Modulators of NLR family pyrin domain containing 3 and methods associated therewith

Abstract

The present disclosure relates generally to small molecule modulators of NLR Family Pyrin Domain Containing 3 (NLRP3), or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, methods of making and intermediates thereof, and methods of using thereof.

Description

Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO COMPOUNDS, COMPOSITIONS, AND METHODSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U. S. C. §119(e) to U. S. Provisional Application Numbers 63 / 736,515, filed December 19, 2024, which is incorporated by reference in its entirety.FIELD

[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

[0003] Inhibition of NLRP3 activation has been shown to result in potent therapeutic effects in animal models of inflammatory diseases. Modulators of NLRP3, inhibitors in particular, have broad therapeutic potential in a wide array of auto-inflammatory and chronic inflammatory diseases that either require better treatment options or for which no adequate therapies exist. Therapies targeting NLRP3 -dependent cytokines are already approved for therapeutic use; however, they have notable disadvantages relative to direct NLRP3 antagonists. There remains a strong impetus for the discovery and clinical development of molecules that antagonize NLRP3.DESCRIPTION

[0004] Provided herein are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, that are useful in treating and / or preventing 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 as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0007] In another embodiment, provided is a method for treating a disease or condition mediated, at least in part, by NLRP3, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof. In some embodiment, the disease or condition is Alzheimer’s disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndromes, gout, inflammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, optic neuritis, oxalate-induced nephropathy, hyperinflammation following influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, type 2 diabetes, obesity, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation triggered by chikungunya virus, or traumatic brain injury.SMRH:4928-6629-9266.2 -1-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0008] In another embodiment, provided is a method for treating a disease or condition is a metabolic diseases, diabetes, obesity-related diseases, obesity related glomerulopathy, lowering body weight, obesity / weight loss independent of diabetes, both weight loss / obesity, or diabetes.

[0009] In another embodiment, provided is a method for treating a disease or condition mediated, at least in part, by TNF-α, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof. In some embodiments the administration is to a subject resistant to treatment with an anti-TNF-a agent. In some embodiments, the disease is a gut disease or condition. In some embodiments, the disease or condition is inflammatory bowel disease, Crohn’s disease, or ulcerative colitis.

[0010] The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, methods of using (or administering) and making the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, and intermediates thereof.

[0011] The disclosure further provides compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, or compositions thereof for use in a method of treating a disease, disorder, or condition that is mediated, at least in part, by NLRP3.

[0012] Moreover, the disclosure provides uses of the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder, or condition that is mediated, at least in part, by NLRP3.

[0013] The description herein sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.1. Definitions

[0014] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0015] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0016] The prefix “Cu-V” indicates that the following group has from u to v carbon atoms. For example, “Ci-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.SMRH:4928-6629-9266.2 -2-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0017] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CFF CFb), sec -butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., - ChE^), and “propyl” includes n-propyl (i.e., -(CFF CFb), and isopropyl (i.e., -CH(CH3)2).

[0018] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group (for example, methylenyl, ethylenyl, and propylenyl), an “arylene” group or an “arylenyl” group (for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene), respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0019] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and1,2-dimethylbutoxy.

[0020] “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” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e.,C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl), or 3 to 5 ring carbon atoms (i.e., C3-5 cycloalkyl). 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. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aromatic ring, regardless of the attachment to the remainder of the molecule.

[0021] “Cyclopropyl” refers to the group consisting of a cyclopropyl moiety.

[0022] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0023] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is SMRH:4928-6629-9266.2 -3-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO substituted with more than one halogen, it may 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, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0024] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0025] “Halocycloalkyl” refers to a cycloalkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. “Halocyclopropyl” refers to a cyclopropyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0026] Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0027] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. 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 have been replaced by deuterium.

[0028] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index. An18F,3H,11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily availableSMRH:4928-6629-9266.2 -4-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0029] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0030] In many cases, the compounds of this 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.

[0031] Provided are also or a pharmaceutically acceptable salt, isotopically enriched analog, deuterated analog, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0032] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., 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. Likewise, pharmaceutically 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, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.SMRH:4928-6629-9266.2 -5-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0033] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0034] “Prodrugs” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the 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 hydroxy functional groups in compounds described herein, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A. C. S. Symposium Series; “Design of Prodrugs,” ed. H.Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.2. Compounds

[0035] Provided herein are compounds that are modulators of NLRP3. In certain embodiments, provided is a compound of Formula I:OH N''NyNor a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, wherein: R1is cyano, halo, C1-5 alkyl, C1-5 alkoxy, C3-C5 cycloalkyl, C1-5 haloalkyl, C1-5 haloalkoxy, or C3-C5 halocycloalkyl;R2is hydrogen, halo, or C1-3 alkyl;R3is C1-3 alkyl; andR4is C1-2 alkyl or C1-2 haloalkyl.

[0036] In certain embodiments, R1is cyano.

[0037] In certain embodiments, R1is chloro.

[0038] In certain embodiments, R1is methyl.SMRH:4928-6629-9266.2 -6-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0039] In certain embodiments, R1is ethyl.

[0040] In certain embodiments, R1is difluoromethyl.

[0041] In certain embodiments, R1is trifluoromethyl.

[0042] In certain embodiments, R1is methoxy.

[0043] In certain embodiments, R1is difluoromethoxy.

[0044] In certain embodiments, R1is trifluoromethoxy.

[0045] In certain embodiments, R1is cyclopropyl.

[0046] In certain embodiments, R1is 2,2,2-trifluoroethyl.

[0047] In certain embodiments, R1is 1,1 -difluoroethyl.

[0048] In certain embodiments, R2is hydrogen.

[0049] In certain embodiments, R2is fluoro.

[0050] In certain embodimetns, R2is methyl.

[0051] In certain embodiments, R3is methyl or ethyl.

[0052] In certain embodiments, R3is methyl.

[0053] In certain embodiments, R4is methyl.

[0054] In certain embodimetns, R4is ethyl.

[0055] In certain embodiments, R4is 2-fluoroethyl.

[0056] In certain embodiments, provided is a compound selected from Table 1 or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof.Table 1Compound No. StructureOH N'" A'Y1OH N'V''fV2JFi J lAI J V 1 1FOOH N-NY"' rrF3SMRH:4928-6629-9266.2 -7-Attorney Docket No.: 95BK-403118-WOTNV-028-26-WOCompound No. StructureOH N'N^N / 'Y^ / ‘F4XX T Y CK OH NV 'fY5 h- zz - F Z h —H / / X X O 'H N'YW6 \ / °Q>F'^O'x^-^7OH N^¥N'-prF8H OH N-NYN'-rVF9X \NVH OHN<-NyN''-r^YF10sJU k1FTOH N'N^N / ,'r^v*F11SMRH:4928-6629-9266.2 -8-Attorney Docket No.: 95BK-403118-WOTNV-028-26-WOCompound No. StructureH OH NV TY12. J YcOH NV ' / V13FOHN-. NYH„.p^F 14F rfVY^YN N1 II J 1 1F 0OHNY '-rY15 AV VF / J TsF F0HN ^YlY16 AV V fJJ1 1FH_N,, _> F OH N" Y | |17J& Y VH OH N ¥ T Y* 18 L J JU i <H.hk / N,, ^F OH N" Y | |19A v YSMRH:4928-6629-9266.2 -9-Attorney Docket No.: 95BK-403118-WOTNV-028-26-WOCompound No. StructureH, N. N / ,OH N Y T T20Y?F21XZ / } -\ >=\ / z / A / OH22 \ / °O O AV iY A / / I _OH N \Z-NrF' 'z— \23 Y zZIvcu?F H Y^Nz, ^F OH N Y 1 T 24 AY IJ Y f LOH25 NY '-YFk26H OH N ' | | 27F>bb|X<FTSMRH:4928-6629-9266.2 -10-Attorney Docket No.: 95BK-403118-WOTNV-028-26-WOCompound No. StructureH OH N -' V I T 28:yCA"?OH N'Ny'N''-<xxy*F29OH NV ' / V 30g Y A r - / / y I _\~z—.( ''z—OH N'-N><f -=N''-rxXXY*FZI311< - OH N''NyNvr^YF32xyv v33Hk l, N.. Nz,OH N Y \ \ 34jy r ■H / Nz, / \^F OH N Y T T35FrVv-JU1 C"1 JFTSMRH:4928-6629-9266.2 -11-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO 3. Methods

