Compounds, Compositions and Methods

Abstract

The present disclosure generally relates to a small molecule modulator of NLR family pyrin domain containing 3 (NLRP3) or its pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug, its and its intermediates, and its method of manufacture and its use.In some embodiments, provided is a compound that modulates the activity of NLRP3.In some embodiments, the compound inhibits the activation of NLRP3.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 245,747, filed September 17, 2021, which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to small molecule modulators of NLR family pyrin domain-containing 3 (NLRP3) and their use as therapeutic agents. [Background technology]

[0003] Inhibition of NLRP3 activation has been shown to have a strong therapeutic effect in animal models of inflammatory diseases. Modulators, especially inhibitors, of NLRP3 have broad therapeutic potential in autoinflammatory and chronic inflammatory diseases that require better treatment options or where no suitable treatment exists. Therapies targeting NLRP3-dependent cytokines have already been approved for therapeutic use, but have notable drawbacks compared to direct NLRP3 antagonists. There remains a strong need for the discovery and clinical development of molecules that antagonize NLRP3. Summary of the Invention [Means for solving the problem]

[0004] Provided herein are compounds, or pharma- ceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that are useful for the treatment and / or prevention of diseases mediated, at least in part, by NLRP3.

[0005] In some embodiments, provided are compounds that modulate the activity of NLRP3. In some embodiments, the compounds inhibit the activation of NLRP3.

[0006] In another embodiment, provided is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0007] In another embodiment, provided is a method for treating a disease or condition mediated at least in part by NLRP3, comprising administering an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0008] In another embodiment, provided is a method for treating a disease or condition mediated at least in part by TNF-α, comprising administering an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. In some embodiments, the administration is to a subject resistant to treatment with an anti-TNF-α agent. In some embodiments, the disease is an intestinal disease or condition. In some embodiments, the disease or condition is inflammatory bowel disease, Crohn's disease, or ulcerative colitis.

[0009] The disclosure also provides compositions, including pharmaceutical compositions; kits, including the compounds, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; methods of using (or administering) and preparing the compounds, or a pharma-ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and intermediates thereof.

[0010] The disclosure further provides a compound, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a composition thereof, for use in a method of treating a disease, disorder, or condition mediated, at least in part, by NLRP3.

[0011] Further, the disclosure provides the use of a compound, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or composition thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition mediated, at least in part, by NLRP3.

[0012] The description herein illustrates exemplary embodiments of the present technology, however, it should be recognized that such description is not intended to limit the scope of the disclosure, but is provided as a description of exemplary embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] 1.Definition As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0014] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes before or after a chemical group are for convenience, and the chemical group may be represented with one or more dashes or without any dashes without loss of ordinary meaning. Wavy or dashed lines drawn through lines in a structure indicate a particular point of attachment of a group. No orientation or stereochemistry is indicated or implied by the order of writing or naming chemical groups unless chemically or structurally necessary.

[0015] "C u-v" indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0016] As used herein, reference to a value or parameter with "about" includes (and describes) embodiments that are directed to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the stated amount. In other embodiments, the term "about" includes ±5% of the stated amount. In certain other embodiments, the term "about" includes ±1% of the stated amount. Additionally, the term "about X" includes a description of "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms can be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0018] Certain commonly used alternative chemical names may also be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, and divalent heteroaryl groups are also referred to as "alkylene" or "alkylenyl" groups (e.g., methylenyl, ethylenyl, propylenyl), "arylene" or "arylenyl" groups (e.g., phenylenyl or naphthylenyl, or quinolinyl in the case of heteroarylene), respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as a moiety, for example, arylalkyl or aralkyl, the last-mentioned group contains the atom that bonds the moiety to the rest of the molecule.

[0019] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4Alkenyl refers to an alkyl group having an aryl group such as 1,2-butadienyl, 1,3-butadienyl, and 1,4-butadienyl. Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkynyl" refers to an alkynyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0021] "Alkoxy" refers to the group "alkyl-O-". Example alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl."

[0023] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0024] "Acyl" is -C(O)R y R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0025] "Amide" is -C(O)NR y R z -C-amide groups, which refer to the -NR y C(O)R z "N-amide" refers to both the "N-amino" and "N-aryl" groups, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0026] "Amino" is -NR y R z R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0027] "Amidino" is -C(NR y )(NR z 2), where R y and R zis independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0028] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with any heteroaryl as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl, regardless of the point of attachment. When one or more aryl groups are fused to a cycloalkyl, the resulting ring system is a cycloalkyl, regardless of the point of attachment.

[0029] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0030] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group refers to the -NR y C(O)OR z "N-carbamoyl" refers to both the "N-carbamoyl" group and the "N-carbamoyl" group, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0031] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x In the formula, R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0032] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of the attachment to the rest of the molecule. Still further, cycloalkyl includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0033] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0034] "Imino" is -C(NR y )R z R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0035] "Imide" is -C(O)NR y C(O)R z R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0036] "Halogen" or "halo" refers to an atom in Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0037] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1-6 or 1-3) hydrogen atoms are replaced with halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, where the halo groups can be, but are not necessarily, the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0038] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced with halogen.

[0039] "Haloalkoxyalkyl" refers to an alkoxyalkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced with halogen.

[0040] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced with a hydroxy group.

[0041] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced with the same or different heteroatom groups, provided that the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include -NRy -, -O-, -S-, -S(O)-, -S(O)2-, and the like, in which R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc. (wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 heteroatoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0042] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple condensed rings, containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1-20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 ring carbon atoms (i.e., C3-8Heteroaryl) and 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain cases, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each having 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and isoquinolyl. , isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl) triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl. Here, the heteroaryl can be bonded through any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered heteroaryl, regardless of the bond to the rest of the molecule (i.e., through any one of the fused rings).Heteroaryl does not encompass or overlap with aryl as defined above. Heteroaryls having only one single ring are also referred to as "monoheteroaryls". Heteroaryls having fused rings are also referred to as "fused heteroaryls".

[0043] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0044] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl can be monocyclic or polycyclic, where the polycyclic rings may be fused, bridged, or spiro, and may contain one or more (e.g., 1-3) oxo (=O) or N-oxide (-O) groups. - ) moiety. Any non-aromatic ring containing at least one heteroatom, regardless of attachment, is considered a heterocyclyl (i.e., it can be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom that can be fused to a cycloalkyl, aryl ring, or heteroaryl ring, regardless of attachment to the remainder of the molecule. As used herein, heterocyclyl refers to a ring having 2-20 ring carbon atoms (i.e., C) having 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxalanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolinyl, and the like. Heterocyclyl includes aryl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" where there are two substitution positions on the same carbon atom. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as, for example, oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl. Here, the heterocyclyl may be attached via either ring of the fused system.

[0045] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0046] "Oxime" is -CR y (=NOH) group, where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0047] "Sulfonyl" is -S(O)R y R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0048] "Sulfinyl" is -S(O)R y R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0049] "Sulfonamide" is -SO2NR y R z Group and -NR y SO2R z R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0050] "Optional" or "optionally" means that the described event or condition may or may not occur, and that the description includes cases where that event or condition occurs and cases where it does not occur. Also, the term "optionally substituted" refers to any one or more (e.g., 1-5 or 1-3) hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0051] As used herein, the term "substituted" refers to a group in which at least one (e.g., 1-5 or 1-3) hydrogen atom has been substituted with, but is not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH, =NNH, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanato, -S(O)OH, -S(O)OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3(in the formula, each R y means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl), replaced by a bond to a non-hydrogen atom, such as, independently, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0052] In certain embodiments, "substituted" means that one or more (e.g., 1-5 or 1-3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(O)R h , -NR g C(O)NR g R h , -NR g C(O)OR h , -NR g S(O) 1-2 R h , -C(O)R g , -C(O)OR g , -OC(O)OR g , -OC(O)R g , -C(O)NR g R h , -OC(O)NR g R h , -OR g , -SR g , -S(O)R g , -S(O)2R g , -OS(O) 1-2 R g , -S(O) 1-2 OR g , -NR g S(O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(O) 1-2 NR g R h , -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" also refers to any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1-5 or 1-3) hydrogen atoms are replaced with -C(O)R g , -C(O)OR g , -C(O)NR g R h, -CH2SO2R g , or -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also refers to one or more (e.g., 1-5 or 1-3) hydrogen atoms being replaced by a bond to amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i means any of the above groups, where two of the radicals, together with the atom to which they are attached, form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0053] It is not intended herein to include polymers or similar infinite structures that are reached by defining a substituent with an unlimited number of further substituents (e.g., a substituted aryl has a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.). Unless otherwise stated, the maximum number of series of substitutions for the compounds described herein is three. For example, a series of substitutions of an aryl group substituted with two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluoros, or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein.

[0054] In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 5. In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 3.

[0055] Any compound or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as "isotopically enriched analogs". Isotopically labeled compounds have the structure represented herein, except that one or more atoms are replaced by an atom having the mass or mass number of a selected atom. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P,32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Various isotopically labeled compounds of the present disclosure include, for example, 3 H and 14 C. Such isotopically labeled compounds may be useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including metabolic studies, reaction kinetics studies, drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0056] The term "isotopically enriched analog" includes "deuterated analog" of the compounds described herein, in which one or more hydrogens, such as hydrogens on carbon atoms, are replaced by deuterium. Such compounds are useful for extending the half-life of any compound when administered to a mammal, particularly a human, due to increased resistance to metabolism. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.Sci.5(12):524-527(1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens are replaced by deuterium.

