NEK7 kinase inhibitors

Abstract

Compounds are provided that have activity as inhibitors of NEK7, the compounds having the following structure (I): [Formula 1] TIFF2023524597000181.tif4551, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 is as defined herein. Methods relating to the preparation and use of such compounds, pharmaceutical compositions comprising such compounds, and methods of modulating NLRP3 inflammasome activity are also provided.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE Embodiments of the present disclosure relate generally to compounds and methods for their preparation and use as therapeutic or prophylactic agents (e.g., for the treatment of inflammation). [Background technology]

[0002] 2. Description of Related Art Inflammasomes are multiprotein complexes whose activation plays a central role in innate immunity and inflammation. To date, four inflammasomes have been described (NLRP1, NLRC4, NLRP3, and AIM2). The NLRP3 inflammasome is composed of NLRP3, ASC, and caspase-I. Its activation leads to the activation of caspase-I, which promotes the secretion of IL-1β and IL-18, cytokines that mediate inflammation in animal disease models of several autoimmune diseases, myocardial infarction, metabolic syndrome, inflammatory bowel disease, and macrophage activation syndrome.

[0003] NEK7 is a member of the NIMA-related kinase (NEK) family that acts as a binding protein for NLRP3 and regulates its oligomerization and activation. NEK7 is a serine / threonine kinase essential for mitotic entry, cell cycle progression, cell division, and mitotic progression. It is expressed in various tissues, including the brain, heart, lung, liver, and spleen. Overexpression of NEK7 induces the production of abnormal cells and is closely associated with tumors such as retinoblastoma, gallbladder cancer, and head and neck cancer.

[0004] Many inhibitors have been widely used to inhibit effector signaling pathways, such as IL-1β or IL-18, without abolishing the inflammatory response. Inhibitors of NLRP3 inflammasome activation that block the NLRP3-NEK7 interaction may exhibit therapeutic or preventive activity in several human diseases, such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the exact mechanism of NLRP3-NEK7 interaction remains unclear.

[0005] Thus, there is a need to develop inhibitors that directly target NEK7 and affect inflammatory responses regulated by the NLRP3 inflammasome in several pathological diseases, such as gout, atherosclerosis, type 2 diabetes, metabolic syndrome, macular degeneration, Alzheimer's disease, multiple sclerosis, and inflammatory bowel disease. Embodiments of the present disclosure fulfill this need and provide further related advantages. Summary of the Invention

[0006] Briefly, embodiments of the present disclosure provide compounds (including pharmaceutically acceptable salts, stereoisomers and prodrugs thereof) that can inhibit NEK7 and / or modulate the activity of the NLRP3 inflammasome.

[0007] In one embodiment, the present invention provides a compound having the following structure (I): [ka] [In the formula, A, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 each of which is as defined below] and a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0008] In another aspect, pharmaceutical compositions containing the disclosed compounds and methods of using same for the treatment of inflammation are also provided. DETAILED DESCRIPTION OF THE INVENTION

[0009] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0010] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof (such as "comprises" and "comprising") are to be interpreted in their open and inclusive sense, i.e., "including, but not limited to."

[0011] In this description, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, where appropriate, and fractions thereof (e.g., tenths and hundredths of integers, etc.), unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise specified. As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the recited components. The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0012] Throughout this specification, a reference to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0014] "Amino" refers to the -NH2 radical.

[0015] "Carboxy" or "carboxyl" refers to the -CO2H radical.

[0016] "Cyano" refers to the -CN radical.

[0017] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0018] "Nitro" refers to the -NO2 radical.

[0019] "Oxo" refers to the =O substituent.

[0020] "Thiol" refers to an --SH substituent.

[0021] "Thioxo" refers to the =S substituent.

