g. as finely dispersed powders or liquid aerosols); for inhalation (e.g. as finely dispersed powders) or for parenteral administration (e.g. as sterile aqueous or oily solutions for intravenous (push or infusion), subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration); or for transdermal (e.g., patches), all in forms well known to those skilled in the art of pharmaceuticals.

[0407] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); mucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and via, for example, subcutaneous or intramuscular implantation of a reservoir or depository.

[0408] The formulation may be in the form of an aqueous solution containing an aqueous medium. The aqueous medium component may contain water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include solubility enhancers, chelating agents, preservatives, tensile agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0409] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as those selected from the group consisting of: hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, atactic methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched-chain β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, atactic methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0410] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and its metal salts, disodium EDTA, trisodium EDTA, and tetrasodium EDTA, and mixtures thereof.

[0411] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of: quaternary ammonium salts such as benzyl halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, hexadecylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben, and mixtures thereof.

[0412] Aqueous mediators may also include tensioning agents to adjust tension (osmotic pressure). Tensioning agents may be selected from glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextran, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0413] Aqueous media may also contain viscosity / suspending agents. Suitable viscosity / suspending agents include those selected from the group consisting of: cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose, and crosslinked acrylic polymers (carbomer), such as polymers crosslinked with acrylic acid and polyolefin ethers or divinyl glycol (carbopol, such as carbopol 934, carbopol 934P, carbopol 971, carbopol 974 and carbopol 974P), and mixtures thereof.

[0414] To adjust the formulation to an acceptable pH (typically from about 5.0 to about 9.0, more preferably from about 5.5 to about 8.5, particularly from about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically an inorganic acid or a metal hydroxide base, selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base—depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0415] Aqueous media may also contain buffers to stabilize pH. When used, buffers are selected from phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0416] The formulation may also contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of: polyoxypropylene-polyoxyethylene block copolymers (poloxamer), polyethoxylated ethers of castor oil, polyoxyethylene-modified sorbitan esters (polysorbate), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyethylene 40 stearate, ethylene glycol esters of fatty acids, glycerol esters of fatty acids, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0417] Oral compositions typically contain an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be combined with excipients and administered in tablet, lozenge, or capsule form. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0418] Compositions intended for oral use may further contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0419] A compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising thereof, may be administered alone as a monotherapy or in combination with one or more other substances and / or treatments. Such combination therapy may be achieved by administering individual components of the treatment simultaneously, sequentially, or separately.

[0420] For example, the effectiveness of treatment can be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual can be increased by administering a compound of formula (I) together with another therapeutic agent (which also includes the treatment regimen) that also has therapeutic benefits.

[0421] When a compound of formula (I) is administered in combination with other therapeutic agents, the compound does not necessarily have to be administered via the same route as the other therapeutic agents, but can be administered via different routes due to different physical and chemical properties. For example, the compound of formula (I) can be administered orally to produce and maintain its good blood levels, while the other therapeutic agent can be administered intravenously.

[0422] The specific choice of other therapeutic agents will depend on the attending physician's diagnosis and their judgment of the individual's condition and appropriate treatment plan. According to this aspect of the disclosure, a combination for treating a disease or symptom is provided, comprising a compound of formula (I) and additional therapeutic agents.

[0423] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of formula (I) in combination with another therapeutic agent, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and pharmaceutical excipients. (5) Use and treatment methods

[0424] Compounds of formula (I) have been found to be useful as inhibitors of NLRP3 activity.

[0425] In some embodiments, the compound of formula (I) modulates NLRP3. In some embodiments, the modulation is inhibition.

[0426] In some aspects, methods are provided for treating a disease or condition in a subject in need, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising thereto. In some embodiments, the disease or condition is associated with aberrant NLRP3 activity, and the method comprises inhibiting aberrant NLRP3 activity to treat the subject.

[0427] In some respects, methods are provided for treating a disease or condition in a subject in need, including administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising thereof.

[0428] In some respects, methods are provided for the therapeutic treatment of the diseases or conditions disclosed herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising thereof.

[0429] In some respects, methods are provided for treating the diseases or conditions disclosed herein in a subject in need, including administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug or polymorph thereof, or a pharmaceutical composition comprising thereof.

[0430] In some respects, methods are provided for the preventive treatment of the diseases or conditions disclosed herein in subjects in need, comprising administering to the subject a preventively effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug or polymorph thereof, or a pharmaceutical composition comprising thereof.

[0431] In some respects, methods are provided for the preventive treatment of the diseases or conditions disclosed herein in subjects in need, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug or polymorph thereof, or a pharmaceutical composition comprising thereof.

[0432] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for regulating NLRP3.

[0433] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for treating the diseases or conditions disclosed herein.

[0434] In some respects, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for inhibiting NLRP3 activity.

[0435] In some respects, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating the diseases or conditions disclosed herein.

[0436] In some implementations, the disease or condition is a disease or condition related to NLRP3 activity.

[0437] In some implementations, the disease or condition is a disease or condition of the central nervous system (CNS), a disease or condition of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory condition, an autoimmune disease, cancer, an infection, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a mental illness, graft-versus-host disease, pain (including conditions related to pain management, such as abnormal pain), or an NLRP3-related disease in a subject who has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0438] In some implementations, the disease or condition is a disease or condition of the central nervous system and / or peripheral nervous system (“PNS”), such as dementia, Alzheimer’s disease (“AD”), epilepsy, traumatic brain injury (“TBI”), multiple sclerosis (“MS”), developmental disorder, acute disseminated encephalopathy, transverse myelitis, Parkinson’s disease (“PD”), amyotrophic lateral sclerosis (“ALS”), Huntington’s disease (“HD”), or spinal cord injury.

[0439] In some implementations, the disease or condition is a primary neurological disorder of the muscles, such as malnutrition or spinal muscular atrophy.

[0440] In some implementations, the disease or condition is an inflammatory condition, such as gout or inflammatory anemia.

[0441] In some implementations, the disease or condition is an autoimmune disease, such as ulcerative colitis.

[0442] In some implementations, the disease or condition is cancer, such as skin cancer or colon cancer.

[0443] In some implementations, the disease or condition is an infection, such as a nerve infection.

[0444] In some implementations, the disease or condition is a metabolic disease, such as diabetes, for example, type 2 diabetes.

[0445] In some implementations, the disease or condition is a cardiovascular disease, such as stroke.

[0446] In some implementations, the disease or condition is a respiratory disease, such as asthma (e.g., antisteroid asthma, severe antisteroid asthma) or chronic obstructive pulmonary disease (“COPD”).

[0447] In some implementations, the disease or condition is a kidney disease, such as acute kidney disease, chronic kidney disease, or rare kidney disease.

[0448] In some implementations, the disease or condition is a liver disease, such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0449] In some implementations, the disease or condition is an eye disease, such as optic neuritis or macular degeneration.

[0450] In some implementations, the disease or condition is a skin disease such as psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0451] In some implementations, the disease or condition is a lymphatic disease.

[0452] In some implementations, the disease or condition is a rheumatic disease, such as osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0453] In some implementations, the disease or condition is a mental illness, such as a neuropsychiatric condition, including depression, major depressive disorder, or treatment-resistant depression.

[0454] In some implementations, the disease or symptom is graft-versus-host disease.

[0455] In some implementations, the disease or condition is pain (including conditions related to pain management), such as pain management addiction, osteoarthritis pain, or abnormal pain.

[0456] In some embodiments, the NLRP3-related disease in subjects identified as carrying germline or somatic non-silent mutations in NLRP3 is cryopyrin-associated autoinflammatory syndrome. In some embodiments, this cryopyrin-associated autoinflammatory syndrome is familial cold-cause autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal episodic multisystem inflammatory disease (NOMID).

[0457] In some implementations, the disease or condition is dementia, Alzheimer's disease (“AD”), epilepsy, traumatic brain injury (“TBI”), multiple sclerosis (“MS”), developmental disorder, acute disseminated encephalopathy, transverse myelitis, Parkinson's disease (“PD”), amyotrophic lateral sclerosis (“ALS”), spinal muscular atrophy, Huntington's disease (“HD”), spinal cord injury, malnutrition, neuroinfection, pain management addiction, neuropsychiatric conditions (e.g., depression, major depressive disorder, or treatment-resistant depression), neonatal paroxysmal multisystem inflammatory disease (“NOMID”), asthma, osteoarthritis, ulcerative colitis, gout, inflammatory anemia, Still's disease, chronic obstructive pulmonary disease (“COPD”), osteoarthritis pain, or hidradenitis suppurativa.

[0458] In other respects, methods for inhibiting NLRP3 activity in cells (e.g., in vitro or in vivo) are provided, comprising exposing the cells to an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. (6) Alternative implementation plans

[0459] This paper further considers implementation scheme 1-36.

[0460] Implementation Scheme 1: Compound of Formula (I): Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein: R 1 It is a halogenated, nitrile-, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 cycloalkyl; Each R 2 and R 3Independently H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, cyano, hydroxy, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups. R 4 It is a C1–C6 alkyl group, –(CH2) p –(C3–C 12 cycloalkyl), –(CH2) p –(3 to 12-membered heterocyclic groups), C6–C 10 Aryl or –(CH2) p –(5 to 10-membered heteroaryl), wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more halo, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups. Z stands for –(CH2). n –(carboxylic acid) or –(CH2) n -Tetraazole; Each R 5 Independently, it is a C1–C6 alkyl group, wherein the alkyl group is optionally substituted with one or more halogenated, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or Two Rs 5 Cyclization with the atoms to which they are attached forms a C3–C group optionally substituted with one or more halogenated, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6It can be H, halogen, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6’ It can be H, halogen, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6” It can be H, halogen, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 7 Independently H or C1–C4 alkyl; n is an integer between 0 and 3; and p is an integer between 0 and 2.

[0461] Implementation Scheme 2: The compound of Implementation Scheme 1, wherein: R 1 It is a brominated, chlorinated, nitrile, C1–C6 alkyl, C1–C6 haloalkyl or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C1–C6 haloalkyl, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 Cycloning together to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, cyano, hydroxy, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups. R 4 It is n-propyl, –(CH2) p –(C3–C 12 cycloalkyl), –(CH2) p –(3 to 12-membered heterocyclic groups), C6–C 10 Aryl or –(CH2) p–(5 to 10-membered heteroaryl), wherein the n-propyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more halo, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy. Z stands for –(CH2). n –(carboxylic acid) or –(CH2) n -Tetraazole; Each R 5 C1–C6 alkyl groups optionally substituted with one or more halogenated, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or Two Rs 5 Cyclization with the atoms to which they are attached forms a C3–C group optionally substituted with one or more halogenated, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6 It can be H, halogen, –OH, C1–C6 alkyl or C1–C6 alkoxy; R 6’ It can be H, halogen, –OH, C1–C6 alkyl or C1–C6 alkoxy; R 6” It can be H, halogen, –OH, C1–C6 alkyl or C1–C6 alkoxy; R 7 Independently H or C1–C4 alkyl; n is an integer between 0 and 3; and p is an integer between 0 and 2.

[0462] Implementation Scheme 3: The compound of any one of Implementation Schemes 1-2 above, wherein R 1 It can be brominated, chlorinated, or nitrile-substituted.

[0463] Implementation Scheme 4: The compound of any one of Implementation Schemes 1-3 above, wherein R 1 It is a C1–C6 alkyl or a C1–C6 haloalkyl.

[0464] Implementation Scheme 5: The compound of any one of Implementation Schemes 1-4 above, wherein R 1 For C3–C 12 Cycloalkyl.

[0465] Implementation Scheme 6: The compound of any one of Implementation Schemes 1-5 above, wherein each R 2 and R 3Independently H, C1–C6 alkyl, C1–C6 haloalkyl, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 Aryl or 5- to 10-membered heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more halo, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy.

[0466] Implementation Scheme 7: The compound of any one of Implementation Schemes 1-6 above, wherein R 2 and R 3 Cycloning together to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halogenated, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups.

[0467] Implementation Scheme 8: The compound of any one of Implementation Schemes 1-7 above, wherein R 4 It is n-propyl.