[0057] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide several therapeutic advantages resulting from increased metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. For PET or SPECT or other imaging studies, 18 F, 3 H, 11C labeled compounds can be useful. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparation methods described below, substituting non-isotopically labeled reagents with readily available isotopically labeled reagents. In this context, it is understood that deuterium is considered as a substituent of the compounds described herein.

[0058] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom that is not specifically designated with a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0059] In many cases, the compounds of the disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0060] Also provided are pharma- ceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for animal or human medicinal use.

[0061] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. In addition, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable non-toxic addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharma-ceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3),

[0033] Suitable amines include, but are not limited to, salts of primary, secondary, and tertiary amines such as mono-, di-, or tricycloalkylamines (i.e., N(substituted alkenyl)3, mono-, di-, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylamine ethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0062] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide tautomer and the imidic acid tautomer. Thus, an amide-containing compound is understood to include its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to include its amide tautomer.

[0063] The compounds described herein, or pharma- ceutically acceptable salts thereof, contain asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be de?ned in terms of absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as Well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, e.g., chromatography and / or fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, e.g., chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0064] "Stereoisomer" refers to a compound consisting of the same atoms joined by the same bonds, but having different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0065] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0066] The relative centers of the compounds depicted herein are shown diagrammatically using a "thick bond" style (thick or parallel lines) and the absolute stereochemistry is represented using wedge bonds (thick or parallel lines).

[0067] "Prodrug" refers to any compound that releases an active parent drug according to the structures described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein such that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds such that the modifications are cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate a free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of the hydroxy functional groups of the compounds described herein, and the like. The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0068] "Halogenation" refers to any chemical reaction that introduces a halogen into a compound. Halogenation can be used to introduce one or more halogen atoms into a compound. The two or more halogen atoms can be the same halogen atom or different halogen atoms. Halogenation includes monohalogenation (introducing one halogen atom into a single carbon atom of a compound), dihalogenation (introducing two halogen atoms into a single carbon atom of a compound), and trihalogenation reactions (introducing three halogen atoms into a single carbon atom of a compound). Additionally, halogenation includes the introduction of halogen atoms into different carbon atoms of a compound.

[0069] Halogenation includes fluorination (introduction of fluorine atoms), chlorination (introduction of chlorine atoms), bromination (introduction of bromine atoms), and iodination (introduction of iodine atoms). Halogenation includes addition reactions in which a halogen atom is added to a compound without removing any atom or atomic group from the compound (e.g., when a halogen atom is added to an unsaturated bond). Halogenation also includes substitution reactions in which an atom of a compound or an atomic group of a compound (e.g., a leaving group) is replaced with a halogen atom. Halogenation also includes condensation reactions in which a precursor molecule having a halogen atom is condensed with a compound to form a by-product molecule (e.g., water, alcohol, etc.), whereby the halogen atom is incorporated into the backbone of the compound and a fragment of the compound remains as part of the by-product molecule. Halogenation reactions can be carried out in the presence of a halogenating reagent alone or other suitable reagents.

[0070] "Halogenating reagent" refers to a chemical reagent used in a halogenation reaction to introduce one or more halogen atoms into a compound. Halogenating reagents include fluorinating reagents (used to introduce fluorine atoms), chlorinating reagents (used to introduce chlorine atoms), brominating reagents (used to introduce bromine atoms), and iodinating reagents (used to introduce iodine atoms).

[0071] 2.Compound Provided herein are compounds that are modulators of NLRP3. In certain embodiments, provided are compounds of formula I: [ka] or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: A is N or CR 1 and X is a halo; Y is O or S; Z is O or S; Each R 1 are independently hydrogen, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 8 Z 1 or Or, two R's 1 together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, where the cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 8 Z 1 Optionally replaced by Each R 2 are independently hydrogen, halo, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 8 Z 1 or Or, two R's 2 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, where the cycloalkyl or heterocyclyl is selected from 1 to 8 Z 1 Optionally replaced by R 3 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 8 Z 1 Optionally replaced by R 4is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may have 1 to 8 Z 1 Optionally replaced by R 5 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may have 1 to 8 Z 1 or Or, R 4 and R 5 Together, they form 1 to 8 Z 1 forming a heterocyclyl or heteroaryl ring optionally substituted with R 6 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl or heterocyclyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C2-6 Heteroalkyl, C 3-10 Cycloalkyl or heterocyclyl has 1 to 5 Z 1b and optionally further substituted with R 7 is hydrogen, halo, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl or heterocyclyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl or heterocyclyl has 1 to 5 Z 1b or Or, R 6 and R 7 is combined with C 3-10 Forming a cycloalkyl or heterocyclyl ring, where C 3-10 The cycloalkyl or heterocyclyl ring may contain 1 to 5 Z 1b and optionally further substituted with each Z 1 are independently halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 5 Z 1a Optionally replaced by Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R 11 Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 5 Z 1a Optionally replaced by each Z 1a are independently halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -C(O)R 13 , -C(O)OR 13 , -S(O) 0-2R 13 , -NR 13 S(O) 0-2 -R 13 , -S(O) 0-2 N(R 13 )2, -NR 13 S(O) 0-2 N(R 13 )2, -NR 13 C(O)N(R 13 )2, -C(O)N(R 13 )2, -NR 13 C(O)R 13 , -OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 5 Z 1b Optionally replaced by Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R 13 Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 5 Z 1b Optionally replaced by each Z 1b are independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 Alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 alkynyl)-, -C(O)N(C 1-6 haloalkyl)-, -C(O)N(C 3-10 cycloalkyl-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)NH-; Here, Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently selected from 1 to 5 halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C3-10 It is optionally further substituted with a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0072] In certain embodiments, each R 1 are independently hydrogen, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 8 Z 1 is optionally replaced by

[0073] In certain embodiments, Y is O.

[0074] In certain embodiments, Z is O.

[0075] In certain embodiments, each R2 are independently hydrogen, halo, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represent 1 to 8 Z 1 is optionally replaced by

[0076] In certain embodiments, each R 2 is hydrogen. In certain embodiments, one R 2 is hydrogen, and the other R 2 is halo. In one embodiment, halo is fluoro. In one embodiment, halo is chloro. In certain embodiments, each R 2 is a halo.

[0077] In certain embodiments, -C(X)(R 2 )(R 2 ) group is -CHF2 or -CH2F.

[0078] In certain embodiments, -C(X)(R 2 )(R 2 ) group is -CHCl2 or -CH2Cl.

[0079] In certain embodiments, two R 2 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, where the cycloalkyl or heterocyclyl is selected from 1 to 8 Z 1 is optionally replaced by

[0080] In certain embodiments, R 3 is hydrogen, halo, or cyano.

[0081] In certain embodiments, R4 is hydrogen.

[0082] In certain embodiments, R 5 is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 8 Z 1 is optionally replaced by

[0083] In certain embodiments, R 5 is cyclobutyl, pyridyl, or pyrimidin-2-yl, where cyclobutyl, pyridyl, or pyrimidin-2-yl is selected from 1 to 5 Z 1 is optionally replaced by

[0084] In certain embodiments, each Z 1 is independently halo or cyano.

[0085] In certain embodiments, R 5 teeth, [ka] where: [ka] represents the point of attachment to the remainder of the compound of formula I.

[0086] In certain embodiments, R 4 and R 5 Together, they form 1 to 8 Z 1 Forms a heterocyclyl or heteroaryl ring optionally substituted with

[0087] In certain embodiments, R 4 and R 5 forms 3,4-dihydroquinolin-1(2H)-yl.

[0088] In certain embodiments, the compound is represented by formula IA: [ka]

[0089] In certain embodiments, A is N or CH.

[0090] In certain embodiments, the compound is represented by formula IB: [ka]

[0091] In certain embodiments, the compound is represented by formula IC: [ka]

[0092] In certain embodiments, R 3 is hydrogen.

[0093] In certain embodiments, R 5 is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may have 1 to 5 Z 1 is optionally replaced by

[0094] In certain embodiments, R 5 is cyclobutyl, pyridyl, or pyrimidin-2-yl, where cyclobutyl, pyridyl, or pyrimidin-2-yl is selected from 1 to 5 Z 1 is optionally replaced by

[0095] In certain embodiments, each Z 1is independently halo or cyano.

[0096] In certain embodiments, R 5 is 5-fluoropyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, pyrimidin-2-yl, or 3-hydroxy-3-methylcyclobutyl.

[0097] In certain embodiments, R 4 and R 5 Together, they form 1 to 8 Z 1 Forms a heterocyclyl or heteroaryl ring optionally substituted with

[0098] In certain embodiments, the compound has formula II: [ka] and ring A is represented by C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 8 Z 1 is optionally replaced by

[0099] In certain embodiments, R 4 is hydrogen or C 1-6 It is an alkyl.

[0100] In certain embodiments, R 4 is hydrogen or methyl.

[0101] In certain embodiments, R 4 is hydrogen.