[0057] ‘ ‘Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0058] ‘ ‘Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0059] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy, and / or veterinary applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0060] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0061] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. 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 the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to SMRH:4928-6629-9266.2 - 12-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The compounds may be further characterized to examine the safety or tolerance dosage in human or nonhuman subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0062] In certain embodiments, provided are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, that modulate the activity of NLR Family Pyrin Domain Containing 3 (NLRP3). In certain embodiments, the compounds provided herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, inhibit the activation of NLRP3.

[0063] NLR proteins are involved in the immune system, helping to start and regulate the immune system’s response to injury, toxins, or invasion by microorganisms. NLRP3 (also known as cryopyrin, NALP3, LRR and PYD domains-containing protein 3), is a protein encoded by the NLRP3 gene (also known as CIAS1). Once activated, NLRP3 molecules assemble, along with other proteins, into inflammasomes. The activation of NLRP3 by cellular stress leads to inflammasome activation and downstream proteolytic events, including the formation of active proinflammatory cytokines such as interleukin (IL)-1β and IL-18 which are then secreted. Among other cytokines, IL-1β and IL-18 are known mediators of inflammation, e.g., artery wall inflammation, atherosclerosis and the aging process.

[0064] In certain embodiments, provided is a method of inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity comprising contacting a cell with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof. The inhibiting can be in vitro or in vivo.

[0065] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, for use in inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0066] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, in the manufacture of a medicament for inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0067] Chronic inflammation responses have been associated with various types of cancer. During malignant transformation or cancer therapy, inflammasomes may become activated in response to certain signals; and IL-1β expression is elevated in a variety of cancers (e.g., breast, prostate, colon, lung, head and neck cancers, melanomas, etc.), where patients with IL-1β producing tumors generally have a worse prognosis.

[0068] In certain embodiments, provided is a method for treating a disease or condition mediated, at least in part, by NLRP3, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, to a subject in need thereof.SMRH:4928-6629-9266.2 -13-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0069] 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 pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof.

[0070] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, for use in treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof.

[0071] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, 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.

[0072] In certain embodiments, provided is a method for treating inflammation, an auto-immune disease, cancer, an infection, a central nervous system disease, a metabolic disease, a cardiovascular disease, a respiratory disease, a liver disease, a renal disease, an ocular disease, a skin disease, a lymphatic condition, a psychological disorder, graft versus host disease, allodynia, and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof.

[0073] In certain embodiments, the disease or condition may be a disease or condition of the immune system, the cardiovascular system, the endocrine system, the gastrointestinal tract, the renal system, the hepatic system, the metabolic system, the respiratory system, the central nervous system, may be a cancer or other malignancy, and / or may be caused by or associated with a pathogen. It will be appreciated that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive.

[0074] In certain embodiments, the disease or condition includes, inflammation, including inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease, inflammation occurring as a symptom of a non-inflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity; auto-immune diseases such as acute disseminated encephalitis, Addison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn’s disease, type 1 diabetes (T1D), Goodpasture’s syndrome, Graves’ disease, Guillain-Barre syndrome (GBS), Hashimoto’s disease, idiopathic thrombocytopenic purpura, Kawasaki’s 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 neuritis, Ord’s thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still’s disease, SMRH:4928-6629-9266.2 -14-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO refractory gouty arthritis, Reiter’s syndrome, Sjogren’s syndrome, systemic sclerosis a systemic connective tissue disorder, Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener’s granulomatosis, alopecia universalis, Behcet’s disease, Chagas’ disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo or vulvodynia; cancer including lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal and squamous cell skin cancer, 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, oesophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumor, lymphoma including cutaneous T cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinuses cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity 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, stomach cancer, testicular cancer, thymus cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor; infections including viral infections (e.g. from influenza virus, human immunodeficiency virus (HIV), alphavirus (such as Chikungunya and Ross River virus), flaviviruses (such as Dengue virus and Zika virus), herpes viruses (such as Epstein Ban- Virus, cytomegalovirus, Varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (Modified vaccinia virus Ankara) and Myxoma virus), adenoviruses (such as Adenovirus 5), or papillomavirus), bacterial infections (e.g. from Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, 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, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections (e.g. from Candida or Aspergillus species), protozoan infections (e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (e.g. from schistosoma, roundworms, tapeworms or flukes) and prion infections; central nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, and amyotrophic SMRH:4928-6629-9266.2 - 15 -Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO lateral sclerosis; metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudo-gout; cardiovascular diseases such as hypertension, ischemia, reperfusion injury including post-MI ischemic 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, aneurysms including abdominal aortic aneurysm, and pericarditis including Dressier’s syndrome; respiratory diseases including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle induced inflammation, cystic fibrosis and idiopathic pulmonary fibrosis; liver diseases including non-alcoholic fatty liver disease (NAFLD), and metabolic dysfunction-associated steatohepatitis (MASH) including advanced fibrosis stages F3 and F4; alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH); renal diseases including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma; skin diseases including dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin diseases, and acne conglobata; lymphatic conditions such as lymphangitis and Castleman’s disease; psychological disorders such as depression and psychological stress; graft versus host disease; allodynia including mechanical allodynia; and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0075] In certain embodiments, the disease, disorder or condition is an autoinflammatory disease such as 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 Syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor antagonist (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still’s disease (AOSD), haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2- associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).

[0076] In certain embodiments, provided is a method for treating a disease or condition selected from asthma, allergic airway inflammation, cryopyrin-associated periodic syndromes, gout, inflammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, optic neuritis, oxalate-induced nephropathy, hyperinflammation following influenza infection, graft- versus-host disease, stroke, silicosis, type 1 diabetes, type 2 diabetes, obesity, obesity-induced inflammation or insulin resistance, SMRH:4928-6629-9266.2 -16-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation triggered by chikungunya virus, or traumatic brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof.

[0077] In certain embodiments, provided is a method for treating a disease or condition selected from an autoinflammatory disorder and / or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (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 nonalcoholic fatty liver disease (NAFLD), non-alcoholic 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 pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof.

[0078] In certain embodiments, provided is a method for treating a disease or condition selected from cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA); hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), Tumor Necrosis Factor (TNF), Receptor-Associated Periodic Syndrome (TRAPS), systemic juvenile idiopathic arthritis, adultonset Still’s disease (AOSD), relapsing polychondritis, Schnitzler’s syndrome, Sweet’s syndrome, Behcet’s disease, anti-synthetase syndrome, deficiency of interleukin 1 receptor antagonist (DIRA), and haploinsufficiency of A20 (HA20) comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof.

[0079] In certain embodiments, provided is a method for treating a disease or condition selected from asthma, allergic airway inflammation, cryopyrin-associated periodic syndromes, gout, inflammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, optic neuritis, oxalate-induced nephropathy, hyperinflammation following influenza infection, graft- versus-host disease, stroke, silicosis, type 1 diabetes, type 2 diabetes, obesity, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation triggered by chikungunya virus, or traumatic brain injury.comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof.SMRH:4928-6629-9266.2 -17-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0080] In certain embodiments, provided is a method for treating a disease or condition that is 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 a gut disease or condition. In some embodiments the disease or condition is inflammatory bowel disease, Crohn’s disease, or ulcerative colitis. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof is administered in combination with an anti-TNF-α agent. In some embodiments, the anti-TNF-a agent is infliximab, etanercept, certolizumab pegol, golimumab, or adalimumab.