[0468] Implementation Scheme 9: The compound of any one of Implementation Schemes 1-8 above, wherein Z is a carboxylic acid.

[0469] Implementation Scheme 10: The compound of any one of Implementation Schemes 1-9 above, wherein Z is a tetrazolium.

[0470] Implementation Scheme 11: The compound of any one of Implementation Schemes 1-10 above, wherein R 5 C1–C6 alkyl groups optionally substituted with one or more of the following: halogen, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy.

[0471] Implementation Scheme 12: A compound of any one of Implementation Schemes 1-11 above, wherein two R 5 Cyclization with the atoms to which they are attached forms a C3–C group optionally substituted with one or more halogenated, cyano, hydroxyl, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 Cycloalkyl.

[0472] Implementation Scheme 13: The compound of any one of Implementation Schemes 1-12 above, wherein R 6 For H.

[0473] Implementation Scheme 14: The compound of any one of Implementation Schemes 1-13 above, wherein R6 It can be a halogen, –OH, C1–C6 alkyl, or C1–C6 alkoxy.

[0474] Implementation Scheme 15: The compound of any one of Implementation Schemes 1-14 above, wherein R 6’ For H.

[0475] Implementation Scheme 16: The compound of any one of Implementation Schemes 1-15 above, wherein R 6’ It can be a halogen, –OH, C1–C6 alkyl, or C1–C6 alkoxy.

[0476] Implementation Scheme 17: The compound of any one of Implementation Schemes 1-16 above, wherein R 6” For H.

[0477] Implementation Scheme 18: The compound of any one of Implementation Schemes 1-17 above, wherein R 6” It can be a halogen, –OH, C1–C6 alkyl, or C1–C6 alkoxy.

[0478] Implementation Scheme 19: The compound of any one of Implementation Schemes 1-18 above, wherein R 7 For H.

[0479] Implementation Scheme 20: The compound of any one of the aforementioned Implementation Schemes 1-19, wherein the compound is selected from the compounds described in Table 1.

[0480] Implementation Scheme 21: The compound of Implementation Scheme 20, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0481] Implementation Scheme 22: The compound of Implementation Scheme 20, or a pharmaceutically acceptable salt thereof.

[0482] Implementation Scheme 23: Isotope derivatives of any of the compounds in Implementation Schemes 1-22 above.

[0483] Implementation Scheme 24: A pharmaceutical composition comprising a compound of any one of Implementation Schemes 1-23 above and one or more pharmaceutically acceptable carriers.

[0484] Implementation Plan 25: A method for treating or preventing NLRP3-related diseases or conditions, comprising administering to a subject a compound of any one of the aforementioned Implementation Plans 1-23.

[0485] Implementation Scheme 26: A method for inhibiting NLRP3, comprising administering to a subject a compound of any one of the aforementioned Implementation Schemes 1-23.

[0486] Implementation Scheme 27: The method of Implementation Scheme 25 or Implementation Scheme 26, wherein the subject is a human being.

[0487] Implementation Scheme 28: The method of any one of Implementation Schemes 25-27, wherein the NLRP3-related disease or condition is inflammation, autoimmune disease, cancer, infection, disease or condition of the central nervous system, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, mental illness, graft-versus-host disease, abnormal pain, or NLRP3-related disease in a subject who has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0488] Implementation Scheme 29: The method of any one of Implementation Schemes 25-27, wherein the disease or condition of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0489] Implementation Scheme 30: The method of any one of Implementation Schemes 25-27, wherein the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

[0490] Implementation Scheme 31: The method of any one of Implementation Schemes 25-27, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0491] Implementation Scheme 32: The method of any one of Implementation Schemes 25-27, wherein the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0492] Implementation Scheme 33: The method of any one of Implementation Schemes 25-27, wherein the NLRP3-related disease in a subject who has been identified as carrying a germline or somatic non-silent mutation in NLRP3 is cryptothermal protein-associated autoinflammatory syndrome.

[0493] Implementation Scheme 34: The method of any one of Implementation Schemes 25-27, wherein the cryptothermal protein-associated autoinflammatory syndrome is familial cold-cause autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal episodic multisystem inflammatory disease.

[0494] Implementation Scheme 35: The compound of any one of the aforementioned Implementation Schemes 1-34, used for the treatment or prevention of NLRP3-related diseases or conditions.

[0495] Implementation Scheme 36: Use of any compound of any of Implementation Schemes 1-34 in the preparation of a medicament for the treatment or prevention of NLRP3-related diseases or conditions.

[0496] This document further considers implementation schemes A1-A76.

[0497] Implementation scheme A1: Compound of formula (I): Or its pharmaceutically acceptable salt, wherein: R 1 It is halogenated, –CN, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 cycloalkyl; Each R 2 and R 3 Independently H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, C3–C 12 Cycloalkyl, 3 to 12-membered heterocyclic groups, C6–C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or R 2 and R 3 They cyclize together with the atoms they are attached to to form C3–C 12 Cycloalkyl or 3 to 12-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy groups; R 4 It is a –C1–C6 alkyl–, –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10 heteroaryl)–, where each instance of L1 is independently –(C(R L1 )2)–, further where R L1 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L1 Groups together with the atoms they are attached to form C 3-4 Cycloalkyl; and wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl; Z is –(L2) n–(carboxylic acid) or –(L2) n – tetrazolium, where each instance of L2 is independently –(C(R L2 )2)–, further where R L2 Each instance is independently H, halogenated, or C1–C3 alkyl, or two R... L2 Groups together with the atoms they are attached to form C 3-4 Cycloalkyl; and wherein the alkyl or cycloalkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy or C3 cycloalkyl groups; Each R 5 Independently, it is a halogenated or C1–C6 alkyl group, wherein the alkyl group is optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups, or two R groups. 5 Cyclization with the atoms to which they are attached to form C3–C atoms optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy groups. 12 cycloalkyl; R 6 It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6’ It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 6” It can be H, halogenated, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl or C1–C6 alkoxy; R 7 Independently H or C1–C4 alkyl; n is an integer of 0, 1, 2, or 3; and p is an integer of 0, 1, or 2.

[0498] Implementation Scheme A2: The compound of Implementation Scheme A1, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each instance is independently H, C1–C3 alkyl, C1–C3 haloalkyl, or R 2 and R 3 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0499] Implementation Scheme A3: The compound of Implementation Scheme A2, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each instance is H.

[0500] Implementation Scheme A4: The compound of Implementation Scheme A2, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0501] Implementation Scheme A5: A compound of any one of Implementation Schemes A1-A4, or a pharmaceutically acceptable salt thereof, wherein R 4 For –(L1) p –(C3–C 12 Cycloalkyl) – or – (L1) p –(3 to 12-membered heterocyclic group)–, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; p is 0; n is 2; and Z is –(L2). n –(carboxylic acid) or –(L2) n -Tetraazole; making NR 7 The minimum number of atoms in which the amide nitrogen is continuously covalently bonded to the terminal carboxylic acid or tetrazolium group is 3.

[0502] Implementation Scheme A6: The compound of Implementation Scheme A5, or a pharmaceutically acceptable salt thereof, wherein –R 4 –Z is a group of formula (i): Where Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl group or a 4- to 5-membered heterocyclic group; each R 4a It is independently a halogenated, C1–C3 alkyl, C1–C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

[0503] Implementation Scheme A7: The compound of Implementation Scheme A6, or a pharmaceutically acceptable salt thereof, wherein the group of formula (i) is:

[0504] Implementation Scheme A8: The compound of Implementation Scheme A7, or a pharmaceutically acceptable salt thereof, wherein the group of formula (i) is:

[0505] Implementation Scheme A9: A compound of any one of Implementation Schemes A1-A4, or a pharmaceutically acceptable salt thereof, wherein R4 For –(L1) p –(C3–C 12 Cycloalkyl) – or – (L1) p –(3 to 12-membered heterocyclic group)–, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more halo, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; p is 1; n is 1; and Z is –(L2). n –(carboxylic acid) or –(L2) n -Tetraazole; making NR 7 The minimum number of atoms in which the amide nitrogen is continuously covalently bonded to the terminal carboxylic acid or tetrazolium group is 3.

[0506] Implementation Scheme A10: The compound of Implementation Scheme A9, or a pharmaceutically acceptable salt thereof, wherein –R 4 –Z is a group of formula (ii): Where Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl group or a 4- to 5-membered heterocyclic group; each R 4a It is independently a halogenated, C1–C3 alkyl, C1–C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

[0507] Implementation Scheme A11: The compound of Implementation Scheme A10, or a pharmaceutically acceptable salt thereof, wherein R L1 At least one instance is a -C1–C3 alkyl group optionally substituted with one or more halogens.

[0508] Implementation Scheme A12: The compound of Implementation Scheme A10, or a pharmaceutically acceptable salt thereof, wherein R L2 At least one instance is a -C1–C3 alkyl group optionally substituted with one or more halogens.

[0509] Implementation Scheme A13: The compound of Implementation Scheme A10, or a pharmaceutically acceptable salt thereof, wherein R L1 and R L2 Each instance is H.

[0510] Implementation Scheme A14: The compound of Implementation Scheme A10, or a pharmaceutically acceptable salt thereof, wherein the group of formula (ii) is:

[0511] Implementation Scheme A15: The compound of Implementation Scheme A14, or a pharmaceutically acceptable salt thereof, wherein the group of formula (ii-a) is:

[0512] Implementation Scheme A16: A compound of any one of Implementation Schemes A1-A4, or a pharmaceutically acceptable salt thereof, wherein R 4 For –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L2) p –(C6–C 10 Aryl)–or–(L2) p –(5 to 10-membered heteroaryl)–, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more haloalkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; p is 0; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n -Tetraazole; making NR 7 The minimum number of atoms in which the amide nitrogen is continuously covalently bonded to the terminal carboxylic acid or tetrazolium group is 3.

[0513] Implementation Scheme A17: The compound of Implementation Scheme A16, or a pharmaceutically acceptable salt thereof, wherein -R 4 –Z is a group of formula (iii): Where Z' is a tetrazolium or carboxylic acid; ring A is a C3–C5 cycloalkyl group or a 4- to 5-membered heterocyclic group; each R 4a It is independently a halogenated, C1–C3 alkyl, C1–C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

[0514] Implementation Scheme A18: The compound of Implementation Scheme A17, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iii) is:

[0515] Implementation Scheme A19: The compound of Implementation Scheme A18, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iii-a) is:

[0516] Implementation Scheme A20: A compound of any one of Implementation Schemes A1-A4, or a pharmaceutically acceptable salt thereof, wherein R 4–(n-propyl)–, optionally substituted with one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n – Tetraazole.

[0517] Implementation Scheme A21: The compound of Implementation Scheme A20, or a pharmaceutically acceptable salt thereof, wherein –R 4 –Z is a group of formula (iv): Where Z' is a tetrazolium or a carboxylic acid; each R 4a It is independently a halogenated, C1–C3 alkyl, C1–C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

[0518] Implementation Scheme A22: The compound of Implementation Scheme A21, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iv) is:

[0519] Implementation Scheme A23: The compound of Implementation Scheme A21, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iv) is:

[0520] Implementation Scheme A24: A compound of any one of Implementation Schemes A21-A23, or a pharmaceutically acceptable salt thereof, wherein R 4a Each instance is independently –CH3, -CF3, C3 cycloalkyl, or fluorinated.

[0521] Implementation Scheme A25: The compound of Implementation Scheme A21, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iv) is:

[0522] Implementation Scheme A26: A compound of any one of Implementation Schemes A1-A4, or a pharmaceutically acceptable salt thereof, wherein p is 1; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n – tetrazolium; and R 4 For –(L1) p –(C6–C 10 Aryl) – or – (L1) p–(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; such that NR 7 The minimum number of atoms in which the amide nitrogen is continuously covalently bonded to the terminal carboxylic acid or tetrazolium group is 3.

[0523] Implementation Scheme A27: The compound of Implementation Scheme A26, or a pharmaceutically acceptable salt thereof, wherein –R 4 –Z is a group in the following formula: Where Z' is a tetrazolium or a carboxylic acid; each R 4a It is independently a halogenated, C1–C3 alkyl, or C1–C3 haloalkyl; and x is 0, 1, 2, or 3.