[0102] In certain embodiments, R 6 is hydrogen.

[0103] In certain embodiments, R 7 is hydrogen.

[0104] In certain embodiments, R 6 and R 7 is combined with C 3-10 Forms a cycloalkyl.

[0105] In certain embodiments, the compound is represented by formula III: [ka]

[0106] In certain embodiments, each R 2 is independently hydrogen or halo.

[0107] In certain embodiments, X is fluoro.

[0108] In certain embodiments, X is fluoro and at least one R 2 is hydrogen.

[0109] In certain embodiments, X is fluoro and one R 2 is hydrogen, and the other R 2 is fluoro.

[0110] In certain embodiments, each R 1 is independently hydrogen or halo.

[0111] In certain embodiments, each R 1 is hydrogen.

[0112] In certain embodiments, ring A is C 3-10 cycloalkyl or heteroaryl, C 3-10 Cycloalkyl or heteroaryl independently have 1 to 5 Z 1 is optionally replaced by

[0113] In certain embodiments, Ring A is cyclobutyl, pyridyl, or pyrimidin-2-yl, where the cyclobutyl, pyridyl, or pyrimidin-2-yl is selected from 1 to 5 Z 1 is optionally replaced by

[0114] In certain embodiments, each Z 1 is independently halo or cyano.

[0115] In certain embodiments, Ring A is 5-fluoropyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, pyrimidin-2-yl, or 3-hydroxy-3-methylcyclobutyl.

[0116] In certain embodiments, provided is a compound selected from Table 1, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof. [Table 1]

[0117] In certain embodiments, provided is a compound selected from Table 2, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof. [Table 2]

[0118] 3. Method "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) suppression of a disease or condition (e.g., alleviation of one or more symptoms resulting from a disease or condition, and / or reducing the severity of the disease or condition); b) slowing or preventing the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of a disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of a disease or condition, enhancing the effect of another drug, slowing the progression of a disease, improving quality of life, and / or prolonging survival).

[0119] "Prevention" or "preventing" refers to any treatment of a disease or condition that keeps the clinical symptoms of the disease or condition from developing. The compounds, in some embodiments, may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0120] "Subject" refers to an animal, such as a mammal (including a human), that has been the object or subject of treatment, observation or experiment. The methods described herein may be useful for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0121] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof means an amount sufficient to effectively perform a treatment that provides a therapeutic benefit, such as alleviating symptoms or delaying disease progression, when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or condition described herein. A therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be easily determined by one of ordinary skill in the art.

[0122] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means inside a living individual, such as inside an animal or human. In this context, the methods described herein may be used therapeutically on an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an individual. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine optimal dosing schedules and / or dosages of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information obtained from such use may be used experimentally or clinically to set up protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to one of skill in the art. Compounds may be further characterized to test for safety or tolerated doses in human or non-human subjects. Such properties may be tested using methods commonly known to those of skill in the art.

[0123] In certain embodiments, provided herein is a compound, or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug, that regulates the activity of NLR family pyrin domain-containing 3 (NLRP3).In certain embodiments, provided herein is a compound, or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug, that inhibits the activity of NLRP3.

[0124] NLR proteins are involved in the immune system and help initiate and regulate the immune system's response to injury, toxins, or microbial invasion. NLRP3 (also known as cryopyrin, NALP3, LRR- and PYD-domain-containing protein 3) is a protein encoded by the NLRP3 gene (also known as CIAS1). Upon activation, NLRP3 molecules assemble, along with other proteins, into inflammasomes. Activation of NLRP3 by cellular stress leads to inflammasome activation and downstream proteolytic events, including the formation and subsequent secretion of active proinflammatory cytokines, such as interleukin (IL)-1β and IL-18. IL-1β and IL-18, among other cytokines, are known mediators of inflammation, e.g., inflammation of the arterial wall, atherosclerosis, and the aging process.

[0125] In certain embodiments, provided is a method of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity, comprising contacting a cell with an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Inhibition can be in vitro or in vivo.

[0126] In certain embodiments, provided are compounds disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0127] In certain embodiments, provided is a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating Alzheimer's disease.

[0128] In certain embodiments, provided are compounds disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in therapy.

[0129] In certain embodiments, the present disclosure provides the use of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for inhibiting (e.g., in vitro or in vivo) inflammasome (e.g., NLRP3 inflammasome) activity.

[0130] In certain embodiments, the present disclosure provides for the use of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in therapy.

[0131] In certain embodiments, the present disclosure provides for the use of a compound disclosed herein, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for treating a disease or condition mediated, at least in part, by NLRP3.

[0132] In certain embodiments, the present disclosure provides for the use of a compound disclosed herein, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for the manufacture of a medicament for treating neurodegenerative diseases, Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation after influenza infection, graft versus host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation caused by chikungunya virus, or traumatic brain injury.

[0133] Chronic inflammatory responses are associated with various types of cancer. During malignant transformation or cancer therapy, inflammasomes can be activated in response to specific signals, IL-Ιβ expression is increased in various cancers (e.g., breast, prostate, colon, lung, head and neck, melanoma, etc.), and patients with IL-Ιβ-producing tumors generally have a poor prognosis.

[0134] In certain embodiments, a method for treating a disease or condition mediated at least in part by NLRP3, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0135] In certain embodiments, provided is a method for treating a disease or condition selected from an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0136] In certain embodiments, provided is a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0137] In certain embodiments, the disclosure provides for the use of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0138] In certain embodiments, provided are methods for treating inflammation, autoimmune diseases, cancer, infectious diseases, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic conditions, psychiatric disorders, graft versus host disease, allodynia, and any disease in which an individual has been determined to have a non-silent germline or somatic mutation in NLRP3, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmacologic acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0139] In certain embodiments, the disease or condition may be a disease or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, liver system, metabolic system, respiratory system, central nervous system, may be a cancer or other malignancy, and / or may be caused by or associated with a pathogen. It is understood that these general embodiments defined according to broad classifications of diseases, disorders and conditions are not mutually exclusive.

[0140] In certain embodiments, the disease or condition is an inflammatory disorder, e.g., inflammation including inflammation resulting from an autoinflammatory disease, inflammation occurring as a symptom of a non-inflammatory disorder, inflammation resulting from an infection, or inflammation secondary to trauma, injury, or autoimmunity; acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyendocrine deficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's disease, or other conditions. Syndrome, Graves' Disease, Guillain-Barre Syndrome (GBS), Hashimoto's Disease, Idiopathic Thrombocytopenic Purpura, Kawasaki Disease, Lupus Erythematosus including Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) including Primary Progressive Multiple Sclerosis (PPMS), Secondary Progressive Multiple Sclerosis (SPMS) and Relapsing Remitting Multiple Sclerosis (RRMS), Myasthenia Gravis, Opsoclonus-Myoclonus Syndrome (OMS), Optic Neuroitis, Ord's Thyroiditis, Pemphigus, Pernicious Anemia, Polyarthritis, Primary Biliary Cirrhosis, Rheumatoid Arthritis (RA), Psoriatic Arthritis, Juvenile Idiopathic Arthritis or Steroiditis Autoimmune diseases such as leukemia, refractory gouty arthritis, Reiter's syndrome, Sjögren's syndrome, systemic connective tissue disorder systemic sclerosis, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Behçet's disease, Chagas' disease, autonomic neuropathy, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler's syndrome, macrophage activation syndrome, Blau's syndrome, vitiligo or vulvodynia; lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, acute lymphoblastic leukemia (AL); Leukemia including acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal squamous cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, pulmonary carcinoid tumors, lymphomas including cutaneous T-cell lymphoma, malignant mesothelioma,Cancers including melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor; viral infections (e.g., influenza virus, human immunodeficiency virus, Infections caused by viruses (e.g., HIV), alphaviruses (e.g., Chikungunya and Ross River viruses), flaviviruses (e.g., Dengue and Zika viruses), herpesviruses (e.g., Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, and KSHV), poxviruses (e.g., Vaccinia virus (e.g., Modified Vaccinia Virus Ankara) and Myxoma virus), adenoviruses (e.g., Adenovirus 5), or papillomaviruses), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillusanthracis, Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa,Infectious diseases including those caused by Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections (e.g. caused by Candida or Aspergillus species), protozoal infections (e.g. caused by Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (e.g. caused by Schistosoma, Nematodes, Tapeworms or Trematodes) and prion infections; Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease Central nervous system diseases such as cerebrovascular disease, Huntington's disease, cerebral malaria, brain injury due to pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, and amyotrophic lateral sclerosis; metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout; hypertension, ischemia, reperfusion injury including post-MI ischemia-reperfusion injury, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, cardiovascular diseases such as pulmonary arterial disease, aneurysms including abdominal aortic aneurysm, and pericarditis including Dressler's syndrome; respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis and idiopathic pulmonary fibrosis; non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (including advanced fibrosis stages F3 and F4); alcoholic fatty liver disease ( liver disease, including AFLD, and alcoholic steatohepatitis (ASH); kidney disease, including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; ophthalmological disease, including ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic neuropathy, dry eye, and glaucoma; dermatitis, including contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), and other cystic skin diseases;and acne congenital anomalies; lymphatic conditions such as lymphangitis and Castleman's disease; psychiatric disorders such as depression and psychological stress; graft-versus-host disease; allodynia, including mechanical allodynia; and any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0141] In certain embodiments, the disease, disorder or condition is selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndromes (TRAPS), hyperimmunoglobulin D-periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency, and the like. These include autoinflammatory diseases such as Diabetic Retardation Syndrome (DIRA), Majeed syndrome, Septic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA), Adult Still's Disease (AOSD), A20 Haploinsufficiency (HA20), Pediatric Granulomatous Arteritis (PGA), PLCG2-Associated Antibody Deficiency and Immune Dysfunction (PLAID), PLCG2-Associated Autoinflammation, Antibody Deficiency, and Immune Dysfunction (APLAID), or Sideroblastic Anemia, B-Cell Immunodeficiency, and Periodic Fever and Developmental Delay (SIFD).