[0022] "Alkyl" means an alkyl group consisting solely of carbon and hydrogen atoms and having from 1 to 12 carbon atoms (C1-C 12 "C" refers to a saturated, straight- or branched-chain hydrocarbon radical having 1 to 8 carbon atoms (C-C alkyl), 1 to 8 carbon atoms (C-C alkyl), or 1 to 6 carbon atoms (C-C alkyl), or any value within these ranges (e.g., C-C alkyl and the like), attached to the rest of the molecule by a single bond (e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like). The carbon numbers referred to relate to the carbon backbone and carbon branches, but do not include carbon atoms carried by any substituents. Unless stated otherwise specifically in the specification, alkyl groups may be optionally substituted.

[0023] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, and having from 2 to 12 carbon atoms (C-C 12 "Alkenyl" refers to an unsaturated, straight- or branched-chain hydrocarbon radical having 2 to 8 carbon atoms (C2-C8 alkenyl), or 2 to 6 carbon atoms (C2-C6 alkenyl), or any value within these ranges, attached to the rest of the molecule by a single bond (e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like). The carbon numbers recited relate to the carbon backbone and carbon branches, but do not include carbon atoms carried by any substituents. Unless otherwise expressly stated in the specification, alkenyl groups may be optionally substituted.

[0024] The term "alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms (C-C 12"Alkynyl" refers to an unsaturated, straight- or branched-chain hydrocarbon radical having from 2 to 9 carbon atoms (C2-C9 alkynyl), or from 2 to 6 carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon-carbon triple bond. Exemplary alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-1-ynyl, but-2-ynyl, and the like. The carbon numbers referred to relate to the carbon backbone and carbon branches, but do not include carbon atoms carried by any substituents. Unless otherwise expressly stated in the specification, alkynyl groups may be optionally substituted.

[0025] "Alkoxy" means a group of the formula -OR a is a radical of the formula a is a group of 1 to 12 carbon atoms (C1-C 12 "C-Calkoxy" refers to a radical that is an alkyl radical containing 1 to 8 carbon atoms (C-Calkoxy), 1 to 8 carbon atoms (C-Calkoxy), or 1 to 6 carbon atoms (C-Calkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.

[0026] "Aminyl" is a group of the formula -NR a R b is a radical of the formula a and R b R each independently refers to a radical that is H or C1-C6 alkyl as defined above. a and R b When both are H, the "aminyl" group is the same as the "amino" group defined above. The C1-C6 alkyl portion of the aminyl group may be optionally substituted unless otherwise specified.

[0027] An "aminylalkylcycloalkyl" is a group of the formula -R a R b NR c R d is a radical of the formula a is cycloalkyl (as defined herein), and R bis C1-C6 alkyl (as defined above), and R c is H or C1-C6 alkyl, and R d refers to a radical that is C1-C6 alkyl. The cycloalkyl and each C1-C6 alkyl portion of an aminylalkylcycloalkyl group may be optionally substituted unless otherwise specified.

[0028] "Aromatic ring" refers to a cyclic, planar molecule or portion of a molecule (i.e., radical) having a resonance-bonded ring that exhibits increased stability compared to other bonding arrangements involving the same atom combination. Generally, an aromatic ring has a set of covalently bonded atoms on the same plane and contains an even number of π electrons (e.g., alternating double and single bonds) that is not a multiple of four (i.e., 4n+2 π electrons, where n=0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, and pyrimidonyl. Unless expressly stated otherwise in this specification, "aromatic ring" includes all radicals, which may be optionally substituted.

[0029] "Aryl" refers to an alkyl group having 6 to 18 carbon atoms, e.g., 6 to 10 carbon atoms (C6-C 10 "(aryl)" refers to a carbocyclic ring system radical containing at least one carbocyclic aromatic ring. In embodiments of the present invention, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may be a fused or bridged ring system. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise expressly stated in the specification, an aryl group may be optionally substituted.

[0030] "Cyanoalkyl" refers to an alkyl group that contains at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless otherwise expressly stated in the specification, a cyanoalkyl group may be optionally substituted.

[0031] "Carbocyclic" or "carbocycle" refers to a ring system in which each of the ring atoms is carbon.