[0524] Implementation Scheme A28: A compound of any one of Implementation Schemes A1-A4, or a pharmaceutically acceptable salt thereof, wherein p is 0; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n – tetrazolium; and R 4 For –(L1) p –(C3–C 12 cycloalkyl)–, –(L1) p –(3 to 12-membered heterocyclic groups)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10-membered heteroaryl), wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more haloalkyl, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; such that NR 7 The minimum number of atoms in which the amide nitrogen is continuously covalently bonded to the terminal carboxylic acid or tetrazolium group is two continuously covalently bonded atoms.

[0525] Implementation Scheme A29: The compound of Implementation Scheme A28, or a pharmaceutically acceptable salt thereof, wherein –R 4 –Z is a group in the following formula: Where Z' is a tetrazolium or a carboxylic acid; each R 4a It is independently a halogenated, C1–C3 alkyl, or C1–C3 haloalkyl; and x is 0, 1, 2, or 3.

[0526] Implementation Scheme A30: The compound of Implementation Scheme A28, or a pharmaceutically acceptable salt thereof, wherein –R 4 –Z groups have the following formula:

[0527] Implementation Scheme A31: A compound of any one of Implementation Schemes A1-A4, or a pharmaceutically acceptable salt thereof, wherein p is 0; n is 0; and Z is –(L2). n –(carboxylic acid) or –(L2) n – tetrazolium; and R 4 For –(L1) p –(C6–C 10 Aryl) – or – (L1) p –(5 to 10-membered heteroaryl)–, wherein the aryl or heteroaryl group is optionally substituted by one or more halogenated, –CN, –OH, amino, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3 cycloalkyl groups; such that NR 7 The minimum number of atoms in which the amide nitrogen is continuously covalently bonded to the terminal carboxylic acid or tetrazolium group is 4.

[0528] Implementation Scheme A32: The compound of Implementation Scheme A31, or a pharmaceutically acceptable salt thereof, wherein –R 4 –Z represents the gene in the following formula: Where Z' is a tetrazolium or a carboxylic acid; and each R 4a It is independently a halogenated, C1–C3 alkyl, or C1–C3 haloalkyl, and x is 0, 1, 2, or 3.

[0529] Implementation Scheme A33: A compound of any one of Implementation Schemes A1-A32, or a pharmaceutically acceptable salt thereof, wherein R 5 Each instance is selected from fluorinated and C1–C6 alkyl groups, or two R groups. 5 They cyclize together with the atoms they are attached to to form C3 cycloalkyl groups.

[0530] Implementation Scheme A34: The compound of Implementation Scheme A33, or a pharmaceutically acceptable salt thereof, wherein R 5 Each instance is identical and is selected from fluorinated and C1–C6 alkyl groups.

[0531] Implementation Scheme A35: The compound of Implementation Scheme A34, or a pharmaceutically acceptable salt thereof, wherein R 5 Each instance is fluorinated or -CH3.

[0532] Implementation Scheme A36: A compound of any one of Implementation Schemes A1-A35, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a halogenated, C1–C3 alkyl, C1–C3 haloalkyl or C3–C5 cycloalkyl.

[0533] Implementation Scheme A37: A compound of any one of Implementation Schemes A1-A36, or a pharmaceutically acceptable salt thereof, wherein R 6 It can be H, halogenated, or –OH.

[0534] Implementation Scheme A38: A compound of any one of Implementation Schemes A1-A37, or a pharmaceutically acceptable salt thereof, wherein R 6’ It can be H, halogenated, –OH, C1–C3 alkyl, C1–C3 haloalkyl or C1–C3 alkoxy.

[0535] Implementation Scheme A39: A compound of any one of Implementation Schemes A1-A38, or a pharmaceutically acceptable salt thereof, wherein R 6” It is H or halogenated.

[0536] Implementation Scheme A40: A compound of any one of Implementation Schemes A1-A39, or a pharmaceutically acceptable salt thereof, wherein the 6,5-bicyclic core of formula (viii) is: Where R 6 R 6’ and R 6” At least one of them is not H.

[0537] Implementation Scheme A41: A compound of any one of Implementation Schemes A1-A40, or a pharmaceutically acceptable salt thereof, wherein the 6,5-bicyclic core has the following formula:

[0538] Implementation Scheme A42: A compound of any one of Implementation Schemes A1-A40, wherein compound (I) has the following formula: Or its pharmaceutically acceptable salt, wherein: Z' is either a tetrazolium or a carboxylic acid; Ring A is a C3–C5 cycloalkyl group or a 4 to 5-membered heterocyclic group; Each R 4a Independently, it is halogenated, C1–C3 alkyl, C1–C3 haloalkyl, or C3 cycloalkyl; and x is 0, 1, 2 or 3.

[0539] Implementation Scheme A43: A compound of any one of Implementation Schemes A1-A40, wherein compound (I) has the following formula: Or a pharmaceutically acceptable salt thereof, wherein R 6 R 6’ and R 6” At least one of them is not H.

[0540] Implementation Scheme A44: The compound of Implementation Scheme A1, which is selected from any compound in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0541] Implementation Scheme A45: A pharmaceutical composition comprising a compound of any one of Implementation Schemes A1-A44, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0542] Implementation scheme A46: A method for treating a disease or condition of a subject in need, comprising administering to the subject a compound of any one of implementation schemes A1-A44, or a pharmaceutically acceptable salt thereof.

[0543] Implementation scheme A47: The method of implementation scheme A46, wherein the disease or condition is an NLRP3-related disease or condition.

[0544] Implementation scheme A48: The method of implementation scheme A46 or A47, wherein the subject is a human being.

[0545] Implementation scheme A49: The method of any one of implementation schemes A46-A48, wherein the disease or condition is a disease or condition of the central nervous system (CNS), a disease or condition of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory condition, an autoimmune disease, cancer, an infection, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a mental illness, graft-versus-host disease, pain (including conditions related to pain management), or an NLRP3-related disease in a subject who has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0546] Implementation Scheme A50: The method of Implementation Scheme A49, wherein the disease or condition of the central nervous system is dementia, Alzheimer's disease (“AD”), epilepsy, traumatic brain injury (“TBI”), multiple sclerosis (“MS”), developmental disorder, acute disseminated encephalopathy, transverse myelitis, Parkinson's disease (“PD”), amyotrophic lateral sclerosis (“ALS”), Huntington's disease (“HD”), or spinal cord injury.

[0547] Implementation scheme A51: The method of implementation scheme A49, wherein the primary neurological disease of the muscle is malnutrition or spinal muscular atrophy.

[0548] Implementation scheme A52: The method of implementation scheme A49, wherein the inflammatory condition is gout or inflammatory anemia.

[0549] Implementation scheme A53: The method of implementation scheme A49, wherein the autoimmune disease is ulcerative colitis.

[0550] Implementation scheme A54: The method of implementation scheme A49, wherein the cancer is skin cancer or colon cancer.

[0551] Implementation scheme A55: The method of implementation scheme A49, wherein the infection is a nerve infection.

[0552] Implementation scheme A56: The method of implementation scheme A49, wherein the metabolic disease is diabetes.

[0553] Implementation scheme A57: The method of implementation scheme A49, wherein the cardiovascular disease is stroke.

[0554] Implementation scheme A58: The method of implementation scheme A49, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.

[0555] Implementation scheme A59: The method of implementation scheme A49, wherein the kidney disease is acute kidney disease, chronic kidney disease or rare kidney disease.

[0556] Implementation scheme A60: The method of implementation scheme A49, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0557] Implementation scheme A61: The method of implementation scheme A49, wherein the eye disease is optic neuritis or macular degeneration.

[0558] Implementation scheme A62: The method of implementation scheme A49, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS) or atopic dermatitis.

[0559] Implementation scheme A63: The method of implementation scheme A49, wherein the rheumatic disease is osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0560] Implementation scheme A64: The method of implementation scheme A49, wherein the mental illness is a neuropsychiatric condition selected from depression, major depressive disorder and treatment-resistant depression.

[0561] Implementation scheme A65: The method of implementation scheme A49, wherein the pain is pain management addiction, osteoarthritis pain, or abnormal pain.

[0562] Implementation scheme A66: The method of implementation scheme A49, wherein the NLRP3-related disease in a subject who has been identified as carrying a germline or somatic non-silent mutation in NLRP3 is cryptothermal protein-associated autoinflammatory syndrome.

[0563] Implementation Plan A67: The method of Implementation Plan A49, wherein the disease or condition is dementia, Alzheimer's disease (“AD”), epilepsy, traumatic brain injury (“TBI”), multiple sclerosis (“MS”), developmental disorder, acute disseminated encephalopathy, transverse myelitis, Parkinson's disease (“PD”), amyotrophic lateral sclerosis (“ALS”), spinal muscular atrophy, Huntington's disease (“HD”), spinal cord injury, malnutrition, neurological infection, pain management addiction, neuropsychiatric condition, neonatal paroxysmal multisystem inflammatory disease (“NOMID”), asthma, osteoarthritis, ulcerative colitis, gout, inflammatory anemia, Still's disease, chronic obstructive pulmonary disease (“COPD”), osteoarthritis pain, or hidradenitis suppurativa.

[0564] Implementation Scheme A68: A method for inhibiting NLRP3 activity in cells, comprising exposing the cells to an effective amount of a compound of any one of Implementation Schemes A1-A44, or a pharmaceutically acceptable salt thereof.

[0565] Implementation scheme A69: The method of implementation scheme A68, wherein the method is an in vitro method.

[0566] Implementation Scheme A70: A method for preparing a compound of formula (I), wherein Z is –(L2). n – Tetrazol, the method comprising substituted indololinone (acetic acid) (i): or its salt; With aminotetrazole (ii): Or its salt coupling, To provide tetrazolium analogues: Or its salt.

[0567] Implementation Scheme A71: A method for preparing compound of formula (I), wherein Z is –(L2). n –Carboxylic acid, the method includes the use of compounds of formula (vo): Or its salt for deprotection. Where PG is C 1-6 Alkyl, C6 aryl or aryl-C 1-6 Alkyl groups, wherein the alkyl and aryl groups are optionally halogenated, C-terminated, or C-terminated. 1-6 Alkyl or C 1-6Alkyl groups are substituted.

[0568] Implementation Scheme A72: The method of Implementation Scheme A71, wherein the compound of formula (vo) or a salt thereof is prepared as follows: substituted indolineone (acetic acid) (i): or its salt; With amino esters (iv): Or its salt coupling, To provide carboxylic acid analogs (va): Or its salt.

[0569] Implementation scheme A73: Compound of formula (vo): or its salt, Where n and R 1 R 2 R 3 R 4 L2, R 5 R 6 R 6’ R 6” and R 7 As defined in implementation scheme A1, and PG is C 1-6 Alkyl, C6 aryl or aryl-C 1-6 Alkyl group, wherein the alkyl group and aryl group are optionally halogenated, C-terminated ... 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0570] Implementation scheme A74: The compound of implementation scheme A73, or a salt thereof, wherein PG is methyl, ethyl or tert-butyl.

[0571] Implementation scheme A75: any compound, composition or method of any one of implementation schemes A1-A74, wherein the compound of formula (I) is an isotope derivative or a pharmaceutically acceptable salt thereof.

[0572] Implementation scheme A76: The compound of implementation scheme A73, which is selected from any of the compounds in Table 3 or their salts. Example

[0573] To provide a fuller understanding of this disclosure, the following embodiments are described. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting this disclosure in any way. Analytical methods

[0574] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz and 300.3 K as described, unless otherwise specified; chemical shifts (δ) were reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument, with 8, 6, or 32 scans. Exemplary NMR solvents included deuterated dimethyl sulfoxide (DMSO–d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3). Other abbreviations: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad.

[0575] 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) and positive ion electrospray ionization. The MS range was 100–1000 Da. The solvent was a gradient of water (H₂O) and / or acetonitrile, which may contain modifiers (typically 0.01–0.04%) such as formic acid (FA), trifluoroacetic acid (TFA), or ammonium carbonate (NH₄HCO₃). ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (minutes).