[0142] In certain embodiments, provided is a method for treating a disease or condition selected from cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever, and an autoinflammatory and / or autoimmune disorder selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, and multiple sclerosis, and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases), comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0143] In certain embodiments, provided are Cryopyrin-Associated Periodic Syndrome (CAPS), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), Neonatal-Onset Multisystem Inflammatory Disease (NOMID), Familial Mediterranean Fever (FMF), Septic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA), Hyperimmunoglobulin D-Periodic Fever Syndrome (HIDS), Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS), Systemic-Onset Juvenile Idiopathic Arthritis, Adult Still's Disease (AOSD), , relapsing polychondritis, Schnitzler's syndrome, Sweet's syndrome, Behcet's disease, antisynthetase syndrome, interleukin-1 receptor antagonist deficiency (DIRA), and A20 haploinsufficiency (HA20), comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmacologic acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0144] In certain embodiments, provided is a method for treating a disease or condition selected from Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, chikungunya virus-induced joint inflammation, or traumatic brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0145] In certain embodiments, methods for treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are provided.

[0146] In certain embodiments, a method for treating Alzheimer's disease is provided.

[0147] In certain embodiments, provided is a method for treating a disease or condition mediated at least in part by TNF-α. In certain embodiments, the disease or condition is resistant to treatment with an anti-TNF-α agent. In some embodiments, the disease is an intestinal disease or condition. In some embodiments, the disease or condition is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the compound disclosed herein or a pharmacologic acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered in combination with an anti-TNF-α agent. In some embodiments, the anti-TNF-α agent is infliximab, etanercept, certolizumab pegol, golimumab, or adalimumab.

[0148] In certain embodiments, the disease or condition is an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0149] In certain embodiments, the disease or condition is an autoinflammatory and / or autoimmune disorder.

[0150] In certain embodiments, the disease or condition is a neurodegenerative disease.

[0151] In certain embodiments, the disease or condition is Parkinson's disease or Alzheimer's disease.

[0152] In certain embodiments, provided is a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0153] In certain embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, or colorectal adenocarcinoma.

[0154] In certain embodiments, provided is a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0155] In certain embodiments, provided is a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating cancer in a subject in need thereof.

[0156] In certain embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, may be administered alone as a monotherapy or in addition to one or more other substances and / or treatments. Such combination treatment may be achieved by the simultaneous, sequential, or separate administration of the individual components of the treatment.

[0157] For example, administration of an adjuvant may enhance the therapeutic effect (i.e., an adjuvant alone may provide minimal therapeutic benefit, but when combined with another therapeutic agent, improves the overall therapeutic benefit to the individual). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering a compound disclosed herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, with another therapeutic agent (including treatment regimen) that also has a therapeutic benefit.

[0158] Other embodiments include the use of the disclosed compounds in therapy.

[0159] 4. Kit Also provided herein is a kit comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and suitable packaging.In certain embodiments, the kit further comprises instructions for use.In one aspect, the kit comprises a compound of the present disclosure, or a pharma- ceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a label and / or instructions for use of the compound in the treatment of an indication, including a disease or condition described herein.

[0160] Also provided herein is an article of manufacture containing a compound described herein, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, or intravenous bag.

[0161] 5. Pharmaceutical Compositions and Modes of Administration The compounds provided herein are usually administered in the form of pharmaceutical compositions. Therefore, also provided herein are pharmaceutical compositions that contain one or more of the compounds described herein, or their pharma- ceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or prodrugs, and one or more pharma- ceutical acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharma- ceutical acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. For example, see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0162] The pharmaceutical composition may be administered in either a single dose or multiple doses.The pharmaceutical composition may be administered in a variety of ways, including, for example, rectal, buccal, intranasal, and transdermal routes.In certain embodiments, the pharmaceutical composition may be administered as an intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalant.

[0163] One mode of administration is parenteral, for example, by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0164] Oral administration may be another route of administration of the compounds described herein. Administration may be, for example, by capsules or enteric coated tablets. In the preparation of pharmaceutical compositions containing at least one compound described herein or its pharma- ceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, the active ingredient is usually diluted with an excipient and / or placed in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material, and serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0165] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweeteners; and flavoring agents.

[0166] Compositions comprising at least one compound described herein or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof can be formulated to provide immediate, sustained or delayed release of the active ingredient after administration to a subject by adopting procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems including polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein utilizes a transdermal delivery device ("patch"). Such transdermal patches can be used to infuse the compounds described herein in controlled amounts continuously or discontinuously. The creation and use of transdermal patches to deliver drugs is well known in the art. Such patches can be made for continuous, pulsatile or on-demand delivery of drugs.

[0167] To prepare solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of a compound described herein or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. When these preformulation compositions are referred to as homogenous, the active ingredient is uniformly dispersed throughout the composition, which allows the composition to be readily separated into equally effective unit dosage forms such as tablets, pills, and capsules.

[0168] The tablets or pills of the compounds described herein may be coated or otherwise prepared to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former.The two components may be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact to the duodenum or be released in a delayed manner.Such enteric layers or coatings may be made of a variety of materials, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0169] Compositions for inhalation or insufflation may include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharma- ceutically acceptable solvents can be nebulized by using an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a tent-like face mask or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally, preferably from a device that delivers the formulation in an appropriate manner.

[0170] Accordingly, embodiments provided herein also include methods for treating a disease or condition, e.g., a disease or condition mediated at least in part by NLRP3, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition described herein.

[0171] 6. Administration The specific dosage level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, and excretion rate, drug combination, and the severity of the particular disease of the subject receiving the therapy. For example, the dosage can be expressed as milligrams of the compounds described herein per kilogram of the subject's body weight (mg / kg). A dosage of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, about 0.1 to 100 mg / kg may be appropriate. In other embodiments, a dosage of 0.5 to 60 mg / kg may be appropriate. In some embodiments, a dosage of about 0.0001 to about 100 mg of the compound per kg body weight, about 0.001 to about 50 mg of the compound per kg body weight, or about 0.01 to about 10 mg of the compound per kg body weight per day may be appropriate. Normalization by subject body weight is particularly useful when adjusting dosages between subjects of widely differing sizes, such as occurs when using a drug in both human children and adults, or when converting an effective dose in a non-human subject, such as a dog, to a dose appropriate for human subjects.

[0172] 7. Compound Synthesis The compounds can be prepared using the methods disclosed herein and routine variations thereof, as will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventionally well known synthetic methods may also be used. The synthesis of typical compounds described herein can be accomplished as described in the following examples. Where available, reagents and starting materials can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0173] Although typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are set forth, it will be understood that other process conditions can be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art from routine optimization procedures.

[0174] Additionally, conventional protecting groups ("PG") may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. Numerous protecting groups are described, for example, in Wuts, PGM, Greene, TW, & Greene, TW (2006) Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and references cited therein. For example, protecting groups for alcohols such as hydroxy include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ions, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, which is removed by acid or base, benzoyl, which is removed by acid or base, benzyl, which is removed by hydrogenation, methoxyethoxymethyl ether, which is removed by acid, dimethoxytrityl, methoxymethyl ether, which is removed by acid, tetrahydropyranyl or tetrahydrofuranyl, which is removed by acid, and trityl, which is removed by acid.Examples of protecting groups for amines include carboxybenzyloxy, which is removed by hydrogenolysis; p-methoxybenzylcarbonyl, which is removed by hydrogenolysis; tert-butyloxycarbonyl, which is removed by concentrated strong acid (such as HCl or CF3COOH) or heating above about 80°C; 9-fluorenylmethyloxycarbonyl, which is removed by a base such as piperidine; acetyl, which is removed by treatment with base; benzoyl, which is removed by treatment with base; benzyl, which is removed by hydrogenolysis; carbamate groups, which are removed by acid and mild heating; p-methoxybenzyl, which is removed by hydrogenolysis; 3,4-dimethoxybenzyl, which is removed by hydrogenolysis; p-methoxyphenyl, which is removed by cerium(IV) ammonium nitrate; tosyl, which is removed by concentrated acid (such as HBr or H2SO4) and a strong reducing agent (sodium or sodium naphthalide in liquid ammonia); troc (trichloroethyl chloroformate), which is removed by insertion of Zn in the presence of acetic acid; and sulfonamide (Nosyl), which is removed by samarium iodide or tributyltin hydride. & Nps).