[0081] In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof is administered in combination with weight loss drug. In some embodiments, the weight loss drug is a GLP-1 agonist.

[0082] In some embodiments, the weight loss drug is tirzepatide (Mounjaro®, Zepbound®), exenatide (Byetta®, Bydureon®, Exendin-4), lixisenatide (Lyxumia®), I i rag In tide (Victoza®, NN2211), dulaglutide (LY2189265, Trulicity®), albiglutide (Tanzeum®), semaglutide (Wegovy®, Rybelsus®, Ozempic®), Retatrutide (LY3437943), mazdutide (LY3305677), efpeglenatide (HM11260C), taspoglutide (R1583, BIM51077, ITM077), survodutide (B 1456906), cotadutide (MEDI0382), pemvidutide (ALT-801), efinopegdutide (MK-6024), efocipegtrutide (HM15211), pegloxenatide (PEX168), pegapamodutide (LY2944876), albenatide (CJC1134PC), utreglutide (GL0034), ZP2929, NNC0113-0987, BPI-3016, TT401, SAR441255, BI-456906, ALT-801, AC-3174, SAR-425899, HM-15211, YH-25723, YH-25724, YH-22241, YH-GLP1, RPC-8844, PB-718, NN-6177, CT-388, CT-868, XW003, XW004, CJC-1134, CJC-1131, AMG133, DD-01, DD-03, DD-14, DD-15, ID110521156, TERN-601, MDR-0001, HPG5119, ECC5004, VK2735, orforglipron (LY3502970), danuglipron (PF06882961), lotiglipron (PF07081532), CT-996, HRS-7535, V-0219, XW014, PF-06882961, LSN3318839, and TTP273.

[0083] In certain embodiments, the disease or condition is an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0084] In certain embodiments, the disease or condition is an autoinflammatory disorder and / or an autoimmune disorder.

[0085] In certain embodiments, the disease or condition is a neurodegenerative disease.

[0086] In certain embodiments, the disease or condition is Parkinson’s disease or Alzheimer’s disease.

[0087] In certain embodiments, provided is a method for treating cancer, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, to a subject in need thereof.

[0088] In certain embodiments, the cancer is metastasizing cancer, gastrointestinal cancer, skin cancer, non-small-cell lung carcinoma, or colorectal adenocarcinoma.

[0089] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, 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.SMRH:4928-6629-9266.2 -18-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0090] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, for use in treating cancer in a subject in need thereof.

[0091] In certain embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, may be administered alone as a sole therapy or can be administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.

[0092] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0093] Other embodiments include use of the presently disclosed compounds in therapy.4. Kits

[0094] Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, and suitable packaging. In certain embodiments, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, and a label and / or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

[0095] Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.5. Pharmaceutical Compositions and Modes of Administration

[0096] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt, or prodrug thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

[0097] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, SMRH:4928-6629-9266.2 -19-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0098] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0099] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0100] Some examples of suitable excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0101] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0102] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched SMRH:4928-6629-9266.2 -20-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO analog, or prodrug thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0103] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0104] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically 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 pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, orally or nasally, from devices that deliver the formulation in an appropriate manner.6. Dosing

[0105] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. In some embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.7. Synthesis of the Compounds

[0106] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art.SMRH:4928-6629-9266.2 -21-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

[0107] It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0108] Additionally, conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various f unctional groups as well as suitable conditions for protecting and deprotecti ng particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N. J., Wiley-Interscience, and references cited therein. For example, protecting groups for alcohols, such as hydroxy, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ion, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, removed by acid or base, benzoyl, removed by acid or base, benzyl, removed by hydrogenation, methoxyethoxymethyl ether, removed by acid, dimethoxytrityl, removed by acid, methoxymethyl ether, removed by acid, tetrahydropyranyl or tetrahydrofuranyl, removed by acid, and trityl, removed by acid. Examples of protecting groups for amines include carbobenzyloxy, removed by hydrogenolysis p-methoxybenzyl carbonyl, removed by hydrogenolysis, tert-butyloxy carbonyl, removed by concentrated strong acid (such as HC1 or CF3COOH), or by heating to greater than about 80 °C, 9 -fluorenylmethyloxy carbonyl, removed by base, such as piperidine, acetyl, removed by treatment with a base, benzoyl, removed by treatment with a base, benzyl, removed by hydrogenolysis, carbamate group, removed by acid and mild heating, p-methoxybenzyl, removed by hydrogenolysis, 3,4-dimethoxybenzyl, removed by hydrogenolysis, p-methoxyphenyl, removed by ammonium cerium(IV) nitrate, tosyl, removed by concentrated acid (such as HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide), troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid, and sulfonamides (Nosyl & Nps), removed by samarium iodide or tributyltin hydride.

[0109] 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 or obvious modifications thereof, 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 SMRH:4928-6629-9266.2 -22-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO 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).

[0110] Scheme I illustrates a general method which can be employed for the synthesis of compounds described herein, wherein each of R1, R2, R3, and R4are independently as defined herein, LG is a suitable leaving group, such as halo (e.g., Cl, Br, or I), and Z is H or a suitable hydroxy protecting group, such as alkyl groups (such as methyl or t-butyl), methyoxymethyl ether groups (MOM), and the like.Scheme I1-1

[0111] The compounds of Formula I are prepared by coupling compound 1-2 and compound 1-1, wherein B is a suitable functional group such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic ester (cyclic or acyclic, such as B(OR50)2, wherein each R50is independently an alkyl or substituted alkyl, or the two R50join to form a cyclic boronic ester, which may be optionally substituted (e.g., pinacol boronic ester)), zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, fluorosulfonyl esters, tin, sodium, hydrogen, and the like. Such reactions are commonly utilized for aromatic functionalization, and are typically conducted in the presence of suitable catalyst such as, but not limited to, a palladium catalyst including [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPhs)4, PdCb(PPh3)2 or tris(dibenzylideneacetone)dipalladium(0), and the like, or a copper catalyst such as CuCl or Cui, and if required, a suitable mediator, co-catalyst and / or base known to one skilled in the art using suitable solvents / solvent mixtures. When Z is a suitable hydroxy protecting group, standard deprotection conditions are employed to achieve compounds of Formula I. Upon reaction completion, compounds of Formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. Compounds 1-1 and 1-2 may be commercially obtained or synthesized according to methods described herein.EXAMPLES

[0112] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.SMRH:4928-6629-9266.2 -23-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO General Experimental Methods

[0113] All solvents used were commercially available and were used without further purification.Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen.

[0114] NMR Spectroscopy:1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using 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 SI, a Bruker Avance 400 instrument equipped with probe 6 SI 400 MHz 5mmID, a Bruker Avance III 400 instrument with nanobay equipped with probe Broadband BBFO 5 mm direct, a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBO probe operating at 400 MHz. All deuterated solvents contained typically 0.03% to 0.05% v / v tetramethylsilane, which was used as the reference signal (set at δ 0.00 for both1H and13C). In certain cases, 'H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker Advance 400 instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (8) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0115] Thin Layer Chromatography: Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel F254 (Merck) plates, Rf is the distance travelled by the compound divided by the distance travelled by the solvent on a TLC plate. Column chromatography was performed using an automatic flash chromatography system over silica gel cartridges or in the case of reverse phase chromatography over C18 cartridges. Alternatively, thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60 F254) from Mancherey-Nagel and UV was typically used to visualize the spots. Additional visualization methods were also employed in some cases. In these cases the TLC plate was developed with iodine (generated by adding approximately 1 g of I2to 10 g silica gel and thoroughly mixing), ninhydrin (available commercially from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g (NH4)6Mo? O24.4H2O, 5 g (NH4)2Ce(IV)(NO3)6in 450 mL water and 50 mL concentrated H2SO4) to visualize the compound.