[0576] Gas chromatography-mass spectrometry (GC-MS) chromatograms and spectra were recorded using an Agilent GCMS 8890–5977 and DetectorChannel FID. GC parameters: DB-5MS, 12m x 0.20mm x 0.33um; column oven temperature: 50.0℃; injection volume: 0.5μL; column flow rate: 1.2mL / min; injection temperature: 300℃; injection mode: split; split ratio: 20:1; detector temperature: 300℃; initial temperature: 50℃ for 1 min, then increased to 300℃ at 40℃ / min for 1.75 min. Makeup gases: He; makeup flow rate: 25.0mL / min; H2; flow rate: 30.0mL / min; gas flow rate: 400.0mL / min; final temperature: 300℃. MS detector in acquisition mode: Start time: 2.00 min; End time: 9.00 min; Acquisition mode: Scan; Interface type: EI threshold: 150; Scan speed: 1562; Start m / z: 50.00; End m / z: 550.00; MS source: 230.00℃; MS quadrupole: 150.00℃; Solvent cutting time: 2.00 min.

[0577] Purification / Separation Methods. The Synthetic Methods section describes the purification and / or separation chromatographic methods used in the purification and / or separation of the illustrative compounds. Rf = Retention Factor; RT = Retention Time (minutes); Prep-HPLC = Preparative High Performance Liquid Chromatography; Prep-SFC = Preparative Supercritical Fluid Chromatography; TLC = Thin-Layer Chromatography. Synthesis method Example 1: N-(3-(1H-tetrazol-5-yl)propyl)-2-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 1) and N-(3-(2H-tetrazol-5-yl)propyl)-2-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 2) (Compound 1)

[0578] A solution of 2-(5-bromo-3,3-dimethyl-2-oxo-indoline-1-yl)acetic acid (1 equivalent, 54 mg, 0.181 mmol) and [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.1 equivalent, 72 mg, 0.190 mmol) in N,N-dimethylformamide (DMF) (0.8 mL) was treated with N,N-diisopropylethylamine (DIPEA) (2.2 equivalent, 0.069 mL, 0.398 mmol) and NaOH (5 equivalent, 0.43 mL, 0.906 mmol) and stirred at room temperature for 20 min. The mixture was directly injected into a C18 reversed-phase column and eluted with 0-100% MeCN / H2O to give N-(3-(1H-tetrazol-5-yl)propyl)-2-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 1) and N-(3-(2H-tetrazol-5-yl)propyl)-2-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 2) (compound 1). LCMS (ES, m / z): RT = 1.97 min, m / z = 409.23 [M+1] + . 1 H NMR(400MHz, DMSO–d6)δ8.30(t,J=5.7Hz,1H),7.62(d,J=2.0Hz,1H),7.41(dd,J=8.3,2.1Hz,1H),6.86( d,J=8.3Hz,1H),4.30(s,2H),3.23–3.08(m,3H),2.95–2.78(m,2H),1.86(p,J=7.2Hz,2H),1.30(s,6H). Example 2: 4-(2-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 2) and methyl 4-(2-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyrate (compound 2-OMe)

[0579] A solution of methyl 4-aminobutyrate hydrochloride (1.1 equivalent, 31 mg, 0.203 mmol) and 2-(5-bromo-3,3-dimethyl-2-oxo-indoline-1-yl)acetic acid (1 equivalent, 55 mg, 0.184 mmol) in N,N-dimethylformamide (DMF) (0.8 mL) was treated with N,N-diisopropylethylamine (DIPEA) (3 equivalent, 0.096 mL, 0.553 mmol) and [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.1 equivalent, 74 mg, 0.194 mmol) and stirred at room temperature for 20 min. Methyl 4-(2-(5-bromo-3,3-dimethyl-2-oxoindololin-1-yl)acetamyl)butyrate (compound 2-OMe) was formed in situ. The mixture was then treated with NaOH (5 equivalents, 0.43 mL, 0.922 mmol) and stirred for 2 hours. The mixture was quenched by adding 6N HCl (0.23 mL). The residue was purified using a C18 reversed-phase column, eluting with 0–100% MeCN / H2O, to give 4-(2-(5-bromo-3,3-dimethyl-2-oxoindololin-1-yl)acetamyl)butyrate (compound 2). LCMS (ES, m / z): RT = 1.99 min, m / z = 385.33 [M+1] + . 1 H NMR (400MHz, DMSO–d6) δ8.20(t,J=5.6Hz,1H),7.60(d,J=2.1Hz,1H),7.40(dd,J=8.3,2.1Hz,1H),6.85(d,J =8.3Hz, 1H), 4.28 (s, 2H), 3.08 (q, J = 6.6Hz, 2H), 2.23 (t, J = 7.4Hz, 2H), 1.63 (p, J = 7.2Hz, 2H), 1.29 (s, 6H). Example 3: 4-(2-(5'-bromo-2'-oxospiro[cyclopentan-1,3'-indoline]-1'-yl)acetamyl)butyric acid (compound 5) and methyl 4-(2-(5'-bromo-2'-oxospiro[cyclopentan-1,3'-indoline]-1'-yl)acetamyl)butyrate (compound 5-OMe)

[0580] A solution of 5'-bromospiro[cyclopentan-1,3'-indoline]-2'-one (1 equivalent, 100 mg, 0.376 mmol) in N,N-dimethylformamide (DMF) (3 mL) was cooled to 0 °C and treated with NaH (1.10 equivalent, 17 mg, 0.413 mmol) with stirring for 20 min. Then, methyl 2-bromoacetate (1.1 equivalent, 0.039 mL, 0.413 mmol) was added, and the reaction was brought to room temperature and stirred for 40 min. The mixture was then treated with NaOH (1.20 equivalent, 0.18 mL, 0.451 mmol) with stirring for 1 h. The mixture was then neutralized with 6N HCl and directly injected into a C18 reversed-phase column, eluted with 0–100% MeCN / H₂O, to give 2-(5'-bromo-2'-oxospiro[cyclopentan-1,3'-indoline]-1'-yl)acetic acid. LCMS (ES, m / z): RT=2.34min, m / z=324.31[M+1] + .

[0581] Step 2: A solution of 2-(5'-bromo-2'-oxo-spiro[cyclopentane-1,3'-indoline]-1'-yl)acetic acid (1 equivalent, 90 mg, 0.278 mmol) and methyl 4-aminobutyrate hydrochloride (1.1 equivalent, 47 mg, 0.305 mmol) in 0.8 mL of N,N-dimethylformamide (DMF) was treated with N,N-diisopropylethylamine (DIPEA) (3 equivalent, 0.15 mL, 0.833 mmol) and [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.1 equivalent, 116 mg, 0.305 mmol) and stirred at room temperature for 20 min. Methyl 4-(2-(5'-bromo-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)acetamyl)butyrate (compound 5-OMe) was formed in situ. The mixture was then treated with a 2N solution of NaOH (5 equivalents, 0.56 mL, 1.4 mmol) and stirred for another 2 hours. The mixture was quenched by adding 6N HCl (0.23 mL). The residue was purified by reversed-phase chromatography, eluting with 0–100% MeCN / H₂O, to give 4-(2-(5'-bromo-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)acetamyl)butyrate (compound 5). LCMS (ES, m / z): RT = 2.20 min, m / z = 411.36 [M+1] + . 1H NMR (400MHz, DMSO–d6) δ12.09(s,1H),8.20(t,J=5.6Hz,1H),7.48(d,J=2.0Hz,1H),7.39(dd,J=8.3,2.0Hz,1H),6.82(d,J=8.4Hz,1H) ,4.27(s,2H),3.17(s,1H),3.08(q,J=6.6Hz,2H),2.23(t,J=7.4Hz,2H),2.07–1.90(m,5H),1.87–1.77(m,2H),1.63(p,J=7.2Hz,2H). Example 4: 4-(2-(3,3-dimethyl-2-oxo-5-(trifluoromethyl)indololin-1-yl)acetamyl)-4-methylvaleric acid (compound 8) and methyl 4-(2-(3,3-dimethyl-2-oxo-5-(trifluoromethyl)indololin-1-yl)acetamyl)-4-methylvaleric acid (compound 8-OMe)

[0582] Step 1: Add methyl 2-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)acetate (280 mg, 0.897 mmol, 1 equivalent), cuprous iodide (I) (342 mg, 1.79 mmol, 2 equivalents), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (153 mg, 1.08 mmol, 1.2 equivalents), sodium iodide (161 mg, 1.08 mmol, 1.2 equivalents), and dioxane (5 mL) to a 20 mL vial at 100 °C. Stir the resulting mixture at 100 °C under a nitrogen atmosphere for 12 h. Monitor the reaction by LCMS. Filter the resulting mixture and wash the filter cake with methanol (MeOH) (3 x 5 mL). Concentrate the filtrate under reduced pressure. Concentrate the resulting mixture under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give methyl 2-(5-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetate (240 mg, 75% yield) as a red oil. LCMS: (ES, m / z): RT = 1.15 min, m / z = 360.2 [M+H] + .

[0583] Step 2: Add methyl 2-(5-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetate (230 mg, 0.640 mmol, 1 equivalent), copper (407 mg, 6.40 mmol, 10 equivalents), diphenyl(trifluoromethyl)sulfonium (490 mg, 1.92 mmol, 3 equivalents), and N,N-dimethylformamide (DMF) (3 mL) to a 20 mL vial at 80 °C. Stir the resulting mixture at 80 °C under a nitrogen atmosphere for 2 h. Monitor the reaction by LCMS. Filter the resulting mixture and wash the filter cake with methanol (MeOH) (2 x 4 mL). Concentrate the filtrate under reduced pressure. Concentrate the resulting mixture under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give methyl 2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetate (150 mg, 78% yield) as a red oil. LCMS: (ES, m / z): RT = 1.15 min, m / z = 302.1 [M+H] + .

[0584] Step 3: 2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetic acid methyl ester (130 mg, 0.432 mmol, 1 equivalent), lithium hydroxide (31.0 mg, 1.30 mmol, 3 equivalents), methanol (MeOH) (2 mL), and water (2 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The mixture was acidified to pH 3 with HCl (2 aq.). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 10 mL). The resulting mixture was concentrated under reduced pressure. This yielded [3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetic acid (100 mg, 81% yield) as a white solid. LCMS: (ES, m / z): RT = 0.68 min, m / z = 288.1 [M+H] + .

[0585] Step 4: Add [3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetic acid (80 mg, 0.279 mmol, 1 equivalent), methyl 4-amino-4-methylpentanoate (48.5 mg, 0.335 mmol, 1.2 equivalent), [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (127 mg, 0.335 mmol, 1.2 equivalent), triethylamine (TEA) (84.5 mg, 0.837 mmol, 3 equivalent), and N,N-dimethylformamide (DMF) (2 mL) to an 8 mL vial at room temperature. Stir the resulting mixture at room temperature for 1 h. Monitor the reaction by LCMS. Extract the resulting mixture with ethyl acetate (EtOAc) (3 x 8 mL). Wash the combined organic layers with water (4 x 10 mL) and dry over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give methyl 4-{2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indolin-1-yl]acetamityl}-4-methylpentanoate (also referred to herein as methyl 4-(2-(3,3-dimethyl-2-oxo-5-(trifluoromethyl)indolin-1-yl)acetamityl)-4-methylpentanoate; compound 8-OMe) (80 mg, 69% yield). LCMS: (ES, m / z): RT = 1.09 min, m / z = 415.1 [M+H] + .