[0175] Furthermore, the compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as enriched mixtures of stereoisomers. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents that are well known in the art. Alternatively, racemic mixtures of such compounds can be resolved, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0176] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0177] General synthesis method Schemes I and II are illustrative of general methods that may be utilized to synthesize the compounds described herein, in which X, Y, Z, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is independently as defined herein; z is H or C 1-6where LG is an alkyl, LG is a leaving group (e.g., halo), Alk is a suitable alkyl group, and Hal is a suitable halogenating reagent (such as a fluorinating reagent). It will be appreciated that any one or more of the compounds used in the processes outlined in Schemes I and II, or any products obtained thereby, may be derivatized at any step of the process to provide various compounds of formula I. [ka]

[0178] In Scheme I, a compound of formula I-1 (also referred to as compound I-1) is first reacted with hydrazine, for example, an excess of hydrazine, in a suitable solvent under suitable reaction conditions (for example, an alcoholic solvent at reflux) to prepare compound I-2. Compound I-3 is obtained by condensation of compound I-2 with an alkoxyethanimidic acid (for example, a slight excess thereof) in the presence of an acid (for example, acetic acid). Alternatively, 2,2-dialkoxyacetic acid or alkyl 2,2-dialkoxyacetate may be used instead to obtain compound I-3. In certain embodiments, the process involves an alcoholic solvent under reflux conditions for about 2-3 days. Compound I-3 is converted to compound I-4 in tetrahydrofuran under acidic conditions at about 60° C. for about 2-4 hours.

[0179] In Scheme II, compound I-4 can then be converted to compound I-8 by a two-step process that includes a halogenation step using a halogenating reagent (Hal) and a coupling reaction with an ester compound having a suitable leaving group I-6. This two-step process can proceed either via compound I-5, if halogenation occurs first, or via compound I-7, if coupling reaction occurs first. The halogenation reaction can be carried out at low temperature using a suitable halogenating reagent in a halogenated solvent (e.g., dichloromethane). The coupling reaction can be carried out under reflux conditions using 2-bromoacetic acid in acetonitrile. [ka]

[0180] Compound I-8 is then coupled with a suitable substituted amine compound I-9 to form a compound of formula (I). z When R is hydrogen or when compound I-8 is a carboxylic acid, it can be reacted with an excess (e.g., about 1.2 equivalents to about 4 equivalents) of compound I-9 in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCI) to prepare a compound of formula (I). The reaction can be allowed to proceed at a suitable temperature of about 0° C. to about 40° C. for about 2 hours to about 18 hours to give the desired product. z C 1-6 If it is an alkyl or if compound I-8 is an ester, it can be reacted with an excess (e.g., about 1.2 equivalents to about 3 equivalents) of compound I-9 in the presence of trimethylaluminum (AlMe3) to give the desired product. The reaction can proceed in a halogenated solvent at a suitable temperature of about 50°C to about 100°C for about 1 hour to about 5 hours. The reaction can be monitored using TLC or a similar method. After completion of the reaction, the crude product is worked up to give the compound of formula (I).

[0181] Alternatively, compound I-5 may be directly converted to a compound of formula (I) via direct alkylation with compound I-10 under condensation conditions. For example, compound I-5 and compound I-10 can be reacted with each other in DMF in a stoichiometric ratio of about 1:1 at a temperature of about 80° C. to about 100° C. for about 30 minutes to about 2 hours to give a compound of formula (I).

[0182] Each step may be a single reaction or may include two or more sub-steps. Also, certain steps or sub-steps may be omitted for simplicity. For example, in some circumstances, a reduction reaction may be performed before the halogenation step. As another example, the ester may be hydrolyzed to the corresponding acid before the condensation reaction with the amine. The above reaction may proceed in a suitable alternative organic solvent, such as an alcohol, an ether (such as tetrahydrofuran), acetonitrile, a chlorinated solvent (such as dichloromethane), etc. The organic solvent may be deoxygenated and / or dried, for example via distillation, as needed, before the reaction begins. The reaction may also be carried out in an air- and / or moisture-free environment (e.g., in a glove box or bag) as needed. Additionally, racemization inhibitors, such as 1-hydroxybenzotriazole, may be used to suppress racemization of single enantiomer chiral molecules, if applicable.

[0183] The appropriate starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. Each of the intermediates or final compounds can be recovered and optionally purified at the end of each reaction by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like.

[0184] In some embodiments, the various substituents of compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, and I-10 used in Scheme I are as defined for Formula I.

[0185] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0186] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: contacting a compound of formula I-5 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0187] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: subjecting a compound of formula I-7 to a halogenation reaction under suitable conditions to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0188] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; contacting a compound of formula I-5 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0189] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: contacting a compound of formula I-4 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-7; subjecting a compound of formula I-7 to a halogenation reaction under suitable conditions to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0190] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; contacting a compound of formula I-5 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0191] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; contacting a compound of formula I-4 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-7; subjecting a compound of formula I-7 to a halogenation reaction under suitable conditions to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0192] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-2 to a compound of formula I-3 under appropriate conditions; converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; contacting a compound of formula I-5 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0193] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-2 to a compound of formula I-3 under appropriate conditions; converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; contacting a compound of formula I-4 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-7; subjecting a compound of formula I-7 to a halogenation reaction under suitable conditions to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0194] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-1 to a compound of formula I-2 under appropriate conditions; converting a compound of formula I-2 to a compound of formula I-3 under appropriate conditions; converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; contacting a compound of formula I-5 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0195] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-1 to a compound of formula I-2 under appropriate conditions; converting a compound of formula I-2 to a compound of formula I-3 under appropriate conditions; converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; contacting a compound of formula I-4 with a compound of formula I-6 under conditions suitable to obtain a compound of formula I-7; subjecting a compound of formula I-7 to a halogenation reaction under suitable conditions to obtain a compound of formula I-8; and A process comprising contacting a compound of formula I-8 with a compound of formula I-9 under conditions suitable to provide a compound of formula I.

[0196] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: A process comprising contacting a compound of formula I-5 with a compound of formula I-10 under conditions suitable to provide a compound of formula I.

[0197] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; and A process comprising contacting a compound of formula I-5 with a compound of formula I-10 under conditions suitable to provide a compound of formula I.

[0198] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; and A process comprising contacting a compound of formula I-5 with a compound of formula I-10 under conditions suitable to provide a compound of formula I.

[0199] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-2 to a compound of formula I-3 under appropriate conditions; converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; and A process comprising contacting a compound of formula I-5 with a compound of formula I-10 under conditions suitable to provide a compound of formula I.

[0200] In certain embodiments, provided is a process for preparing a compound of formula I, comprising: converting a compound of formula I-1 to a compound of formula I-2 under appropriate conditions; converting a compound of formula I-2 to a compound of formula I-3 under appropriate conditions; converting a compound of formula I-3 to a compound of formula I-4 under appropriate conditions; subjecting a compound of formula I-4 to a halogenation reaction under suitable conditions to obtain a compound of formula I-5; and A process comprising contacting a compound of formula I-5 with a compound of formula I-10 under conditions suitable to provide a compound of formula I. EXAMPLES

[0201] The following examples are included to illustrate specific embodiments of the present disclosure. It will be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in the implementation of the present invention, and therefore can be considered as constituting specific modes of its implementation. However, those skilled in the art should understand in light of this disclosure that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the present invention and still obtain equivalent or similar results.

[0202] General Experimental Method All solvents used were commercially available and were used without further purification. Reactions were typically carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0203] NMR spectroscopy: 1H nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz or one of the following instruments: a Bruker Avance 400 instrument equipped with probe DUAL 400 MHz S1, probe 6 S1 400 MHz 5 mm 1 H- 13 The NMR studies were carried out using a Bruker Avance 400 instrument equipped with CID, a Bruker Avance III 400 instrument equipped with a nanobay equipped with a probe Broadband BBFO 5mm direct, and a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400BBO probe operating at 400 MHz. All deuterated solvents typically contained 0.03%–0.05% v / v tetramethylsilane, which was used as a reference signal ( 1 H and 13 C are both set to δ 0.00). In a particular case, 1 H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Advance 400 instrument operating at 400 MHz with the indicated solvents at near room temperature unless otherwise indicated. In all cases the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations to designate major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0204] Thin layer chromatography: When thin layer chromatography (TLC) is used, it refers to silica gel TLC using silica gel F254 (Merck) plates, where Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography was performed on silica gel cartridges using an automated flash chromatography system, or on C18 cartridges for reversed phase chromatography. Alternatively, thin layer chromatography (TLC) was performed on Mancherey-Nagel's Alugram® (silica gel 60 F254), and UV was typically used to visualize spots. In some cases, additional visualization methods were also employed. In these cases, the TLC plates were stained with iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing well), ninhydrin (commercially available from Aldrich), or Magic Stain (25 g of (NH4)6Mo7O 24 The compounds were visualized by development with 1.4H2O (generated by thoroughly mixing 5 g of (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4).