[0116] Liquid Chromatography-Mass Spectrometry and HPLC Analysis: HPLC analysis was performed on Shimadzu 20AB HPLC system with a photodiode array detector and Luna-C18(2) 2.0x50 mm, 5 pm column at a flow rate of 1.2 mL / min with a gradient solvent Mobile phase A (MPA, H2O+O. O37 % (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). LCMS was detected under 220 and 254 nm or used evaporative light scattering (ELSD) detection as well as positive electrospray ionization (MS). Semi -preparative HPLC was performed by either acidic or neutral conditions. Acidic: Luna C18 100 x 30 mm, 5 pm; MPA: HC1 / H20=0.04%, or formic acid / H2O=0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 x 25, 5 pm; MPA: 10 mM NH4HCO3 in H2O; MPB: ACN. Gradient for both conditions: 10% of MPB to 80% of MPB over 12 min at a flow rate of 20 mL / min, then 100% MPB over 2 min, 10% MPB over 2 min, UV detector. SFC analysis was performed SMRH:4928-6629-9266.2 - 24-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO on Thar analytical SFC system with a UV / Vis detector and series of chiral columns including AD, AS-H, OJ, OD, AY and IC, 4.6 x 100 mm, 3 jam column at a flow rate of 4 mL / min with a gradient solvent Mobile phase A (MPA, CO2): Mobile phase B (MPB, MeOH+0.05 % (v / v) IP Am) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB). SFC preparative was performed on Thar 80 preparative SFC system with a UV / Vis detector and series of chiral preparative columns including AD-H, AS-H, OJ-H, OD-H, AY-H and IC-H, 30x250 mm, 5 an column at a flow rate of 65 mL / min with a gradient solvent 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). LC-MS data were also collected using an UPLC-MS Acquity™ system equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternated positive and negative electrospray ionization mode. The column used was a Cortecs UPLC Cl 8, 1.6 pm, 2.1 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.1% formic acid in water) and ending at 95% B (B: 0.1% formic acid in MeCN) over 2.0 min with a total run time of 2.5 min. The column temperature was at 40 °C with the flow rate of 0.8 mL / min.Intermediate 16-chloro-7V-((31?,51?)-5-fluoro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine

[0117] tert-butyl ( (3 / ?.5 / ?)-5-fluoro- l-methylpiperidin-3-yl)carbamate: To a solution of tert-butyl ((37?,57?)-5-fluoropiperidin-3-yl)carbamate (29.5 g, 135 mmol) in THF (600 mL) at 0 °C were added DIEA (43.6 g, 338 mmol) and iodomethane (19.2 g, 135 mmol). The mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to provide a residue that was used directly.

[0118] (3 / ?.5 / ?)-5-fhion)- Lmethylpiperidin-3-amine hydrochloride: To a solution of tert-butyl ((37?,57?)-5-fluoro-l-methylpiperidin-3-yl)carbamate (27 g, 116 mmol) in EtOAc (100 mL) was added HC1 (2M in EtOAc, 500 mL). The mixture was stirred for 12 h. The reaction mixture was concentrated under reduced pressure to provide a residue that was used directly.

[0119] 6-chloro-7V-((31f,51f)-5-fluoro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine: To a solution of 3,6-dichloro-5-methyl-l,2,4-triazine (15 g, 91.4 mmol) and (37?, 5R)-5 -fluoro- 1-methylpiperidin-3 -amine hydrochloride (18.8 g, 91.5 mmol) in 1,4-dioxane (450 mL) was added NaHCOs (31 g, 366 mmol). The mixture was stirred at 85 °C for 16 h. The reaction mixture was quenched with H2O (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 260.2, 262.2 [M+H]+.SMRH:4928-6629-9266.2 -25-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO Intermediate 26-chloro-A^-((31f,51f)-l-ethyl-5-fluoropiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amineBocHN,,

[0120] te -butyl ((37?,57?)-l-ethyl-5-fluoropiperidin-3-yl)carbamate: To a solution of tert-butyl ((37?,57?)-5-fluoropiperidin-3-yl)carbamate (3.0 g 13.8 mmol) in THF (45 mL) at 0 °C were added DIEA (3.5 g, 27.5 mmol) and EtI (2.57 g, 16.5 mmol) at 0 °C. The solution was stirred at 40 °C for 8 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0121] (31f,51f)-l-ethyl-5-fluoropiperidin-3-amine hydrochloride: A solution of tert-butyl ((37?,57?)-l-ethyl-5-fluoropiperidin-3-yl)carbamate (3.2 g 13 mmol) in HC1 (2M in EtOAc, 100 mL) was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to provide a residue that was used directly.

[0122] 6-chloro-iV-((31f,51f)-l-ethyl-5-fluoropiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine: To a solution of (37?,57?)-l-ethyl-5-fhioropiperidin-3-amine hydrochloride (2.23 g, 12.2 mmol) and 3,6-dichloro-5 -methyl- 1, 2, 4-triazine (2.0 g, 12.2 mmol) in 1,4-dioxane (50 mL) was added NaHCCf (4.1 g, 48.8 mmol). The mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 274.1, 276.1 [M+H]+.Intermediate 36-chloro-iV-((31f,51f)-l-ethyl-5-fluoropiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amineF F

[0123] 4-bromo-3-(methoxymethoxy)benzaldehyde: To a solution of 4-bromo-3-hydroxybenzaldehyde (25 g, 124 mmol) in DCM (300 mL) were added DIEA (32 g, 249 mmol) and bromo(methoxy)methane (18.6 g, 149 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was diluted with H2O (300 mL) and extracted with DCM (3 x 70 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatograph.

[0124] l-bromo-4-(difluoromethyl)-2-(methoxymethoxy)benzene: Solution 1: 4-bromo-3-(methoxymethoxy)benzaldehyde (14.0 g, 57 mmol) in DCE (140 mL); Solution 2: DAST (18.4 g, 114.3 mmol) in DCE (140 mL). Solution 1 was pumped by Pump 1 (6.8 mL / min) into a flow reactor (FLR1, SMRH:4928-6629-9266.2 - 26-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO PFA, Coils reactor, 3.175(1 / 8”) mm, 68.06 mL, 25 °C) with concurrent pumping of Solution 2 by Pump 2 (6.8 mL / min) into the same reactor. The residence time of flow reactor 1 was 5 min. Pump 1 and Pump 2 were started at the same time and the reaction mixture was collected for 30 mins. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into sat. aq. NaHCO? (300 mL), and then extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0125] 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane:To a solution of l-bromo-4-(difluoromethyl)-2-(methoxymethoxy)benzene (10.0 g, 37.4 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(l,3,2-dioxaborolane) (12.4 g, 48.7 mmol) in 1,4-dioxane (150 mL) were added KO Ac (7.35 g, 74.89 mmol) and Pd(dppf)C12 (1.37 g, 1.87 mmol). The reaction solution was stirred at 100 °C for 6 h. The reaction mixture was filtered through a Celite pad. The filtrate was diluted with H2O (200 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with PE (70 mL), filtered, and the solution was concentrated under reduced pressure to provide a residue that was used directly.Example 12-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-5- (trifluoromethyl)phenol (Compound 35)