[0586] Step 5: At room temperature, add methyl 4-{2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetamyl}-4-methylpentanoate (60 mg, 0.145 mmol, 1 equivalent) and lithium hydroxide (10.4 mg, 0.435 mmol, 3 equivalents), methanol (MeOH) (1 mL), and water (1 mL) to an 8 mL vial. Monitor the reaction by LCMS. Dilute the resulting mixture with water (8 mL). Acidify the mixture to pH 3 with HCl (2 aq.). Extract the resulting mixture with ethyl acetate (EtOAc) (3 x 8 mL). Wash the combined organic layers with water (4 x 7 mL) and dry over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. Concentrate the resulting mixture under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC (XBridge Prep 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: 19% B to 29% B, 29% B over 8 min; wavelength: 254 nm; HPLC RT (min): 7) to give 4-(2-(3,3-dimethyl-2-oxo-5-(trifluoromethyl)indololin-1-yl)acetamito)-4-methylvaleric acid (compound 8) (19.5 mg) as a white solid. LCMS: (ES, m / z): RT = 0.67 min, m / z = 401.0 [M+H) + . 1 H NMR(400MHz, DMSO–d6)δ8.16(s,1H),7.77(d,J=1.9Hz,1H),7.64–7.57(m,1H),7.01(d,J=8.2Hz ,1H),4.31(s,2H),2.18(t,J=8.0Hz,2H),1.84(m,J=9.1,6.9Hz,2H),1.34(s,6H),1.23(s,6H). Example 5: 4-(2-(5-cyclopropyl-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)-4-methylvaleric acid (compound 9) and methyl 4-(2-(5-cyclopropyl-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)-4-methylvaleric acid (compound 9-OMe)

[0587] Step 1: Add methyl 2-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)acetate (150 mg, 0.48 mmol, 1 equivalent), cyclopropylboronic acid (206 mg, 2.4 mmol, 5 equivalents), [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (70.3 mg, 0.09 mmol, 0.2 equivalents), Na2CO3 (153 mg, 1.44 mmol, 3 equivalents), dioxane (1.5 mL), and H2O (0.3 mL) to an 8 mL sealed tube. Stir the resulting mixture at 60 °C under a nitrogen atmosphere for 2 h. Monitor the reaction by LCMS. Extract the resulting mixture with ethyl acetate (EtOAc) (3 x 3 mL). Wash the combined organic layers with water (3 x 2 mL) and dry over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1) to give methyl 2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetate (95 mg, 43% yield), a yellow oil. LCMS: (ES, m / z): RT = 1.57 min, m / z = 274 [M+1] + .

[0588] Step 2: Place methyl 2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetate (140 mg, 0.51 mmol, 1 equivalent), methanol (MeOH) (1.5 mL), H₂O (0.30 mL), and LiOH (24.5 mg, 1.02 mmol, 2 equivalents) in an 8-mL vial. Stir the resulting solution at 25 °C for 2 h. Monitor the reaction by LCMS. Concentrate the resulting mixture under reduced pressure. The crude product (5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetic acid can be used directly in the next step without further purification. LCMS: (ES, m / z): RT = 0.77 min, m / z = 260 [M+1] + .

[0589] Step 3: Add (5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (150 mg, 0.57 mmol, 1 equivalent), methyl 4-amino-4-methylpentanoate (101 mg, 0.69 mmol, 1.2 equivalent), [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (264 mg, 0.69 mmol, 1.20 equivalent), N,N-dimethylformamide (DMF) (1.50 mL), and triethylamine (TEA) (176 mg, 1.73 mmol, 3 equivalent) to a 25 mL sealed tube. Stir the resulting mixture at room temperature for 2 h. Monitor the reaction by LCMS. Quench the reaction by adding water (3 mL) at room temperature. Extract the resulting mixture with ethyl acetate (EtOAc) (3 x 5 mL). The combined organic layers were washed with water (3 x 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate 1:1) to give methyl 4-[2-(5-cyclopropyl-3,3-dimethyl-2-oxoindolino-1-yl)acetamitanoate (also referred to herein as methyl 4-(2-(5-cyclopropyl-3,3-dimethyl-2-oxoindolino-1-yl)acetamitanoate; compound 9-OMe) as a pale yellow oil (130 mg, 41% yield). LCMS: (ES, m / z): RT = 0.92 min, m / z = 387 [M+1] + .

[0590] Step 4: Add methyl 4-[2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetamyl]-4-methylpentanoate (120 mg, 0.31 mmol, 1 equivalent), LiOH (14.9 mg, 0.62 mmol, 2 equivalents), H₂O (0.20 mL), and methanol (MeOH) (1 mL) to an 8 mL vial. Stir the resulting mixture at room temperature for 2 h. Monitor the reaction by LCMS. Extract the resulting mixture with ethyl acetate (EtOAc) (3 x 4 mL). Wash the combined organic layers with water (3 x 4 mL) and dry over anhydrous Na₂SO₄. After filtration, concentrate the filtrate under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH(9:1)) to give 4-[2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetamido]-4-methylvaleric acid (120 mg, 62% purity), which was a yellow oil. The crude product was purified by Prep-HPLC (2#SHIMADZU(HPLC–01): XBridge Prep OBD C18 column, 19*250mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: methanol (MeOH); flow rate: 20mL / min; gradient: 54%B to 54%B, 54%B over 12min; wavelength: 254 / 220nm) to give 4-(2-(5-cyclopropyl-3,3-dimethyl-2-oxoindoline-1-yl)acetamitano)-4-methylvaleric acid (compound 9) (9.1mg, 8% yield) as a white solid. LCMS: (ES, m / z): RT = 0.80min, m / z = 373 [M+1] + . 1 H NMR (400MHz, methanol-d4) δ7.05(d,J=1.9Hz,1H),7.00(d,J=8.1Hz,1H),6.77(d,J=8.0Hz,1H),4.33(s,2H),2.26(t,J=7.8 Hz,2H),1.99(t,J=7.9Hz,2H),1.92(d,J=8.7Hz,1H),1.37(d,J=15.5Hz,12H),0.98–0.89(m,2H),0.69–0.60(m,2H). Example 6: 4-(1-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)cyclopropane-1-carboxamido)butyric acid (compound 15) and methyl 4-(1-(5-bromo-3,3-dimethyl-2-oxoindoline-1-yl)cyclopropane-1-carboxamido)butyrate (compound 15-OMe)

[0591] Step 1: Place 5-bromo-3,3-dimethyl-1H-indol-2-one (120 mg, 0.5 mmol, 1 equivalent) (compound 24a of Fensome et al., J. Med. Chem. (2008) 1861-1873), triphenylphosphine (PPh3) (262.18 mg, 1 mmol, 2 equivalents), and dichloromethane (DCM) (3 mL) into a 25-mL double-necked round-bottom flask. Then, methyl propargylate (50.4 mg, 0.6 mmol, 1.2 equivalents) is added dropwise with stirring at 0 °C. The resulting solution is stirred at 25 °C for 2 h. The reaction progress is monitored by LCMS. The resulting mixture is concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2:1) to give methyl 2-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)prop-2-enoate (120 mg, 67% yield), a brownish-yellow oil. LCMS: (ES, m / z): RT = 0.92, m / z = 324.0 [M+H] + .

[0592] Step 2: Sodium tert-butoxide (t-BuONa) (119 mg, 1.2 mmol, 2 equivalents) and dimethyl sulfoxide (DMSO) (5 mL) were placed in a 50 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Trimethylsulfonium iodide (271 mg, 1.234 mmol, 2 equivalents) was then added dropwise with stirring at 0 °C. Methyl 2-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)prop-2-enoate (200 mg, 0.617 mmol, 1 equivalent) in tetrahydrofuran (THF) (1 mL) was added over 1 h at 0 °C. The resulting solution was stirred at 0 °C for 6 h. The reaction progress was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 3 mL). The combined organic layers were washed with water (3 x 3 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give methyl 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylate (10 mg, 4.3% yield) as a white solid. LCMS: (ES, m / z): RT = 1.11, m / z = 338.0 [M+H] + .

[0593] Step 3: Place methyl 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylic acid (20 mg, 0.059 mmol, 1 equivalent), methanol (MeOH) (0.5 mL), and H₂O (0.1 mL) into an 8-mL vial. Stir the resulting solution at 25 °C for 2 h. Monitor the reaction progress by LCMS. Concentrate the resulting mixture under vacuum. The crude product, 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylic acid, can be used directly in the next step without further purification. LCMS: (ES, m / z): RT = 0.82, m / z = 323.9 [M+H] + .

[0594] Step 4: Place 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylic acid (30 mg, 0.093 mmol, 1 equivalent), methyl 4-aminobutyrate hydrochloride (17.1 mg, 0.112 mmol, 1.2 equivalent), [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (42.2 mg, 0.112 mmol, 1.2 equivalent), triethylamine (TEA) (18.7 mg, 0.186 mmol, 2 equivalent), and N,N-dimethylformamide (DMF) (1 mL) into an 8-mL vial. Stir the resulting solution at 25 °C for 2 h. Monitor the reaction progress by LCMS. Extract the resulting mixture with ethyl acetate (EtOAc) (3 x 3 mL). The combined organic layers were washed with water (3 x 3 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate (1:1)) to give methyl 4-{[1-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropyl]formamido}butyrate (also referred to herein as methyl 4-(1-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropane-1-carboxamido)butyrate (compound 15-OMe) as a white solid (13 mg, 32% yield). LCMS: (ES, m / z): RT = 1.12, m / z = 423.1 [M+H] + .

[0595] Step 5: Place methyl 4-{[1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropyl]formamido}butyrate (10 mg, 0.024 mmol, 1 equivalent), LiOH (2.83 mg, 0.120 mmol, 5 equivalent), methanol (MeOH) (0.5 mL), and H₂O (0.1 mL) into an 8-mL vial. Stir the resulting solution at 25 °C for 2 h. Monitor the reaction progress by LCMS. Concentrate the resulting mixture under vacuum. Acidify / alkalize / neutralize the residue to pH 5 with concentrated HCl. Extract the resulting mixture with ethyl acetate (EtOAc) (3 x 3 mL). Wash the combined organic layers with water (1 x 3 mL) and dry over anhydrous MgSO₄. After filtration, concentrate the filtrate under reduced pressure. This yielded 4-{[1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropyl]formamido}butyric acid (7.2 mg), which was purified by reversed-phase chromatography (Xselect CSH C18 OBD column 30*150 mm). 5 μm, n; mobile phase A: acetonitrile (MeCN), mobile phase B: water (0.05% TFA); flow rate: 60 mL / min; gradient: 34% B to 44% B, 44% B over 10 min; wavelength: 254 / 220 nm; RT1 (min): 7.17; run number: 0), yielding a white solid trifluoroacetic acid (TFA) salt of 4-(1-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropane-1-carboxamido)butyric acid (compound 15) (also referred to herein as 4-{[1-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropyl]formamido}butyric acid) (7.2 mg, 58% yield). LCMS: (ES, m / z): RT = 0.68, m / z = 409.0 [M+H] + . 1 H NMR(400MHz, DMSO–d6)δ12.00(s,1H),7.68(t,J=5.9Hz,1H),7.60(d,J=2.1Hz,1H),7.44(dd,J=8.3,2.1Hz,1H),6.85 (d, J=8.3Hz, 1H), 3.04 (q, J=6.7Hz, 2H), 2.13 (t, J=7.4Hz, 2H), 1.58 (dd, J=14.5, 7.4Hz, 4H), 1.21 (d, J=75.7Hz, 8H). Example 7: 4-(2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 16) and 4-(2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 16-OMe)

[0596] Step 1: N-iodosuccinimide (NIS) (450 mg, 1.99 mmol, 1.2 equivalent) was added in portions to an ice-cold solution of 5-bromo-3,3-dimethyl-1H-indol-2-one (400 mg, 1.66 mmol, 1 equivalent) in acetic acid (AcOH) (4 mL), followed by stirring at 50 °C for 3 h. Then concentrated H₂SO₄ (49.01 mg, 0.50 mmol, 0.3 equivalent) was added at room temperature. The resulting mixture was stirred at 50 °C for another 2 h. The reaction mixture was quenched with ice / water (10 mL). The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1) to give 5-bromo-7-iodo-3,3-dimethyl-1H-indol-2-one (500 mg, 82% yield) as a brown solid. LCMS: (ES, m / z): RT = 0.85 min, m / z = 366 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ10.49(s,1H),7.70(d,J=1.9Hz,1H),7.57(d,J=1.9Hz,1H),1.27(s,6H).