[0205] Liquid Chromatography Mass Spectrometry and HPLC Analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system equipped with a photodiode array detector and a Luna-C18(2) 2.0×50 mm, 5 μm column using a gradient of mobile phase A (MPA, HO+0.037% (v / v) TFA):mobile phase B (MPB, ACN+0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB) at a flow rate of 1.2 mL / min. LCMS was performed with detection at 220 nm and 254 nm or with evaporative light scattering (ELSD) detection and positive electrospray ionization (MS). Semi-preparative HPLC was performed using either acidic or neutral conditions. Acidic: Luna C18 100x30mm, 5μm; MPA: HCl / H2O=0.04% or formic acid / H2O=0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150x25, 5μm; MPA: 10mM NH4HCO3 / H2O; MPB: ACN. Gradient for both conditions: 10% MPB to 80% MPB at 20mL / min flow rate for 12min, then 100% MPB for 2min, 10% MPB for 2min, UV detector. SFC analyses were performed on a Thar analytical SFC system equipped with a UV / Vis detector and a series of chiral columns including AD, AS-H, OJ, OD, AY and IC, 4.6×100 mm, 3 μm columns, using a gradient of mobile phase A (MPA, CO2):mobile phase B (MPB, MeOH+0.05% (v / v) IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB) at a flow rate of 4 mL / min. SFC fractionation was performed on a Thar80 preparative SFC system equipped with a UV / Vis detector and a series of chiral preparative columns including AD-H, AS-H, OJ-H, OD-H, AY-H and IC-H, 30 × 250 mm, 5 μm columns, using a gradient of mobile phase A (MPA, CO2):mobile phase B (MPB, MeOH + 0.1% (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10% MPB) at a flow rate of 65 mL / min.LC-MS data was also acquired using a UPLC-MS Acquity™ system coupled to a Waters single quadrupole mass spectrometer equipped with a PDA detector and operated in alternating positive and negative electrospray ionization modes. The column used was a Cortecs UPLC C18, 1.6 μm, 2.1×50 mm. A 2.0 min linear gradient was applied starting with 95% A (A: 0.1% formic acid / water) and ending with 95% B (B: 0.1% formic acid / MeCN) with a total run time of 2.5 min. The column temperature was 40° C. and the flow rate was 0.8 mL / min.

[0206] Intermediate 1 [ka] 4H-Thieno[3,2-b]pyrrole-5-carbohydrazide: To a solution of ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (10.0 g, 55.2 mmol) in EtOH (100 mL) was added NH2NH2·H2O (21.8 g, 426 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give a residue which was used directly. LCMS: m / z = 182.0 [M+H] + .

[0207] 5-(diethoxymethyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one: To a solution of 4H-thieno[3,2-b]pyrrole-5-carbohydrazide (8.5 g, 46.9 mmol) and methyl 2,2-diethoxyethanimidate (9.07 g, 56.3 mmol) in MeOH (240 mL) was added AcOH (8.45 g, 141 mmol). The reaction mixture was stirred at 90° C. for 60 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 294.0 [M+H] + .

[0208] 8-Oxo-7,8-dihydrothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-5-carbaldehyde: To a solution of 5-(diethoxymethyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-8(7H)-one (4.5 g, 15.3 mmol) in THF (70 mL) was added aqueous HCl (70 mL, 6 M). The reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give a residue which was used directly. LCMS: m / z = 238.0 [M+H2O+H] + .

[0209] Intermediate 2 [ka] 5-(Difluoromethyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-8(7H)-one: To a solution of 8-oxo-7,8-dihydrothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-5-carbaldehyde (600 mg, 2.74 mmol) in dichloromethane (DCM) (10 mL) at 0° C., bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (1.82 g, 8.21 mmol) was added. The reaction mixture was stirred at 15° C. for 16 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (NaHCO3) (10 mL) and filtered. The collected solid was triturated with MeCN (2 mL), filtered, and dried under reduced pressure to give a residue which was used directly. LCMS: m / z = 242.0 [M+H] + .

[0210] Methyl 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate: To a solution of 5-(difluoromethyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (900 mg, 3.73 mmol) and Cs2CO3 (2.43 g, 7.46 mmol) in acetonitrile (MeCN) (10 mL) was added methyl 2-bromoacetate (856 mg, 5.60 mmol). The reaction mixture was heated to 90 °C and stirred for 1 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (EtOAc) (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 314.2 [M+H] + .

[0211] Intermediate 3 [ka] 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetic acid: To a solution of methyl 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate (600 mg, 1.92 mmol) in THF (6 mL) was added a solution of LiOH·HO (161 mg, 3.83 mmol) in water (2.0 mL). The reaction mixture was stirred at 15 °C for 3 h. The reaction mixture was diluted with water (5 mL) and washed with MTBE (2 mL). The aqueous portion was then adjusted to pH = 3 by the addition of citric acid. The precipitate was collected by filtration and dried under reduced pressure to give a residue which was used directly. LCMS: m / z = 300.2 [M+H] + .

[0212] Intermediate 4 [ka] Methyl 2-(5-formyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)acetate: To a solution of 8-oxo-7,8-dihydrothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-5-carbaldehyde (2.3 g, 10.49 mmol) in DMF (20 mL) was added Cs2CO3 (6.84 g, 20.98 mmol) followed by 2-methyl 2-bromoacetate (1.77 g, 11.54 mmol, 1.09 mL) at 0 °C under N2. The mixture was stirred at 15 °C for 2 h. The mixture was quenched with water (30 mL) at 0 °C and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was used directly. LCMS: m / z = 310.0 [M+H2O+H] + .

[0213] 2-(5-(hydroxymethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)methyl acetate: To a solution of 2-(5-formyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)methyl acetate (2.0 g, 6.87 mmol) in MeOH (30 mL) at 0 °C, NaBH4 (519 mg, 13.7 mmol) was added. The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl (60 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 294.0 [M+H] + .

[0214] Methyl 2-(5-(fluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate: To a solution of methyl 2-(5-(hydroxymethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate (150 mg, 0.51 mmol) in DCM (3.0 mL) at -78 °C was added N,N-diethylethanamine trihydrofluoride (165 mg, 1.02 mmol) and (difluoro-λ 4 -sulfanylidene)-diethyl-ammonium tetrafluoroborate (234 mg, 1.02 mmol) was added. The reaction mixture was stirred at 15° C. for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 296.0 [M+H] + .

[0215] Intermediate 5 [ka] Methyl 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate: To a solution of methyl 2-(5-formyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate (160 mg, 0.55 mmol) in DCM (2.0 mL) at -78 °C was added N,N-diethylethanamine trihydrofluoride (266 mg, 1.65 mmol, 0.27 mL) and then (difluoro-λ)- 4-sulfanylidene)-diethyl-ammonium tetrafluoroborate (377 mg, 1.65 mmol) was added. The reaction mixture was stirred at 15° C. for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 314.0 [M+H] + .

[0216] Intermediate 6 [ka] 4H-Pyrrolo[2,3-d]thiazole-5-carbohydrazide: To a solution of NH2NH2·H2O (10.4 g, 204 mmol) in MeOH (50 mL) was added ethyl 4H-pyrrolo[2,3-d]thiazole-5-carboxylate (5.9 g, 25.5 mmol). The reaction mixture was stirred at 15° C. for 48 h. The reaction mixture was filtered. The collected solid was dried under reduced pressure to give a residue which was used directly. LCMS: m / z = 183.2 [M+H] + .

[0217] 5-(diethoxymethyl)thiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one: To a solution of 4H-pyrrolo[2,3-d]thiazole-5-carbohydrazide (2.86 g, 15.7 mmol) and methyl 2,2-diethoxyethanimidate (3.04 g, 18.8 mmol) in MeOH (90 mL) was added AcOH (2.83 g, 47.1 mmol). The reaction mixture was stirred at 90° C. for 32 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 295.0 [M+H] + .

[0218] Methyl 2-(5-(diethoxymethyl)-8-oxothiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate: To a solution of methyl 2-bromoacetate (270 mg, 1.77 mmol) and Cs2CO3 (886 mg, 2.72 mmol) in DMF (5.0 mL) at 0 °C was added 5-(diethoxymethyl)thiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (400 mg, 1.36 mmol). The reaction mixture was stirred at 15 °C for 3 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue which was used directly.

[0219] 2-(5-formyl-8-oxothiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)methyl acetate: To a solution of 2-(5-(diethoxymethyl)-8-oxothiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)methyl acetate (600 mg, 1.64 mmol) in DCM (9.0 mL) was added TFA (3.0 mL). The reaction mixture was stirred at 15° C. for 16 h. The reaction mixture was concentrated under reduced pressure, resuspended in EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (3 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was used directly. LCMS: m / z = 293.0 [M+H] + .

[0220] Methyl 2-(5-(difluoromethyl)-8-oxothiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate: To a solution of methyl 2-(5-formyl-8-oxothiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate (300 mg, 1.03 mmol) in DCM (2.0 mL) at -78 °C was added N,N-diethylethanamine trihydrofluoride (496 mg, 3.08 mmol) and (difluoro-λ 4 -sulfanylidene)-diethyl-ammonium tetrafluoroborate (705 mg, 3.08 mmol) was added. The reaction mixture was stirred at 15° C. for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 315.0 [M+H] + .