[0126] To a solution of 6-chloro-A-((37?,57?)-5-fluoro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine (60 mg, 0.23 mmol, Intermediate 1) and 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (100 mg, 0.35 mmol) in H2O (0.4 mL) and 1,4-dioxane (2 mL) were added K2CO3 (96 mg, 0.69 mmol) and Pd(dppf)C12 (17 mg, 0.023 mmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 386.1 [M+H]+.Example 25-chloro-2-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]phenol (Compound 31)SMRH:4928-6629-9266.2 - 27-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0127] To a solution of 6-chloro-A-((37?,57?)-5-fhioro- l-methylpiperidin-3-yl)-5-methyl- l,2,4-triazin-3-amine (50 mg, 0.19 mmol, Intermediate 1) and 5-chloro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (98 mg, 0.39 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added Pd(dppf)C12 (16 mg, 0.02 mmol) and CS2CO3 (125 mg, 0.39 mmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. The residue was further purified by silica gel preparative thin-layer chromatography. LCMS: m / z = 352.0, 354.0 [M+H]+.Example 32-[3-[[(31f,51f)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-5- (trifluoromethyl)phenol (Compound 30)

[0128] To a solution of 6-chloro-iV-((37?,57?)- l-ethyl-5-fluoropiperidin-3-yl)-5-methyl- 1,2,4-triazin-3-amine (190 mg, 0.70 mmol, Intermediate 2) and 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (300 mg, 1.04 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added K2CO3 (192 mg, 1.39 mmol) and Pd(dppf)C12 (51 mg, 0.07 mmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 400.1 [M+H]+.Example 45-chloro-2-[3-[[(31f,51f)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]phenol (Compound 29)

[0129] To a solution of 6-chloro-iV-((37?,57?)- l-ethyl-5-fhioropiperidin-3-yl)-5-methyl- 1,2,4-triazin-3-amine (150 mg, 0.55 mmol, Intermediate 2) and 5-chloro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (210 mg, 0.82 mmol) in 1,4-dioxane (4 mL) and H2O (0.8 mL) were added Pd(dppf)C12 (45 mg, 0.06 mmol) and CS2CO3 (357 mg, 1.10 mmol). The mixture was stirred at 100 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 366.1, 368.0 [M+H]+.SMRH:4928-6629-9266.2 -28-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO Example 52-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-5-methyl-phenol (Compound 32)

[0130] To a solution of 6-chloro-A-[(37?,57?)-5-fluoro- l-methyl-3-piperidyl ]-5-methyl- 1,2,4-triazin-3-amine (2.6 g, 10.0 mmol, Intermediate 1) and (2-hydroxy-4-methyl-phenyl)boronic acid (1.83 g, 12.0 mmol) in 1,4-dioxane (25 mL) and H2O (5 mL) were added K2CO3 (4.15 g, 30.0 mmol) and Pd(dppf)C12 (733 mg, 1.00 mmol). The mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 332.0 [M+H]+.Example 62-[3-[[(31f,51f)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-5-methyl-phenol (Compound 25)

[0131] To a solution of 6-chloro-iV-((37?,57?)- l-ethyl-5-fhioropiperidin-3-yl)-5-methyl- 1,2,4-triazin-3-amine (50 mg, 0.18 mmol, Intermediate 2) and (2-hydroxy-4-methylphenyl)boronic acid (55 mg, 0.36 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added K2CO3 (50 mg, 0.36 mmol) and Pd(dppf)C12 (13 mg, 0.02 mmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 346.1 [M+H]+.Example 75-(difluoromethyl)-2-[3-[[(31f,51f)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6- yl]phenol (Compound 23)

[0132] 6-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-iV-((31f,51f)-l-ethyl-5-fluoropiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine: To a solution of 2-(4-(difhioromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (172 mg, 0.55 mmol, Intermediate 3) and 6-chloro-A-((37?,57?)-l-ethyl-5-fhioropiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine (100 mg, 0.37 mmol, Intermediate 2) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added K2CO3 (101 mg, 0.73 mmol) SMRH:4928-6629-9266.2 - 29-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO and Pd(dppf)C12 (27 mg, 0.04 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (1 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0133] 5-(difluoromethyl)-2-[3-[[(31f,51f)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]phenol: To a solution of 6-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-iV-((37?,57?)-l-ethyl-5-fhioropiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine (160 mg, 0.38 mmol) in DCM (2 mL) was added TFA (614 mg, 5.38 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with triethylamine (1 mL) and then diluted with MeCN (1 mL). The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 382.1 [M+H]+.Example 83-fluoro-2-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-5-methyl- phenol (Compound 19)

[0134] iV-((31f,51f)-5-fluoro-l-methylpiperidin-3-yl)-6-(2-fluoro-6-methoxy-4-methylphenyl)-5-methyl-l,2,4-triazin-3-amine: To a solution of 6-chloro-A-((37?,57?)-5-fhioro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine (2.0 g, 7.70 mmol) and (2-fluoro-6-methoxy-4-methylphenyl)boronic acid (2.13 g, 11.5 mmol) in 1,4-dioxane (40 mL) and H2O (8 mL) were added CS2CO3 (5.02 g, 15.4 mmol) and XPhos Pd G3 (652 mg, 0.77 mmol). The mixture was stirred at 100 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0135] 3-fluoro-2-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-5-methyl-phenol: To a solution of iV-((37?,57?)-5 -fluoro- 1 -methylpiperidin-3-yl)-6-(2-fhioro-6-methoxy-4-methylphenyl)-5-methyl-l,2,4-triazin-3-amine (1.0 g, 2.75 mmol) in DMA (20 mL) were added NaOH (220 mg, 5.50 mmol) and dodecane- 1 -thiol (1.11 g, 5.50 mmol) at 0 °C. The mixture was stirred at 100 °C for 2 h. The reaction mixture was adjusted to pH = 6 with 6 M HC1 (aq.) and extracted with EtOAc (5 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 350.0 [M+H]+.SMRH:4928-6629-9266.2 -30-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO Example 95-(difluoromethyl)-2-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6- yl]phenol (Compound 16)

[0136] 6-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-iV-((31f,51f)-5-fluoro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine: To mixture of 6-chloro-A-((37?,57?)-5-fluoro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine (3.0 g, 11.5 mmol, Intermediate 1), 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.4 g, 17.3 mmol, Intermediate 3), Na2CO3(2.45 g, 23.1 mmol) in 1,4-dioxane (100 mL) and H2O (20 mL) was added XPhos Pd G3 (978 mg, 1.16 mmol). The mixture was stirred at 100 °C for 5 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0137] 5-(difluoromethyl)-2-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]phenol: To a solution of 6-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine (3.6 g, 8.75 mmol) in MeOH (25 mL) at 0 °C was added HC1 (6M in water, 24.8 mL). The reaction solution was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The mixture was adjusted to pH = 7-8 with 2N NaOH (aq.) and extracted with DCM: / '-PrOH (V: V = 5:1, 3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 368.0 [M+H]+.Example 105-(difluoromethoxy)-2-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6- yl]phenol (Compound 14)OH OH OMOM OMOM OMOM

[0138] 4-bromo-3-hydroxyphenyl 4-methylbenzenesulf onate: To a solution of 4-bromobenzene-l,3-diol (50 g, 264 mmol) in acetone (750 mL) were added K2COs (110 g, 793 mmol) and p-TosCl (55.5 g, 291 mmol). The mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.SMRH:4928-6629-9266.2 -31-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO

[0139] 4-bromo-3-(methoxymethoxy)phenyl 4-methylbenzenesulfonate: To a solution of NaH (13.3 g, 332 mmol, 60% purity) in THF (1000 mL) was added 4-bromo-3 -hydroxyphenyl 4-methylbenzenesulfonate (95 g, 277 mmol). The reaction mixture was stirred at 0 °C for 30 min.Bromo(methoxy)methane (41.5 g, 332 mmol) was added to the reaction mixture and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition of sat. aq. NH4CI (300 mL) at 0 °C and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0140] 4-bromo-3-(methoxymethoxy)phenol: To a solution of 4-bromo-3-(methoxymethoxy)phenyl 4-methylbenzenesulfonate (90 g, 232 mmol) in EtOH (1200 mL) at 0 °C was added KOH (65.2 g, 1.16 mol, 4M in water). The mixture was stirred at 60 °C for 2 h. The reaction was adjusted to pH = 7 with 2M HC1 (aq.). The mixture was concentrated under reduced pressure. The residue was diluted with H2O (600 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0141] l-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene: To a mixture of 4-bromo-3-(methoxymethoxy)phenol (40 g, 171 mmol) in MeCN (400 mL) at 0 °C was added a solution of KOH (192 g, 343 mmol) in H2O (400 mL). The reaction mixture was stirred at 25 °C for 30 min. The reaction was cooled to -20 °C and diethyl (bromodifluoromethyl)phosphonate (91.6 g, 343 mmol) was added to the reaction mixture. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0142] 2-(4-(difluoromethoxy)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane: To mixture of l-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (11 g, 38.9 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(l,3,2-dioxaborolane) (19.8 g, 77.7 mmol) and KOAc (11.4 g, 116 mmol) in 1,4-dioxane (300 mL) was added Pd(dppf)Cl2•CH2Cl2(3.17 g, 3.89 mmol). The reaction mixture was stirred at 100 °C for 8 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (3 x 50 mL). The combined filtrates were diluted with H2O (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), driedover anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0143] 6-(4-(difluoromethoxy)-2-(methoxymethoxy)phenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine: To a mixture of 6-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine (2.0 g, 7.70 mmol, Intermediate 1) and 2-(4-(difluoromethoxy)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.16 g, 10.0 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) were added Na2CO3(1.63 g, 15.4 mmol) and XPhos Pd G3 (652 mg, 0.77 mmol). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was SMRH:4928-6629-9266.2 - 32-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0144] 5-(difluoromethoxy)-2-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]phenol: To a mixture of 6-(4-(difluoromethoxy)-2-(methoxymethoxy)phenyl)-iV-((37?,57?)-5-fluoro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine (4.0 g, 9.36 mmol) in MeOH (15 mL) at 0 °C was added HC1 (6M in water, 15.60 mL). The reaction mixture was stirred at 20 °C for 12 h. The mixture was adjusted to pH = 6-7 with 2N NaOH (aq.) and extracted with DCM: / '-PrOH (V: V = 3:1, 3 x 20 mL). The organic layers were combined and dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 384.0 [M+H]+.Example 112-[3-[[(31f,51f)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-5- (trifluoromethoxy)phenol (Compound 6)

[0145] To a solution of 6-chloro-A-((37?,57?)-5-fhioro-l-methylpiperidin-3-yl)-5-methyl-l,2,4-triazin-3-amine (100 mg, 0.39 mmol, Intermediate 1) and (2-hydroxy-4-(trifluoromethoxy)phenyl)boronic acid (128 mg, 0.58 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added K2CO3 (106 mg, 0.77 mmol) and Pd(dppf)C12 (31 mg, 0.04 mmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 402.0 [M+H]+.

[0146] Comparative compounds A and B in Table 4 were prepared according to the examples disclosed herein.

[0147] Compounds in Table 2 was, or can be, made via similar procedures as those described above.Table 2No. Name LCMS1 3-fluoro-2- [3- [ [(37?,57?) -5 -fluoro- 1 -methyl-3-piperidyl]amino]-5 - m / z = 366.2 methyl-l,2,4-triazin-6-yl]-5-methoxy-phenol [M+H]+2 5 -(difluoromethoxy)-3-fluoro-2- [3- [ K 3 / ?, 5 / ?) -5 -fluoro- 1 -methyl-3- m / z = 402.0 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+3 5-cyclopropyl-3-fhioro-2-[3-[[(37?,57?)-5-fluoro-l-methyl-3- m / z = 376.0 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+4 5 -chloro-3 -fluoro-2- [3 - [ [ (37?, 57?) -5 -fluoro- 1 -methyl-3 - m / z = 370.0, piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol 371.9 [M+H]+SMRH:4928-6629-9266.2 -33-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO No. Name LCMS 5 5-(difluoromethyl)-3-fluoro-2-[3-[[(37?,57?)-5-fluoro-l-methyl-3- m / z = 386.0 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+7 2-[3-[[(37?,57?)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl- m / z = 348.0 l,2,4-triazin-6-yl]-5-methoxy-phenol [M+H]+8 2-[3-[[(37?,57?)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl- m / z = 400.1 l,2,4-triazin-6-yl]-5-(2,2,2-trifluoroethyl)phenol [M+H]+9 5 -( 1, 1 -difluoroethyl)-2- [3 - [ [ (37?, 57?) -5 -fluoro- 1 -methyl-3- m / z = 382.0 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+10 2- [5 -ethyl-3- [ [(3R,5R)-5 -fluoro- 1 -methyl-3-piperidyl]amino]- m / z = 400.1 l,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [M+H]+11 5-ethyl-2-[3-[[(37?,57?)-5-fhioro-l-methyl-3-piperidyl]amino]-5- m / z = 346.1 methyl- 1,2,4-triazin-6-yl]phenol [M+H]+12 5 -ethyl-3 -fluoro-2- [ 3 - [ [( 37?, 57?) - 5 -fluoro- 1 -methyl-3 - m / z = 364.2 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+13 5 -(difluoromethyl)-2- [3 - [ [ (37?, 57?) - 1 -ethyl-5 -fluoro-3- m / z = 400.1 piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-3-fluoro-phenol [M+H]+15 5-(difluoromethyl)-2-[3-[[(37?,57?)-5-fluoro-l-(2-fluoroethyl)-3- m / z = 400.1 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+17 2-[3-[[(37?,57?)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl- m / z = 364.2 l,2,4-triazin-6-yl]-3-fluoro-5-methyl-phenol [M+H]+18 5 -cyclopropyl-2- [3- [ [(37?, 57?)- 1 -ethyl-5 -fluoro-3 -piperidyl] amino] - m / z = 372.0 5 -methyl- 1,2,4-triazin-6-yl]phenol [M+H]+20 5 -(difluoromethyl)-2- [3 - [ [ (37?, 57?) - 1 -ethyl-5 -fluoro-3- m / z = 396.0 piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-3-methyl-phenol [M+H]+21 5-(difluoromethoxy)-2-[3-[[(37?,57?)-l-ethyl-5-fluoro-3- m / z = 398.0 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+22 2-[3-[[(37?,57?)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl- m / z = 416.2 l,2,4-triazin-6-yl]-5-(trifluoromethoxy)phenol [M+H]+24 5 -chloro-2- [3 - [ [(37?,57?) - 1 -ethyl-5 -fluoro-3-piperidyl]amino]-5 - m / z = 384.0, methyl- 1,2, 4-triazin-6-yl] -3-fluoro-phenol 386.0 [M+H]+SMRH:4928-6629-9266.2 -34-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO No. Name LCMS26 5 -chloro-2- [3- [[(3R,5R)- 1 -ethyl-5 -fluoro-3-piperidyl]amino]-5 - m / z = 380.1, methyl- 1,2, 4-triazin-6-yl] -3-methyl -phenol 382.0 [M+H]+27 2-[3-[[(3R,5R)-l-ethyl-5-fluoro-3-piperidyl]amino]-5-methyl- m / z = 414.1 l,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol [M+H]+28 3-fluoro-2- [3- [ [(3R,5R)-5 -fluoro- 1 -methyl-3-piperidyl]amino]-5 - m / z = 404.0 methyl-l,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [M+H]+33 5 -cyclopropyl-2- [3- [ [(3R,5R)-5 -fluoro- 1 -methyl-3- m / z = 358.1 piperidyl]amino]-5 -methyl- 1,2, 4-triazin-6-yl]phenol [M+H]+34 4-[3-[[(3R,5R)-5-fluoro-l-methyl-3-piperidyl]amino]-5-methyl- m / z = 343.1 l,2,4-triazin-6-yl]-3-hydroxy-benzonitrile [M+H]+BIOLOGICAL EXAMPLE 1Biochemical and Cellular Assays of the CompoundsProcedure for culturing THP-1 cells