[0597] Step 2: NaH (60%, in mineral oil) (164 mg, 4.09 mmol, 3 equivalents) was added to a solution of 5-bromo-7-iodo-3,3-dimethyl-1H-indol-2-one (500 mg, 1.36 mmol, 1 equivalent) in N,N-dimethylformamide (DMF) (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. Then, tert-butyl 2-bromoacetate (320 mg, 1.63 mmol, 1.2 equivalents) was added dropwise to the above solution at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1) to give tert-butyl 2-(5-bromo-7-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetate (500 mg, 76% yield) as a yellow-green solid. LCMS: (ES, m / z): RT = 0.92 min, m / z = 480 [M+H]+ . 1 H NMR (400MHz, DMSO–d6) δ7.83(d,J=2.0Hz,1H),7.70(d,J=2.0Hz,1H),4.74(s,1H),4.02(s,1H),1.43(d,J=2.5Hz,9H),1.31(s,6H).

[0598] Step 3: At room temperature, NaOH (208 mg, 5.20 mmol, 5 equivalents) was added to a stirred solution of 2-(5-bromo-7-iodo-3,3-dimethyl-2-oxoindol-1-yl) tert-butyl acetate (500 mg, 1.04 mmol, 1 equivalent) in pyridine (4 mL) and H₂O (8 mL), followed by the addition of cuprous oxide (I)(Cu₂O) (29.8 mg, 0.20 mmol, 0.2 equivalents). The resulting mixture was stirred at 110 °C for 12 h. The mixture was filtered, and the filtrate was neutralized to pH 2 with 1 N HCl aqueous solution. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography to give (5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (200 mg, 52% yield) as a brown solid. LCMS: (ES, m / z): RT = 0.70 min, m / z = 314 [M+H] + . 1 HNMR (400MHz, DMSO–d6) δ12.12(s,1H),7.02(d,J=1.9Hz,1H),6.87–6.82(m,1H),4.37(s,1H),4.04(d,J=7.1Hz,1H),1.25(s,6H).

[0599] Step 4: At room temperature, triethylamine (TEA) (96.6 mg, 0.95 mmol, 3 equivalents) was added to a stirred solution of (5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (100 mg, 0.31 mmol, 1 equivalent) and methyl 4-aminobutyrate (44.8 mg, 0.38 mmol, 1.2 equivalents) in N,N-dimethylformamide (DMF) (2.5 mL), followed by [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145.25 mg, 0.38 mmol, 1.2 equivalents). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give 2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)-N-(4-methoxy-4,4-dioxobutyl)acetamide (also referred to herein as 4-(2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindololin-1-yl)acetamamido)butyric acid; compound 16-OMe) as a grayish-white solid (65 mg, 48% yield). LCMS: (ES, m / z): RT = 0.52 min, m / z = 413 [M+H] + .

[0600] Step 5: LiOH (8.37 mg, 0.35 mmol, 3 equivalents) was added to a solution of 2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)-N-(4-methoxy-4,4-dioxobutyl)acetamide (50 mg, 0.116 mmol, 1 equivalent) in methanol (MeOH) (2 mL) and H₂O (0.5 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The mixture was acidified to pH 2 with 1N HCl aqueous solution. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (YMC-ActusTriart C18 ExRS, 30*150 mm, 5 μm; mobile phase: water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (10% to 22% over 10 min); detector: UV 254 nm) to give 4-(2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamamido)butyric acid (compound 16) (26.3 mg, 55% yield) as a white solid. LCMS: (ES, m / z): RT = 0.67 min, m / z = 399.00 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ7.95(s,1H),6.99(s,1H),6.80(s,1H),4.42(s,2H),3.05(d,J=5.9Hz,2H),2.17(s,2H),1.62(d,J=7.0Hz,2H),1.26(s,6H). Example 8: 4-(2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 24) and methyl 4-(2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyrate (compound 24-OMe)

[0601] Step 1: Under a nitrogen atmosphere, n-butyllithium (n-BuLi) (2.5 M in hexane, 10.5 mL, 26.46 mmol, 2 equivalents) was added dropwise in portions to a solution of 7-fluoro-1,3-dihydroindol-2-one (2 g, 13.23 mmol, 1 equivalent) in tetrahydrofuran (THF) (40 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. Then, methyl iodine (MeI) (4.69 g, 33.08 mmol, 2.5 equivalents) was slowly added, and the mixture was stirred at 0 °C for 2 h, followed by further stirring at ambient temperature for 16 h. The reaction was monitored by LCMS. The reaction was quenched with saturated NH4Cl (40 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (4 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18 silica gel; mobile phase, MeCN aqueous solution, 10% to 50% gradient over 30 min; detector, UV 254 nm) to give 7-fluoro-3,3-dimethyl-1H-indol-2-one (1.3 g, 54% yield) as a brown solid. LCMS: (ES, m / z): RT = 0.73 min, m / z = 180 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ10.81(s,1H),7.15(dd,J=7.3,1.1Hz,1H),7.08(m,J=10.4,8.5,1.1Hz,1H),6.98(m,J=8.4,7.3,4.8Hz,1H),1.27(s,6H).

[0602] Step 2: Bromine (Br2) (892 mg, 5.58 mmol, 1 equivalent) was added dropwise to a solution of 7-fluoro-3,3-dimethyl-1H-indol-2-one (1 g, 5.58 mmol, 1 equivalent) in acetic acid (AcOH) (4 mL) and dichloromethane (DCM) (40 mL) over 4 min at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The reaction was monitored by LCMS. The reaction was quenched at 0 °C with saturated aqueous NaHSO3 solution (20 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (4:1) to give 5-bromo-7-fluoro-3,3-dimethyl-1H-indol-2-one (1.10 g, 73% yield) as a yellow solid. LCMS (ES, m / z): RT = 0.83 min, m / z = 258 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ10.97(s,1H),7.45(d,J=1.8Hz,1H),7.41(dd,J=9.8,1.8Hz,1H),1.28(s,6H).

[0603] Step 3: K₂CO₃ (535 mg, 3.87 mmol, 2 equivalents) and ethyl bromoacetate (388 mg, 2.32 mmol, 1.2 equivalents) were added to a solution of 5-bromo-7-fluoro-3,3-dimethyl-1H-indol-2-one (500 mg, 1.93 mmol, 1 equivalent) in N,N-dimethylformamide (DMF) (30 mL) at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The reaction progress was monitored by LCMS. The resulting solution was diluted with water (200 mL) and extracted with ethyl acetate (EtOAc) (4 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18 silica gel; mobile phase, MeCN aqueous solution, 10% to 50% gradient over 10 min; detector, UV 254 nm) to give ethyl 2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (550 mg, 78% yield) as a pale yellow solid. LCMS: (ES, m / z): RT = 1.03 min, m / z = 344 [M+H] + .

[0604] Step 4: LiOH (13.9 mg, 0.58 mmol, 2 equivalents) was added to a solution of ethyl 2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (100 mg, 0.20 mmol, 1 equivalent) in methanol (MeOH) (5 mL) and water (1 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and dissolved in water (5 mL). The residue of the mixture was acidified to pH 5 with 1 N HCl aqueous solution. The precipitated solid was collected by filtration and washed with H2O (20 mL). This yielded (5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (85 mg, 88% yield) as a white solid. LCMS: (ES, m / z): RT = 0.84 min, m / z = 316 [M+H] + .

[0605] Step 5: To a solution of (5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (100 mg, 0.31 mmol, 1 equivalent) in N,N-dimethylformamide (DMF) (3 mL), methyl 4-aminobutyrate (44.5 mg, 0.37 mmol, 1.2 equivalent), triethylamine (TEA) (96 mg, 0.94 mmol, 3 equivalent), and [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (132 mg, 0.34 mmol, 1.1 equivalent) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was diluted with H2O (40 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:2), to give methyl 4-[2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindolino-1-yl)acetamitano]butyrate (also known as methyl 4-(2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindolino-1-yl)acetamitano)butyrate (compound 24-OMe) (120 mg, 87% yield) as a pale yellow solid. LCMS: (ES, m / z): RT = 0.87 min, m / z = 415 [M+H] + .

[0606] Step 6: At room temperature, methyl 4-[2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetamyl]butyrate (150 mg, 0.36 mmol, 1 equivalent) was added to H2O. 2LiOH (17.3 mg, 0.72 mmol, 2 equivalents) was added to a solution of O (0.40 mL) and methanol (MeOH) (2 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue of the mixture was acidified to pH 4 with 1 N HCl aqueous solution. The aqueous layer was extracted with ethyl acetate (EtOAc) (4 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (2#SHIMADZU(HPLC-01)): column: XSelect CSH C18 OBD column 30*150mm 5μm; mobile phase A: acetonitrile (MeCN), mobile phase B: water (0.05% TFA); flow rate: 60mL / min; gradient: 30%B to 38%B, 38%B over 10min; wavelength: 254 / 220nm) to give 4-(2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindoline-1-yl)acetamamido)butyric acid (compound 24) (53.2mg, 37% yield) as a white solid. LCMS (ES, m / z): RT = 0.73min, m / z = 401 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ8.17(t,J=5.6Hz,1H),7.53(d,J=1.7Hz,1H),7.43(dd,J=11.0,1.8H z, 1H), 4.35 (d, J = 1.8Hz, 2H), 3.09 (m, 2H), 2.22 (t, J = 7.4Hz, 2H), 1.63 (m, 2H), 1.32 (s, 6H). Example 9: 4-(2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 27) and methyl 4-(2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyrate (compound 27-OMe)

[0607] Step 1: At room temperature, K₂CO₃ (158 mg, 1.15 mmol, 3 equivalents) and CH₃I (271 mg, 1.91 mmol, 5 equivalents) were added to a solution of (5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (the product of Step 3 in Example 7) (120 mg, 0.38 mmol, 1 equivalent) in N,N-dimethylformamide (DMF) (4 mL). The resulting mixture was stirred at room temperature and under air atmosphere for 12 h. The reaction progress was monitored by LCMS. The resulting mixture was diluted with H₂O (20 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (7:1) to give methyl 2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (125 mg, 96% yield) as a white solid. LCMS: (ES, m / z): RT = 0.92 min, m / z = 342 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ7.29(d,J=1.6Hz,1H),7.17(d,J=1.6Hz,1H),4.61(s,2H),3.77(s,3H),3.68(s,3H),1.29(s,6H).

[0608] Step 2: NaOH (28.1 mg, 0.70 mmol, 2 equivalents) was added to a solution of methyl 2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (120 mg, 0.35 mmol, 1 equivalent) in methanol (MeOH) (5 mL) and H₂O (1 mL) at room temperature. The resulting mixture was stirred at room temperature and under air atmosphere for 2 h. The reaction progress was monitored by LCMS. After the reaction was complete, the residue was concentrated under reduced pressure and redissolved in water (5 mL), then acidified to pH 4 with 1N HCl aqueous solution. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This produces a white solid of (5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (110 mg, 96% yield). LCMS: (ES, m / z): RT = 1.20 min, m / z = 328 [M+H] + .

[0609] Step 3: At room temperature, triethylamine (TEA) (55.5 mg, 0.55 mmol, 2 equivalents) was added to a solution of (5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (90 mg, 0.27 mmol, 1 equivalent) and methyl 4-aminobutyrate (38.6 mg, 0.33 mmol, 1.2 equivalents) in N,N-dimethylformamide (DMF) (3 mL), followed by the addition of [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (125 mg, 0.33 mmol, 1.2 equivalents). The resulting mixture was stirred at room temperature and under air atmosphere for 2 h. The reaction progress was monitored by LCMS. After the reaction was complete, the resulting mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (EtOAc) (3 x 20 mL). The combined organic layers were washed with brine (1 x 15 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1), to give methyl 4-[2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindolino-1-yl)acetamitano]butyrate (also known as methyl 4-(2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindolino-1-yl)acetamitano)butyrate, compound 27-OMe) as a white solid (90 mg, 77% yield). LCMS: (ES, m / z): RT = 1.25 min, m / z = 427 [M+H] + . 1 H NMR(400MHz, DMSO–d6)δ8.01(t,J=5.6Hz,1H),7.24(d,J=1.6Hz,1H),7.12(d,J=1.6Hz,1H),4.40(s,2H),3 .75(s,3H),3.59(s,3H),3.08(q,J=6.4Hz,2H),2.32(t,J=7.2Hz,2H),1.67(p,J=7.2Hz,2H),1.28(s,6H).