[0221] Example 1 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)-N-(5-fluoropyrimidin-2-yl)acetamide [ka]

[0222] To a solution of 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)acetic acid (50 mg, 0.17 mmol) and 5-fluoropyrimidin-2-amine (28 mg, 0.25 mmol) in pyridine (1.0 mL) was added EDCI (54 mg, 0.28 mmol). The reaction mixture was stirred at 15° C. for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 395.0 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.60 (s, 2H), 7.73 (d, J = 5.2 Hz, 1H), 7.64 (s, 1H), 7.52-7.44 (m, 1H), 7.14-6.84 (t, J = 51.6 Hz 1H), 5.18 (br s, 2H).

[0223] Example 2 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)-N-(pyrimidin-2-yl)acetamide [ka]

[0224] To a mixture of pyrimidin-2-amine (19 mg, 0.20 mmol) and 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetic acid (50 mg, 0.17 mmol) in pyridine (2.0 mL) was added EDCI (48 mg, 0.25 mmol). The reaction mixture was stirred at 35° C. for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 377.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (br s, 1H), 8.69 (d, J = 5.0 Hz, 2H), 7.89 (d, J = 5.6 Hz, 1H), 7.71 (s, 1H), 7.54-7.26 (m, 2H), 7.22 (t, J = 4.8 Hz, 1H), 5.11 (s, 2H).

[0225] Example 3 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide [ka]

[0226] To a solution of 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)acetic acid (100 mg, 0.33 mmol) and 3-cis-amino-1-methylcyclobutanol HCl salt (60 mg, 0.43 mmol) in DMF (2.0 mL) at 0° C. was added 1-hydroxybenzotriazole (HOBt) (68 mg, 0.50 mmol), N,N-diisopropylethylamine (DIPEA) (130 mg, 1.00 mmol, 0.17 mL) and EDCI (96 mg, 0.50 mmol). The reaction mixture was stirred at 15° C. for 16 h. The reaction mixture was heated to 35° C. and stirred for an additional 4 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC. LCMS: m / z = 383.0 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.71 (d, J = 5.6 Hz, 1H), 7.61 (s, 1H), 7.52-7.41 (m, 1H), 6.98 (t, J = 51.6 Hz, 1H), 4.74 (s, 2H), 3.94-3.90 (m, 1H), 2.50-2.33 (m, 2H), 2.14-1.98 (m, 2H), 1.33 (s, 3H).

[0227] Example 4 N-(5-cyano-3-fluoropyridin-2-yl)-2-[12-(difluoromethyl)-9-oxo-5-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),3,7,11-tetraen-10-yl]acetamide [ka]

[0228] To a solution of methyl 2-(5-(difluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate (80 mg, 0.26 mmol) and 6-amino-5-fluoro-pyridine-3-carbonitrile (46 mg, 0.33 mmol) in dichloroethane (DCE) (2.0 mL) was added AlMe3 (1M in n-heptane, 0.51 mL). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 419.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (br s, 1H), 8.74 (d, J = 1.2 Hz, 1H), 8.44 (dd, J = 1.4, 10.2 Hz, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.71 (s, 1H), 7.57-7.25 (m, 2H), 5.03 (s, 2H).

[0229] Example 5 2-(5-(fluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)-N-(5-fluoropyrimidin-2-yl)acetamide [ka]

[0230] To a solution of methyl 2-(5-(fluoromethyl)-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate (30 mg, 0.10 mmol) and 5-fluoropyrimidin-2-amine (23 mg, 0.20 mmol) in DCE (1.0 mL) was added AlMe3 (1M in n-heptane, 0.22 mL). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 377.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.12 (s, 1H), 8.78 (s, 2H), 7.90-7.82 (m, 1H), 7.62 (s, 1H), 7.55-7.48 (m, 1H), 5.97-5.69 (m, 2H), 5.02 (s, 2H).

[0231] Example 6 2-(5-(difluoromethyl)-8-oxothiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)-N-(5-fluoropyrimidin-2-yl)acetamide [ka]

[0232] To a solution of methyl 2-(5-(difluoromethyl)-8-oxothiazolo[5',4':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl)acetate (67 mg, 0.21 mmol) and 5-fluoropyrimidin-2-amine (48 mg, 0.40 mmol) in DCE (1.0 mL) was added AlMe3 (1M in n-heptane, 0.47 mL). The reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 396.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.49 (s, 2H), 8.47 (br s, 1H), 7.60 (s, 1H), 7.33 (t, J = 52.4 Hz, 1H), 5.46 (br s, 2H).

[0233] Biological Example 1 Biochemical assay of compounds THP-1 cell culture procedure The compounds provided herein were tested in the following assays. A cell culture medium containing RPMI1640 medium (89%), FBS (10%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM) was utilized. The freezing medium consisted of 90% FBS and 10% DMSO. THP-1 cells were removed from liquid nitrogen and placed in a 37°C water bath and thawed until no traces of ice remained. The cells were then added to 9 mL of warmed cell culture medium and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded and the cells were resuspended in fresh cell culture medium. THP-1 cells were then split and cultured in cell culture medium and passaged every 2-3 days. The cell density was 5×10 5 ~1.5×10 6 Maintain viable cells / mL between 0.01 and 0.1.

[0234] For freezing, resuspend the cells in fresh freezing medium to a cell density of 5 × 10 6The cell suspension was adjusted to 1 mL cells / mL. The cell suspension was aliquoted into 1 mL per vial and the vials were transferred to a -80° C. freezer. After 1 day at -80° C., the cell vials were transferred to a liquid nitrogen freezer for storage.

[0235] Assay procedure for IL-1β secretion in 384-well plates PMA was dissolved in DMSO to make a stock solution of 5 mg / mL and stored at -20°C in 10 μl aliquots for single use. PMA was added to normal growth medium. LPS was diluted with 1 mL of water to obtain a stock solution of 1 mg / mL and stored at -20°C in 15 μl aliquots for single use. Nigericin was diluted to 5 mg / mL (6.7 mM) in ice-cold 100% ethanol and stored at -20°C in 75 μL aliquots for single use. Serum-free medium contains RPMI1640 medium (99%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM). Two control conditions were used to quantify and normalize dose-response curves of test compounds: high control = 25 ng / mL LPS, 5 μM nigericin, 0.5% DMSO, low control = 25 ng / mL LPS, 0.5% DMSO.

[0236] Day 1: Differentiation with PMA Dilute THP-1 cells to 1.0 x 10 6 A suspension was obtained at a concentration of cells / mL, and the total volume of suspension required to allow for the desired number of assay plates was prepared. PMA (final concentration 5 ng / mL) was added to the growth medium, and the cells were incubated at 37°C in a humidified atmosphere of 5% CO2 for 40 hours.

[0237] Day 3: Plating with sequential stimulation of LPS and nigericin All media was carefully aspirated from each culture flask. Cells were carefully washed with 1x DPBS. Cells were then quickly digested with Trypsin LE for 5 min at 23°C and immediately resuspended in cell growth media. After resuspension, cells were centrifuged at 1000 rpm for 3 min and the supernatant was discarded. Cells were resuspended in DPBS and centrifuged again at 1000 rpm for 5 min. The supernatant was discarded and the cell pellet was resuspended in serum-free media supplemented with LPS (final concentration 25ng / mL) allowing 30K THP-1 cells in 45μL of media to be dispensed into each well of a 384-well PDL-coated plate. The 384-well plate was then incubated for 2 hours at 37°C in a humidified atmosphere of 5% CO2. Test compounds spanning the desired concentration range were then dispensed by Tecan. All wells were normalized to a final concentration of 0.5% DMSO. The plate was then incubated for 1 hour at 37°C in a humidified atmosphere of 5% CO2. 5 μL of 5 mg / mL nigericin stock solution was then added to each of the appropriate wells and the plate was centrifuged at 1000 rpm for 30 seconds. The plate was immediately returned to a 37°C incubator in a humidified atmosphere of 5% CO2 for 2 hours. After this, 35 μL / well of supernatant was harvested, transferred to a v-bottom plate and centrifuged at 1000 rpm for 1 minute. These supernatant aliquots were analyzed using the IL-Iβ detection kit as described below. If necessary, test samples can also be flash frozen and stored at -80°C until analysis.

[0238] IL-1β detection To prepare each ELISA plate, the capture antibody (mAb Mt175) was diluted in PBS to a final concentration of 2 μg / mL, and then 20 μL of this solution was added to each well of the ELISA plate. Each plate was incubated overnight at 4° C. The next day, the capture antibody solution was removed and discarded. Each ELISA plate was washed four times with PBST, followed by the addition of 25 μL / well of blocking buffer (Licor-927-40010) supplemented with 0.1% Tween® 20. Each ELISA plate was then incubated for 1 hour at 23° C. After this, the blocking buffer was removed and discarded. Each ELISA plate was washed four times with PBST. During this time, the v-bottom plates containing the supernatant aliquots from the assay runs were centrifuged at 300 g for 5 minutes, after which the supernatant samples were transferred to each ELISA plate at 15 μL / well. Each ELISA plate was then incubated for 2 hours at 23° C. After this, the supernatant samples were removed and discarded. Each ELISA plate was washed four times with PBST. 15 μL / well of 0.5 μg / mL mAb 7P10-biotin (diluted 1:1000 in blocking buffer) was added to each ELISA plate. Each ELISA plate was then incubated at 23° C. for 1 hour. After this, the antibody solution was removed and discarded. Each ELISA plate was washed 4 times with PBST. 20 μL / well of streptavidin-HRP (diluted 1:2000 in blocking buffer) was added to each ELISA plate. Each ELISA plate was then incubated at 23° C. for 1 hour. After this, the buffer was removed and discarded. Each ELISA plate was washed 4 times with PBST. 20 μL / well of HRP substrate was added to each ELISA plate. Each ELISA plate was then incubated at 23° C. for 2 minutes. After this, 40 μL / well of stop solution was added to each ELISA plate. Each ELISA plate was centrifuged at 1200 rpm for 30 seconds.