[0148] Compounds as provided herein were tested in the following assay. Cell culture medium employed contained RPMI 1640 medium (89%), FBS (10%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM). Freezing medium was made up of 90% FBS and 10% DMSO. THP-1 cells were removed from the liquid nitrogen and placed into a 37 °C water bath to thaw, until signs of ice dissipated. The cells were then added to 9 mL of warm cell culture medium and centrifuged for 5 minutes at 1000 rpm. The supernatant was discarded, and the cells were resuspended in new cell culture medium. THP-1 cells were then split and cultured in the cell culture medium, being passaged every 2-3 days with the cell density will be maintained between 5xl05and 1.5xl06viable cells / mL.

[0149] To freeze, cells were resuspended with fresh freezing medium, adjusting the cell density to 5xl06cells / mL. The cell suspension was partitioned into 1 mL aliquots per vial, and the vials were transferred to a -80 °C freezer. After one day at -80 °C, the cell vials were transferred to liquid nitrogen freezer for storage.Procedure for IL-lp secretion assay in 384-well plates

[0150] PMA was dissolved in DMSO to make a stock solution at 5 mg / ml and stored in 10 pl aliquots at -20°C for single use. PMA is added to normal growth medium. LPS was diluted with 1 mL of water solution to provide a 1 mg / mL stock solution and stored in 15 pL aliquots at -20 °C for single use.Nigericin is diluted in ice cold 100% ethanol to 5 mg / ml (6.7 mM) and stored in 75 pL aliquots at -20 °C for single use. Serum-free media contains RPMI 1640 medium (99%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM). The two control conditions used to qualify and normalize test compound dose-response curves were as follows: High Control = 25 ng / mL LPS, 5 pM Nigericin, 0.5% DMSO, Low Control = 25 ng / mL, LPS, 0.5% DMSO.SMRH:4928-6629-9266.2 -35-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO Day 1: Differentiation with PMA

[0151] THP-1 cells were diluted to provide a suspension at a concentration of l. OxlO6cells / mL with the total volume of suspension required to enable the desired number of assay plates. The growth media was supplemented with PMA (5 ng / mL final concentration) and the cells were incubated at 37 °C under a humidified atmosphere of 5% CO2 for 40 h.Day 3: Plating with sequential LPS and nigericin stimulation

[0152] All media was carefully aspirated from each culture flask. The cells were washed carefully with lx DPBS. The cells were then briefly digested with trypsin LE for 5 minutes at 23 °C and immediately resuspended in cell growth media. After resuspension, the cells were centrifuged at 1000 rpm for 3 minutes and the supernatant was discarded. The cells were resuspended in DPBS and once again centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded and the cell pellet was resuspended in serum-free media supplemented with LPS (25 ng / mL final concentration) to enable the distribution of 30K THP-1 cells within 45 pL of media into each well of 384-well PDL-coated plates. The 384-well plates were then incubated at 37 °C under a humidified atmosphere of 5% CO2 for 2 h. Following this period, test compounds were dispensed by Tecan across the desired concentration range with all wells normalized to a final 0.5 % DMSO concentration. The plates were then then incubated at 37 °C under a humidified atmosphere of 5% CO2 for 1 h. Following this period, 5 pL of the 5 mg / mL nigericin stock solution was added to each of the appropriate wells and plates were centrifuged at 1000 rpm for 30 seconds. The plates were the immediately reintroduced to the incubator at 37 °C under a humidified atmosphere of 5% CO2 for 2 h. After this time, 35 pL / well of supernatant was collected and transferred into v-bottom plate and centrifuged at 1000 rpm for 1 minute. These supernatant aliquots were analyzed using an IL-1 detection kit as described below. If needed, the test samples could be snap frozen and stored at -80 °C until analyzed.IL-1 / 3 detection

[0153] To prepare each ELISA plate, capture antibody (mAb Mtl75) was diluted with PBS to a final concentration of 2 pg / mL and then 20 pL of this solution was added to each well of the ELISA plate. Each plate was allowed to incubate overnight at 4 °C. The next day, the capture antibody solution was removed and discarded. Each ELISA plate was washed 4 times with PBST followed by the addition of 25 pL / well of blocking buffer (Licor-927-40010) supplemented with 0.1% Tween 20. Each ELISA plate was then allowed to incubate for 1 hour at 23 °C. After this time, the blocking buffer was removed and discarded. Each ELISA plate was washed 4 times with PBST. During this time, the v-bottomed plates containing the supernatant aliquots from the assay run were centrifuged at 300 g for 5 minutes before transferring 15 pL / well of the supernatant sample to each ELISA plate. Each ELISA plate was then allowed to incubate for 2 h at 23 °C. After this time, the supernatant samples were removed and discarded. Each ELISA plate was washed 4 times with PBST. To each ELISA plate was added 15 pL / well of mAb7P10-biotin at 0.5 pg / mL (1:1000 diluted in blocking buffer). Each ELISA plate was then allowed to incubate for 1 h at 23 °C. After this time, the antibody solution was removed and discarded. Each ELISA plate was washed 4 times with PBST. To each ELISA plate was added 20 SMRH:4928-6629-9266.2 -36-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO pL / well of streptavidin-HRP (1:2000 diluted in blocking buffer). Each ELISA plate was then allowed to incubate for 1 h at 23 °C. After this time, the buffer was removed and discarded. Each ELISA plate was washed 4 times with PBST. To each ELISA plate was added 20 pL / well of HRP substrate. Each ELISA plate was then allowed to incubate for 2 minutes at 23 °C. After this time, to each ELISA plate was added 40 pL / well of stop solution. Each ELISA plate was centrifuged at 1200 rpm for 30 seconds.

[0154] The plate was then read at 450 nm in a microplate reader. Percent inhibition was calculated as follows:% inhibition rate = (treated samples-high control) / (low control -high control) xlOO

[0155] Activity of the tested compounds is provided in Table 3 below as follows: +++ = IC50 < 1 pM; ++ = IC501-10 µM; + = IC50 > 10 pM.Table 3No. Activity nM No. Activity nM No. Activity nM 1 +++ 17 13 +++ 14 25 +++ 14 2 +++ 24 14 +++ 9 26 +++ 16 3 +++ 24 15 +++ 790 27 +++ 16 4 +++ 22 16 +++ 17 28 +++ 54 5 +++ 42 17 +++ 7 29 +++ 12 6 +++ 23 18 +++ 7 30 +++ 13 7 +++ 28 19 +++ 15 31 +++ 21 8 +++ 646 20 +++ 12 32 +++ 14 9 +++ 24 21 +++ 15 33 +++ 30 10 +++ 44 22 +++ 18 34 +++ 613 11 +++ 15 23 +++ 28 35 +++ 2012 +++ 18 24 +++ 14MDR1-MDCK Permeability