[0610] Step 4: NaOH (15.9 mg, 0.40 mmol, 2 equivalents) was added to a solution of methyl 4-[2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butyrate (85 mg, 0.20 mmol, 1 equivalent) in methanol (MeOH) (2 mL) and H₂O (0.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction progress was monitored by LCMS. After the reaction was complete, the residue was concentrated under reduced pressure and redissolved in water (10 mL), then acidified to pH 4 with 1N HCl aqueous solution. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (column: XSelect CSH PrepC18 OBD column, 19*250mm, 5μm; mobile phase A: water (0.05% FA), mobile phase B: acetonitrile (MeCN); flow rate: 25 mL / min; gradient: 42% B to 42% B, 42% B over 8 min; wavelength: 254 nm; HPLC RT (min): 7.6) to give 4-(2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamamido)butyric acid (compound 27) (43.0 mg, 54% yield) as a white solid. LCMS (ES, m / z): RT = 1.41 min, m / z = 413 [M+H] + . 1 H NMR(400MHz, DMSO–d6)δ12.04(s,1H),8.02(t,J=5.6Hz,1H),7.24(d,J=1.6Hz,1H),7.12(d,J=1.6Hz,1H), 4.39(s,2H),3.75(s,3H),3.08(q,J=6.4Hz,2H),2.23(t,J=7.2Hz,2H),1.63(d,J=7.2Hz,2H),1.28(s,6H). Example 10: 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 28) and methyl 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyrate (compound 28-OMe)

[0611] Step 1: To a solution of (5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (the product of Step 3 in Example 7) (240 mg, 0.76 mmol, 1 equivalent), methyl 4-aminobutyrate hydrochloride (141 mg, 0.91 mmol, 1.2 equivalent), and triethylamine (TEA) (232 mg, 2.29 mmol, 3 equivalent) in N,N-dimethylformamide (DMF) (5 mL), [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (349 mg, 0.91 mmol, 1.20 equivalent) was added, and the resulting solution was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding water (15 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18 silica gel; mobile phase, MeCN aqueous solution (0.1% TFA), in a 10% to 50% gradient over 10 min; detector, UV 254 nm) to give methyl 4-[2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butyrate (190 mg, 60% yield) as a yellow oil. LCMS: (ES, m / z): RT = 0.762 min, m / z = 413.0 [M+H] + .

[0612] Step 2: A solution of methyl 4-[2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butyrate (150 mg, 0.36 mmol, 1 equivalent), methyl[2-(methylamino)ethyl]amine (64.0 mg, 0.72 mmol, 2 equivalents), and NaI (435 mg, 2.90 mmol, 8 equivalents) in dioxane (8 mL) was stirred at 120 °C under a nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:2) to give methyl 4-[2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindolin-1-yl)acetamitano]butyrate (also known as methyl 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindolin-1-yl)acetamitano)butyrate, compound 28-OMe) (100 mg, 60% yield). LCMS: (ES, m / z): RT = 0.778 min, m / z = 460.9 [M+H]+ .

[0613] Step 3: A solution of methyl 4-[2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butyrate (80.0 mg, 0.17 mmol, 1 equivalent) and NaOH (104 mg, 2.61 mmol, 15.0 equivalent) in methanol (3 mL) and water (3 mL) was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The reaction was dissolved by adding water (20 mL) at room temperature. The residue was acidified to pH 6 with 2N HCl (aqueous solution). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:7) to give 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindololin-1-yl)acetamitano)butyric acid (80 mg, 85% purity), which was a yellow oil. This was further purified by Prep-HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile (MeCN); flow rate: 25 mL / min; gradient: 30% B to 40% B, 40% B over 10 min; wavelength: 254 nm). RT (min): 9) Purification yielded 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindoline-1-yl)acetamitano)butyric acid (compound 28) (39.9 mg, 66% yield) as a white solid. LCMS: (ES, m / z): RT = 1.295 min, m / z = 446.9 [M+H]+. 1 H NMR (400MHz, DMSO–d6) δ12.03(s,1H),9.96(s,1H),7.97(t,J=5.6Hz,1H),7.18(d,J=1.6Hz,1H),7.01(d,J =1.6Hz, 1H), 4.43 (s, 2H), 3.07 (q, J = 6.6Hz, 2H), 2.22 (t, J = 7.4Hz, 2H), 1.62 (p, J = 7.3Hz, 2H), 1.26 (s, 6H). Example 11: N-(3-(1H-tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 1) and N-(3-(2H-tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 2) (Compound 29)

[0614] Step 1: SOCl2 (13.6 mg, 0.12 mmol, 0.3 equivalent) was added to a solution of (5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (the product of Step 3 in Example 7) (120 mg, 0.30 mmol, 1 equivalent) in methanol (MeOH) (5 mL) at room temperature. The resulting mixture was stirred at 70 °C for 2 h. The reaction progress was monitored by LCMS. After the reaction was complete, the residue was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (7:1) to give methyl 2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (125 mg, 100% yield) as a white solid. LCMS: (ES, m / z): RT = 0.92 min, m / z = 328 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ10.19(s,1H),7.11(d,J=1.6Hz,1H),6.86(d,J=2.4Hz,1H),3.75(d,J=3.2Hz,3H),4.64(s,2H),1.28(s,6H).

[0615] Step 2: To a solution of methyl 2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (125 mg, 0.52 mmol, 1 equivalent) in tetrahydrofuran (THF) (6 mL), 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-Phos) (90.0 mg, 0.45 mmol, 0.80 equivalent), zinc bromo(cyclopropyl)zinc (0.5 M in THF) (3 mL, 1.50 mmol, 3 equivalent), and tris(dibenzylacetone)dipalladium(O) (Pd2(dba)3) (140 mg, 0.16 mmol, 0.30 equivalent) were added. The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. The resulting mixture was diluted with H2O (50 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), in a 10% to 50% gradient over 10 min; detector, UV 254 nm) to give methyl 2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetate (105 mg, 62% yield) as a brown solid. LCMS: (ES, m / z): RT = 1.20 min, m / z = 290 [M+H] + . 1 H NMR(400MHz, DMSO–d6)δ9.55(s,1H),6.60(d,J=1.6Hz,1H),6.40(d,J=1.6Hz,1H),3.67 (d,J=11.2Hz,4H),1.81(m,1H),1.67–1.42(m,2H),1.32(d,J=7.2Hz,3H),1.25(s,6H).

[0616] Step 3: NaOH (30.4 mg, 0.76 mmol, 2 equivalents) was added to a solution of methyl 2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (105 mg, 0.38 mmol, 1 equivalent) in methanol (MeOH) (5 mL) and H₂O (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the residue was concentrated under reduced pressure and redissolved in water (5 mL), then acidified to pH 4 with 1N HCl aqueous solution. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give (5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (95 mg, 91% yield) as a white solid. LCMS: (ES, m / z): RT=1.25min, m / z=276[M+H] + .

[0617] Step 4: At room temperature, triethylamine (TEA) (62 mg, 0.61 mmol, 2 equivalents) was added to a solution of (5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (80 mg, 0.31 mmol, 1 equivalent) and 3-(1H-1,2,3,4-tetrazol-5-yl)propyl-1-amine (46.7 mg, 0.37 mmol, 1.2 equivalents) in N,N-dimethylformamide (DMF) (3 mL), followed by the addition of [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (128.1 mg, 0.34 mmol, 1.1 equivalents). The resulting mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the residue was purified by reversed-phase rapid chromatography (C18 silica gel; mobile phase, acetonitrile (MeCN) aqueous solution (0.1% FA), in a 10% to 50% gradient over 10 min; detector, UV 254 nm) to give N-(3-(1H-tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 1) and N-(3-(2H-tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamide (tautomer 2) as white solids (compound 29) (9.3 mg, 62% yield). LCMS: (ES, m / z): RT = 1.26 min, m / z = 385 [M+H] + . 1H NMR (400MHz, DMSO–d6) δ8.04(t,J=5.6Hz,1H),6.54(d,J=1.6Hz,1H),6.43(d,J=1.6Hz,1H),4.42(s,2H),3.08(q,J=6.4Hz,2 H), 2.74 (t, J = 7.2Hz, 2H), 1.79 (m, J1 = 8.4, J2 = 4.4Hz, 1H), 1.71 (q, J = 7.2, 6.8Hz, 2H), 1.24 (s, 6H), 0.85 (m, 2H), 0.54 (m, 2H). Example 12: 4-(2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 36) and methyl 4-(2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyrate (compound 36-OMe)

[0618] Step 1: Under a nitrogen atmosphere and at 0 °C, n-butyllithium (n-BuLi) (2.5N) (6.13 mL, 15.32 mmol, 2.5 equivalents) was added dropwise to a solution of 6-methoxy-1,3-dihydroindole-2-one (1 g, 6.12 mmol, 1 equivalent) and LiCl (649 mg, 15.32 mmol, 2.5 equivalents) in 100 mL of tetrahydrofuran (THF). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 30 min. MeI (1739.70 mg, 12.25 mmol, 2 equivalents) was added dropwise to the mixture over 20 min at 0 °C. The resulting mixture was stirred at 0 °C for another 1 h. The reaction was quenched by adding water / ice (20 mL) at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (8:1) to give 6-methoxy-3,3-dimethyl-1H-indol-2-one (200 mg, 17% yield) as a yellow solid. 1 H NMR (400MHz, DMSO–d6) δ10.24(s,1H),7.16(d,J=8.2Hz,1H),6.51(dd,J=8.2,2.4Hz,1H),6.41(d,J=2.3Hz,1H),3.73(s,3H),1.21(s,6H).

[0619] Step 2: 6-Methoxy-3,3-dimethyl-1H-indol-2-one (200 mg, 1.04 mmol, 1 equivalent), N,N-dimethylformamide (DMF) (8 mL), and N-bromosuccinimide (NBS) (186 mg, 1.046 mmol, 1 equivalent) were added to a 20 mL vial at room temperature. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The reaction was quenched by adding water / ice (20 mL) at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2:1), to give 5-bromo-6-methoxy-3,3-dimethyl-1H-indol-2-one (190 mg, 67% yield) as a yellow solid. LCMS (LCMS, ESI): RT=0.735min, m / z 270[M+H] + . 1 H NMR (400MHz, DMSO–d6) δ10.42(s,1H),7.50(s,1H),6.59(s,1H),3.83(s,3H),1.23(s,6H).

[0620] Step 3: A solution of 5-bromo-6-methoxy-3,3-dimethyl-1H-indol-2-one (150 mg, 0.55 mmol, 1 equivalent) in tetrahydrofuran (THF) (10 mL) was treated with NaH (60% dispersion in mineral oil) (26.65 mg, 1.11 mmol, 2 equivalents) for 30 min at 0 °C under a nitrogen atmosphere, followed by dropwise addition of ethyl bromoacetate (185 mg, 1.11 mmol, 2 equivalents) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding water / ice (20 mL) at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 50 mL) and dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1) to give ethyl 2-(5-bromo-6-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (170 mg, 86% yield) as a yellow solid. LCMS (LCMS, ESI): RT = 928 min, m / z = 356 [M+H] + . 1 H NMR (400MHz, DMSO–d6) δ7.59 (s, 1H), 6.99 (s, 1H), 4.60 (s, 2H), 4.15 (q, J = 7.1Hz, 2H), 3.85 (s, 3H), 1.28 (s, 6H), 1.21 (d, J = 7.2Hz, 3H).

[0621] Step 4: BBr3 (1N in DCM) (0.56 mL, 0.56 mmol, 2 equivalents) was added dropwise to a solution of ethyl 2-(5-bromo-6-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (100 mg, 0.28 mmol, 1 equivalent) in dichloromethane (DCM) under a nitrogen atmosphere and stirred at 0 °C. The resulting mixture was stirred at room temperature and under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched with water / ice at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give (5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (70 mg, 79% yield) as a yellow solid. LCMS (LCMS, ESI): RT=667min, m / z=314[M+H] + .