[0239] The plates were then read at 450 nm in a microplate reader. The % inhibition was calculated as follows: % Inhibition = (treated sample - high control) / (low control - high control) x 100

[0240] The activity of the tested compounds is shown in Table 3 below: +++=IC 50 <10 μM;++=IC 50 10-15 μM; +=IC 50 >15μM. [Table 3]

[0241] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0242] The embodiments illustratively described herein may be suitably practiced in the absence of any element or elements, or limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," and "containing" are to be interpreted broadly and without limitation. Furthermore, the terms and expressions employed herein are used as terms of description and not of limitation. In the use of such terms and expressions, there is no intention to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed embodiments.

[0243] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0244] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to be illustrative and not limiting of the scope of the invention. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains.

Claims

1. Compounds of Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein A is N or CR １ and X is halo; Y is O or S; Z is O or S; Each R １ are independently hydrogen, halo, cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １１ ) ２ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -S(O) ０－２ R １１ , -NR １１ S (O) ０－２ -R １１ , -S(O) ０－２ N (R １１ ) ２ , -NR １１ S (O) ０－２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 8 Z １ or optionally replaced by Or, two R's １ together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl independently contain 1 to 8 Z １ optionally replaced by Each R ２ are independently hydrogen, halo, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 8 Z １ or optionally replaced by Or, two R's ２ together with the atom to which they are attached form a cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is selected from 1 to 8 Z １ optionally replaced by R ３ is hydrogen, halo, cyano, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl may be one to eight Z １ optionally replaced by R ４ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with 1 to 8 Z １ optionally replaced by R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with 1 to 8 Z １ or optionally replaced by Or, R ４ and R ５ together, 1 to 8 Z １ forming a heterocyclyl or heteroaryl ring optionally substituted with R ６ is hydrogen, halo, cyano, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ cycloalkyl, or heterocyclyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ Cycloalkyl or heterocyclyl is one to five Z １ｂ and optionally further substituted with R ７ is hydrogen, halo, cyano, hydroxy, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ cycloalkyl, or heterocyclyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ Cycloalkyl or heterocyclyl is one to five Z １ｂ or Or, R ６ and R ７ is combined with C ３－１０ Forms a cycloalkyl ring or a heterocyclyl ring, wherein said C ３－１０ The cycloalkyl or heterocyclyl ring may be a ring having 1 to 5 Z １ｂ and optionally further substituted with Each Z １ are independently halo, cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １１ ) ２ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -S(O) ０－２ R １１ , -NR １１ S (O) ０－２ -R １１ , -S(O) ０－２ N (R １１ ) ２ , -NR １１ S (O) ０－２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z １ａ optionally replaced by Each R １１ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R １１ Each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z １ａ optionally replaced by Each Z １ａ are independently halo, cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １３ ) ２ , -OR １３ , -C(O)R １３ , -C(O)OR １３ , -S(O) ０－２ R １３ , -NR １３ S (O) ０－２ -R １３ , -S(O) ０－２ N (R １３ ) ２ , -NR １３ S (O) ０－２ N (R １３ ) ２ , -NR １３ C(O)N(R １３ ) ２ , -C(O)N(R １３ ) ２ , -NR １３ C(O)R １３ , -OC(O)N(R １３ ) ２ , or -NR １３ C(O)OR １３ where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z １ｂ optionally replaced by Each R １３ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R １３ Each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z １ｂ optionally replaced by Each Z １ｂ are independently halo, cyano, hydroxy, —SH, —NH ２ , -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C １－６ Alkyl, -L-C ２－６ alkenyl, -L-C ２－６ Alkynyl, -L-C １－６ Haloalkyl, -L-C ３－１０ cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; Each L is independently —O—, —NH—, —S—, —S(O)—, or —S(O) ２ -, -N(C １－６ alkyl)-, -N(C ２－６ alkenyl)-, -N(C ２－６ alkynyl)-, -N(C １－６ haloalkyl)-, -N(C ３－１０ cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C １－６ alkyl)-, -C(O)N(C ２－６ alkenyl)-, -C(O)N(C ２－６ alkynyl)-, -C(O)N(C １－６ haloalkyl)-, -C(O)N(C ３－１０ cycloalkyl)-, —C(O)N(heterocyclyl)-, —C(O)N(aryl)-, —C(O)N(heteroaryl)-, —NHC(O)-, —NHC(O)O-, —NHC(O)NH-, —NHS(O)-, or —S(O) ２ NH-, Here, Z １ｂ and each C of L １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, and heteroaryl independently represent 1 to 5 halo, cyano, hydroxy, —SH, —NH ２ , -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－１０ Optionally further substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl).

2. 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Y is O.

3. 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Z is O.

4. 2. The compound of claim 1 , wherein the compound is represented by Formula IA, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: 【Chemistry 2】

5. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein A is N or CH.

6. 10. The compound of claim 1, wherein the compound is represented by formula IB, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: 【Chemistry 3】

7. 2. The compound of claim 1 , wherein the compound is represented by formula IC, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: 【Chemistry 4】

8. R ３ is hydrogen, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

9. R ５ But C ３－１０ cycloalkyl or heteroaryl, wherein said C ３－１０ The cycloalkyl or heteroaryl independently has 1 to 5 Z １ 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, optionally substituted with

10. R ５ is cyclobutyl, pyridyl, or pyrimidin-2-yl, wherein said cyclobutyl, pyridyl, or pyrimidin-2-yl is selected from the group consisting of 1 to 5 Z １ 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, optionally substituted with

11. Each Z １ is independently halo or cyano, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

12. R ５ is 5-fluoropyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, pyrimidin-2-yl, or 3-hydroxy-3-methylcyclobutyl, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

13. R ４ and R ５ But together, 1 to 8 Z １ 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein the compound forms a heterocyclyl or heteroaryl ring optionally substituted with

14. 2. The compound of claim 1 , wherein the compound is represented by Formula II, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: 【Chemistry 5】 (Wherein, ring A is C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl may be one to eight Z １ (optionally replaced by ).

15. R ４ is hydrogen or C １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:

16. R ４ 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: is hydrogen or methyl.

17. R ４ is hydrogen, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

18. R ６ is hydrogen, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

19. R ７ is hydrogen, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

20. R ６ and R ７ But, they combine to form C ３－１０ 2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, which forms a cycloalkyl.

21. 15. The compound of claim 14, wherein the compound is represented by Formula III, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: 【Chemistry 6】

22. Each R ２ is independently hydrogen or halo, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

23. 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein X is fluoro.

24. X is fluoro and at least one R ２ is hydrogen, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

25. X is fluoro and one of R ２ is hydrogen, and the other R ２ 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein is fluoro.

26. Each R １ is independently hydrogen or halo, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

27. Each R １ is hydrogen, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

28. Ring A is C ３－１０ cycloalkyl or heteroaryl, wherein said C ３－１０ The cycloalkyl or heteroaryl independently has 1 to 5 Z １ 22. The compound of claim 21, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, optionally substituted with

29. Ring A is cyclobutyl, pyridyl, or pyrimidin-2-yl, wherein said cyclobutyl, pyridyl, or pyrimidin-2-yl is selected from the group consisting of 1 to 5 Z １ 29. The compound of claim 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, optionally substituted with

30. Each Z １ is independently halo or cyano, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

31. 22. The compound of claim 21, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Ring A is 5-fluoropyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, pyrimidin-2-yl, or 3-hydroxy-3-methylcyclobutyl.

32. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof.

33. A pharmaceutical composition comprising a compound of claim 1 or 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

34. 34. The pharmaceutical composition of claim 33 for treating a disease or condition mediated at least in part by NLRP3.

35. 35. The pharmaceutical composition of claim 34, wherein the disease or condition is Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation caused by chikungunya virus, or traumatic brain injury.

36. 36. The pharmaceutical composition of claim 35, wherein the disease is nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

37. 36. The pharmaceutical composition of claim 35, wherein the disease is Alzheimer's disease.

38. 34. A composition comprising the compound of claim 1 or 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for treating a disease or condition mediated at least in part by NLRP3.

39. 39. The composition of claim 38, wherein the disease or condition is Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation caused by chikungunya virus, or traumatic brain injury.

40. 38. A composition comprising a compound of claim 1 or 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in therapy.

41. 41. A composition comprising a compound of claim 1 or 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating Alzheimer's disease.

42. 36. Use of a compound of claim 1 or 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for the manufacture of a medicament for treating neurodegenerative diseases, Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, chikungunya virus-induced joint inflammation, or traumatic brain injury.

43. A composition comprising the compound of claim 1 or 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for treating neurodegenerative diseases, Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation caused by chikungunya virus, or traumatic brain injury.

Images