[0156] The blood brain barrier (BBB) separates circulating blood from the extracellular fluid of the central nervous system (CNS). The passive membrane permeability (Papp) and MDR1 (P-glycoprotein) substrate efflux potential were determined using the MDCK I (Madin-Darby canine kidney) cell line engineered to overexpress the human MDR1 gene as an in vitro model of the effective permeability of a compound through the BBB. A bidirectional assay was conducted with a MDR1-MDCK I cell monolayer in a 96-Transwell plate format in the absence or presence of MDR1 inhibitor (GF120918). Assays were run in duplicate in transport buffer (HBSS with 10.0 mM HEPES, pH 7.4) with 1% bovine serum albumin at the receiver side for 90 min at 37°C, using a test article concentration of 1 pM. Monolayer integrity was confirmed using Lucifer yellow, appropriate positive controls for passive permeability and MDR1 transport were included, and recoveries of test article were verified in each experiment. Following incubation, samples from donor and receiver compartments are removed and quenched with acetonitrileSMRH:4928-6629-9266.2 -37-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO containing an appropriate internal standard (IS). Protein was precipitated by centrifugation for 20 min at 3220 g, and supernatants diluted in ultra-pure water (if necessary) prior to analysis. Samples were analyzed by LC-MS / MS using appropriate multiple reaction monitoring mass transitions for selectively measuring analytes and IS. Papp(apparent permeability expressed in cm / sec [centimeter / second]) in both apical to basolateral (A to B) and basolateral to apical (B to A) directions were calculated according to the following equation:P<sp};(cm / sec) ~ ---7---- x 7-7 - -7-7 or -7 - — x -7-7-” ' di (Aren x CAj) Area, x Ttmtiwhere VR is the solution volume in the receiver chamber (apical or basolateral side), Area is the surface area for the insert membrane), Time is incubation time expressed in seconds, C is the peak area ratio (analyte / IS) in the receiver chamber, CA is the average of the initial and final concentrations in the donor chamber, and Co is the initial peak area ratio in the donor chamber.

[0157] Monolayer efflux ratios (ER) were derived using the following equation:ER =P“^B t°A)Papp(A to B)In vitro Human Clearance

[0158] Test compound was incubated with suspensions of cryopreserved hepatocytes from Sprague Dawley rat, beagle dog, cynomolgus monkey, and human and monitored for its depletion over 180 min to determine its metabolic clearance.

[0159] Cryopreserved hepatocytes were purchased from commercial vendors and stored in a cryofreezer until use. For the clearance assay, vials of hepatocytes were quickly thawed in a water bath at 37.0°C and the partially melted cell suspension was transferred to tubes containing pre-warmed thawing medium and mixed well. Cells were pelleted with gentle centrifugation, supernatants were discarded, and the resulting cell pellets were re-suspended by adding an appropriate volume of pre-warmed incubation medium. The viability and cell density was determined using Trypan Blue exclusion then suspensions diluted to l. OxlO6cells / mL with the necessary volume of incubation medium. Hepatocyte suspensions were aliquoted for test compound incubations and pre-incubated in a 37.0°C incubator for about 10 minutes. Test compound was added such that its incubation concentration was 0.5 pM and hepatocytes were l. OxlO6cells / mL. Incubations were conducted at 37.0°C in an incubator at 5.0% CO2 with constant shaking for up to 180 min from test compound addition. At specified time points, aliquots of incubation samples were transferred into wells containing 5x-volumes of ice-cold stop solution containing internal standard. Precipitate plates were thoroughly mixed and centrifuged at 3220 x g for 20 minutes. The supernatants were diluted with ultrapure water for LC-MS / MS analysis.

[0160] The test compound and internal standard were selectively measured by multiple reaction monitoring and the relative concentration of test compound determined as the analyte-to-internal standard peak area ratios. These peak area ratios were converted to percentage remaining by comparison to initial (t=0) samples with the following equation:SMRH:4928-6629-9266.2 -38-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO Area ratio at each time point% Remaining = - - -:- - - x 100Area ratio at t=0

[0161] From linear regression of the natural logarithm of % remaining vs time plot, ti / 2 was determined and according to the following equations, ke and CLintwere calculated for describing the metabolic clearance of the test compound in hepatocytes.ke= ln(2) / t1 / 2= 0.693 / t1 / 2= ke / million cells per mL

[0162] Improvements were sought for CNS penetrant compound A that was found to have a high degree of instability in the human hepatocyte assay. Surprisingly, addition of (R)-F to the piperidine ring was found to significantly improve stability in compounds 35, 14, 31, and 32, although with varying degrees of potency loss.

[0163] Alternatively, replacement of the CF3 group in compound A with OCF2 gave compound B having modestly improved stability along with reduced CNS penetrance and potency. It was surprisingly found that by adding (R)-F to compound B gave compound 14 having significantly improved stability as well as improved CNS penetrance, but with little potency loss from the fluorine addition compared to the other compounds in Table 4.Table 4IL-10 IC50 MDR1 effluxratioCmpd. Structure nM (higher pL / min / 106= less potent) (higher = less cells (higher =CNS penetrant) less stable)A ft 1N5 1.8 3.71 1H OH N'N^N / ,r^B 8 4.1 2.9OH NV -TY35 11V? X 20 1.3 0.7 F^JU1SMRH:4928-6629-9266.2 -39-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO IL-10 IC50 MDR1 effluxratio pL / min / 10 Cmpd. Structure nM (higher6= less potent) (higher = less cells (higher =CNS penetrant) less stable)O OH N^YN / 'Y / ^F141F1 [fb''xbN9 2.3 0.5 (> o\ z—F 0 ^1 # I^ J 1 1\~z-. HOHN'<z- V —NyN''-r^YF< -=16 irW ZI M 17 3.5 0.5 FyU1 1Fq -31 21 2.1 1.2b- IZ32 Z> Z - 14 1.6 1.1 z <— / / A x\ / °SMRH:4928-6629-9266.2 -40-

Claims

1. Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO What is claimed is:

1. A compound or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, selected from:

4. 6.SMRH:4928-6629-9266.2 -41- Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO7.

8. SMRH:4928-6629-9266.2 -42- Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO10.

2. A compound or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, of claim 1 selected from:

14.

3. A compound or a pharmaceutically acceptable salt of claim 2 that is17.SMRH:4928-6629-9266.2 -43- Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO19.

4. A compound or a pharmaceutically acceptable salt of claim 2 that is23.

24. F5. A compound or a pharmaceutically acceptable salt of claim 2 that is27.

6. A compound or a pharmaceutically acceptable salt of claim 2 that is31.

7. A compound or a pharmaceutically acceptable salt of claim 2 that is35.

8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable carrier.

9. A method for treating a disease or condition mediated, at least in part, by NLRP3, the method comprising administering an effective amount of the pharmaceutical composition of claim 8, to a subject in need thereof.

10. The method of claim 9, wherein the disease or condition is Alzheimer’s disease, Parkinson’s disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndromes, gout, inflammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, optic neuritis, oxalate-induced nephropathy, hyperinflammation following influenza infection, graft- versus- SMRH:4928-6629-9266.2 -44-Attorney Docket No.: 95BK-403118-WO TNV-028-26-WO host disease, stroke, silicosis, type 1 diabetes, type 2 diabetes, obesity, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation triggered by chikungunya virus, or traumatic brain injury.

11. The method of claim 10, wherein the disease is nonalcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatohepatitis (MASH).

12. The method of claim 10, wherein the disease is obesity.

13. The method of claim 10, wherein the disease is a metabolic diseases, diabetes, obesity related diseases, obesity related glomerulopathy, lowering body weight, obesity / weight loss independent of diabetes, both weight loss / obesity, or diabetes.43.SMRH:4928-6629-9266.2 -45-

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