[0622] Step 5: Add (5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (60 mg, 0.19 mmol, 1 equivalent), methyl 4-aminobutyrate (26.8 mg, 0.23 mmol, 1.2 equivalent), triethylamine (TEA) (58.0 mg, 0.57 mmol, 3 equivalent), and N,N-dimethylformamide (DMF) (3 mL) to an 8 mL vial, and add [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (87.2 mg, 0.23 mmol, 1.20 equivalent) at room temperature. Stir the resulting mixture at room temperature under a nitrogen atmosphere for 1 h. Monitor the reaction progress by LCMS. The residue was purified by reversed-phase rapid chromatography (C18 silica gel; mobile phase, aqueous acetonitrile (MeCN) solution (60% to 70% gradient over 10 min); detector, UV 254 nm) to give methyl 4-[2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamitano]butyrate (also known as methyl 4-(2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamitano)butyrate, compound 36-OMe) as a yellow solid (50 mg, 63% yield). LCMS (LCMS, ESI): RT = 705 min, m / z = 413 [M+H] + .

[0623] Step 6: Add methyl 4-[2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butyrate (50.0 mg, 0.12 mmol, 1 equivalent), NaOH (9.68 mg, 0.24 mmol, 2 equivalent), methanol (MeOH) (1 mL), and H2O (1 mL) to an 8 mL vial at room temperature. Stir the resulting mixture at room temperature and under air atmosphere for 2 h. Monitor the reaction progress by LCMS. After the reaction is complete, concentrate the residue under reduced pressure and redissolve it in water (5 mL). Acidify the residue to pH 6 with 2N HCl (aqueous solution), and extract the aqueous layer with ethyl acetate (EtOAc) (3 x 20 mL), then dry it with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (C18 silica gel; mobile phase, aqueous acetonitrile (MeCN) solution (10% to 30% gradient over 10 min); detector, UV 254 nm) to give 4-(2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindoline-1-yl)acetamitanoic acid)butyric acid (compound 36) as a white solid (20.7 mg, 43% yield). LCMS (LCMS, ESI): RT = 1.211 min, m / z = 398.95 [M+H] + . 1 H NMR(400MHz,DMSO–d6)δ8.70(s,1H),7.04(s,1H),6.00(s,1H),4.03(s,2H),3.06( q, J=6.0Hz, 2H), 1.98 (t, J=6.9Hz, 2H), 1.63 (dt, J=12.0, 6.0Hz, 2H), 1.18 (s, 6H). Example 13: 4-(2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyric acid (compound 56) and methyl 4-(2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindoline-1-yl)acetamyl)butyrate (compound 56-OMe)

[0624] Step 1: A solution of ethyl bromoacetate (1.29 g, 7.75 mmol, 2 equivalents) in tetrahydrofuran (THF) (10 mL) was treated with NaH (186 mg, 7.75 mmol, 2 equivalents) for 30 min at 0 °C and under a nitrogen atmosphere, followed by dropwise addition of 5-bromo-4-fluoro-3,3-dimethyl-1H-indol-2-one (1.0 g, 3.88 mmol, 1 equivalent) (Compound 36a, Fensome et al., J. Med. Chem. (2008) 1861-1873) at room temperature. The resulting mixture was stirred at room temperature and under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding water (100 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 100 mL). The combined organic layers were washed with water (3 x 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, eluting with petroleum ether / ethyl acetate (1:1) to give ethyl 2-(5-bromo-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (900 mg, 54% yield) as a white solid. LCMS: (ES, m / z): RT = 0.996 min, m / z = 344 [M+1] + .

[0625] Step 2: To a stirred solution of ethyl 2-(5-bromo-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (200 mg, 0.58 mmol, 1 equivalent) and cyclopropylboronic acid (250 mg, 2.9 mmol, 5 equivalent) in dioxane (5 mL) and H₂O (1 mL), a complex of [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) with dichloromethane (Pd(dppf)Cl₂-DCM) (85.0 mg, 0.11 mmol, 0.2 equivalent) and Na₂CO₃ (185 mg, 1.74 mmol, 3 equivalent) was added. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1), to give ethyl 2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (90 mg, 48% yield) as a grayish-white solid. LCMS: (ES, m / z): RT = 1.03 min, m / z = 306 [M+H] + .

[0626] Step 3: LiOH (39.2 mg, 1.63 mmol, 5 equivalents) was added to a stirred solution of ethyl 2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (100 mg, 0.32 mmol, 1 equivalent) in MeOH (5 mL) and H₂O (1 mL). The resulting solution was stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (4 mL) and adjusted to pH 5 with HCl (aqueous solution, 1 M). The precipitated solid was collected by filtration and washed with water (3 x 5 mL) to give (5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (80 mg, 88% yield) as a grayish-white solid. LCMS: (ES, m / z): RT = 1.03 min, m / z = 278 [M+H] + .

[0627] Step 4: Triethylamine (TEA) (73.0 mg, 0.72 mmol, 2 equivalents) and [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (165 mg, 0.43 mmol, 1.20 equivalents) were added to a stirred solution of (5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (100 mg, 0.36 mmol, 1 equivalent) and methyl 4-aminobutyrate (50.7 mg, 0.433 mmol, 1.2 equivalents) in N,N-dimethylformamide (DMF) (2 mL). The resulting solution was stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1) to give methyl 4-[2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamitano]butyrate (also known as methyl 4-(2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamitano)butyrate; compound 56-OMe) (120 mg, 71% yield). LCMS: (ES, m / z): RT = 0.98 min, m / z = 377 [M+H] + .

[0628] Ste...

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is halo, –CN, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C 12 Cycloalkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3- to 12-membered heterocyclic, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl or C1-C6 alkoxy, or R 2 and R 3 Cyclize with the atoms to which they are attached to form a C3–C 12 Cycloalkyl or 3- to 12-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more halo, –CN, –OH, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; R 4 is –C1–C6 alkyl–, –(L1) p –(C3–C 12 Cycloalkyl)-,-(L1) p –(3- to 12-membered heterocyclic group)–, –(L1) p –(C6–C 10 Aryl) – or – (L1) p -(5- to 10-membered heteroaryl)-, wherein each instance of L1 is independently -(C(R L1 )2)–, further wherein R L1 Each instance of is independently H, halo or C1-C3 alkyl, or two R L1 The groups together with the atoms to which they are attached form the C 3-4 Cycloalkyl; and wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halo, –CN, –OH, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3 cycloalkyl; Z is – (L2) n –(Carboxylic acid) or –(L2) n -tetrazolyl, wherein each instance of L2 is independently -(C(R L2 )2)–, further wherein R L2 Each instance of is independently H, halo or C1-C3 alkyl, or two R L2 The groups together with the atoms to which they are attached form the C 3-4 Cycloalkyl; and wherein the alkyl or cycloalkyl is optionally substituted with one or more halo, –CN, –OH, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3 cycloalkyl; Each R 5 are independently halo or C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halo, –CN, –OH, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl or C1-C6 alkoxy, or both R 5 The cyclized residues, together with the atoms to which they are attached, form C3-C6 optionally substituted with one or more halo, –CN, –OH, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl or C1-C6 alkoxy. 12 Cycloalkyl; R 6 is H, halo, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy; R 6’ is H, halo, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy; R 6” is H, halo, –OH, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, or C1–C6 alkoxy; R 7 are independently H or C1-C4 alkyl; n is an integer of 0, 1, 2 or 3; and p is an integer of 0, 1 or 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each instance of is H.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Cyclize together with the atoms to which they are attached to form a C3 cycloalkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -R 4 - Z is a group of formula (i): wherein Z' is tetrazole or carboxylic acid; Ring A is a C3-C5 cycloalkyl or a 4- to 5-membered heterocyclic group; each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the group of formula (i) is:

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein the group of formula (i) is:

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -R 4 - Z is a group of formula (ii): wherein Z' is tetrazole or carboxylic acid; Ring A is a C3-C5 cycloalkyl or a 4- to 5-membered heterocyclic group; each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R L1 At least one example of is -C1-C3 alkyl optionally substituted with one or more halo.

9. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R L2 At least one example of is -C1-C3 alkyl optionally substituted with one or more halo.

10. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R L1 and R L2 Each instance of is H.

11. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the group of formula (ii) is:

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the group of formula (ii-a) is:

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -R 4 - Z is a group of formula (iii): wherein Z' is tetrazole or carboxylic acid; Ring A is a C3-C5 cycloalkyl or a 4- to 5-membered heterocyclic group; each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iii) is:

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iii-a) is:

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -R 4 - Z is a group of formula (iv): Wherein Z' is tetrazole or carboxylic acid; each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2 or 3.

17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iv) is:

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iv) is:

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein the group of formula (iv) is:

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -R 4 -Z is a group of the formula: Wherein Z' is tetrazole or carboxylic acid; each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl; and x is 0, 1, 2 or 3.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein -R 4 -Z is a group of the formula: Wherein Z' is tetrazole or carboxylic acid; each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl; and x is 0, 1, 2 or 3.

22. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein -R 4 The -Z group has the formula:

23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -R 4 -Z is a group of the formula: wherein Z' is tetrazole or carboxylic acid; and each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl, and x is 0, 1, 2 or 3.

24. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 5 Each instance of R is selected from fluoro and C1-C6 alkyl, or two R 5 Cyclize together with the atoms to which they are attached to form a C3 cycloalkyl.

25. The compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein R 5 Each instance of is fluoro or -CH3.

26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the 6,5-bicyclic core of formula (viii): Has the following formula: Where R 6 , R 6’ and R 6” At least one of them is not H.

27. The compound according to any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein the 6,5-bicyclic core has the formula:

28. A compound according to any one of claims 1 to 27, wherein the compound of formula (I) has the following formula: or a pharmaceutically acceptable salt thereof, wherein: Z' is tetrazole or carboxylic acid; Ring A is a C3-C5 cycloalkyl group or a 4- to 5-membered heterocyclic group; Each R 4a are independently halo, C1-C3 alkyl, C1-C3 haloalkyl or C3 cycloalkyl; and x is 0, 1, 2, or 3.

29. A compound according to any one of claims 1 to 28, wherein the compound of formula (I) has the following formula: (IG), or a pharmaceutically acceptable salt thereof, wherein R 6 , R 6’ and R 6” At least one of them is not H.

30. The compound according to claim 1, which is selected from any one of the compounds in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

32. A method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-30, or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the disease or disorder is a NLRP3-associated disease or disorder.

34. The method of claim 32 or 33, wherein the subject is a human.

35. The method of any one of claims 32-34, 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 disease of muscle, an inflammatory disorder, an autoimmune disease, cancer, an infection, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft-versus-host disease, pain (including disorders related to pain management), or a NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3.

36. A method for preparing a compound of formula (I), wherein Z is -(L2) n -tetrazolyl, the method comprising reacting a substituted indolinone (acetic acid) (i): or its salts; With aminotetrazolyl (ii): or a salt thereof, To provide tetrazole analogs: or a salt thereof.

37. A method for preparing a compound of formula (I), wherein Z is -(L2) n -carboxylic acid, the method comprising treating a compound of formula (vo): or its salt for deprotection, Where PG is C 1-6 Alkyl, C6 aryl or aryl-C 1-6 wherein the alkyl and aryl groups are optionally substituted with one or more halogenated, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

38. The method according to claim 37, wherein the compound of formula (vo) or a salt thereof is prepared by reacting a substituted indolinone (acetic acid) (i): or its salts; With amino ester (iv): or a salt thereof, To provide the carboxylic acid analog (va): or a salt thereof.

39. Compound of formula (vo): or a salt thereof, Where n, R 1 , R 2 , R 3 , R 4 , L2, R 5 , R 6 , R 6’ , R 6” and R 7 As defined in claim 1, and PG is C 1-6 Alkyl, C6 aryl or aryl-C 1-6 wherein the alkyl and aryl groups are optionally substituted with one or more halogenated, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

40. The compound according to claim 39, which is selected from any one of the compounds in Table 3, or a salt thereof.

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