[0032] "Cycloalkyl" means a cycloalkyl group consisting solely of carbon and hydrogen atoms, which may be a fused or bridged ring system, having from 3 to 15 ring carbon atoms (C-C 15 cycloalkyl), 3 to 10 ring carbon atoms (C3-C 10 "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic radical having from 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), or 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges, such as from 3 to 4 carbon atoms (C3-C4 cycloalkyl), which is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, cycloalkyl groups may be optionally substituted.

[0033] "Alkylcycloalkyl" refers to a group of the formula -R a R b where R a is a cycloalkyl group, and R b refers to a radical group that is an alkyl group (as defined above). Unless stated otherwise specifically in the specification, an alkylcycloalkyl group may be optionally substituted.

[0034] "Fused" refers to any ring structure described herein that is fused to another ring structure.

[0035] "Halo" refers to bromo, chloro, fluoro, or iodo.

[0036] "Haloalkyl" refers to an alkyl radical (defined above) substituted with one or more halo radicals (defined above), such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, haloalkyl groups may be optionally substituted.

[0037] "Halocycloalkyl" refers to a cycloalkyl radical (defined above) substituted with one or more halo radicals (defined above), such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, halocycloalkyl groups may be optionally substituted.

[0038] A "haloalkylcycloalkyl" is a group of the formula -R a R b where R a is a cycloalkyl group, and R b refers to a radical group that is a haloalkyl group (defined above). Unless stated otherwise specifically in the specification, a haloalkylcycloalkyl group may be optionally substituted.

[0039] "Hydroxylalkyl" refers to an alkyl radical (defined above) that is substituted with one or more hydroxyl radicals. The hydroxyalkyl radical is attached to the backbone through an alkyl carbon atom. Unless otherwise expressly stated in the specification, a hydroxylalkyl group may be optionally substituted.

[0040] "Heterocyclyl" refers to a 3- to 18-membered, e.g., 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having 1 to 10 ring carbon atoms (e.g., 2 to 10) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless expressly stated otherwise in the specification, a heterocyclyl radical is partially or fully saturated and can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused, spirocyclic, and / or bridged ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolidine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.

[0041] "Haloheterocyclylalkyl" refers to a group of the formula -R a R b where R a is an alkyl group, and R b refers to a radical group that is a haloheterocyclyl group (as defined above). Unless stated otherwise specifically in the specification, a haloheterocyclylalkyl group may be optionally substituted.

[0042] "Heterocyclylalkyl" refers to a group of the formula -R a R b where Ra is an alkyl group, and R b refers to a radical group that is a heterocyclyl group (as defined above). Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

[0043] "Heteroaryl" refers to a 5- to 18-membered, e.g., 5- to 6-membered, ring system radical containing 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can be a fused or bridged ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and isoindole. Examples of heteroaryl include, but are not limited to, phenyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise explicitly in the specification, heteroaryl groups may be optionally substituted.

[0044] Oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl each have the following structure: [ka] wherein oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl are intended to mean oxazolyl, isoxazolyl, The thiazolyl is bonded to the rest of the molecule by a covalent bond to one of the carbon atoms in the ring of thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl.

[0045] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl) in which at least one hydrogen atom (e.g., one, two, three, or all hydrogen atoms) has been replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0046] In some specific embodiments, the optional substitutions are halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C 10 Independently selected from the group consisting of aryl, 5- or 6-membered heteroaryl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl.

[0047] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to achieve its intended use, such as, but not limited to, the treatment of a disease as defined below. A therapeutically effective amount may vary depending on the intended therapeutic use (in vivo) or the subject and condition being treated, such as the subject's weight and age, the severity of the condition, the method of administration, and the like, and can be easily determined by one skilled in the art. The term also applies to a dose that induces a specific response in target cells, such as a decrease in platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compound selected, the administration regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0048] As used herein, "treatment" or "treating" refers to an approach for obtaining beneficial or desired results, including, but not limited to, a therapeutic effect and / or a prophylactic effect, with respect to a disease, disorder, or condition. Therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that the subject experiences improvement even though the subject still suffers from the underlying disease. A prophylactic effect includes delaying or eliminating the onset of the disease or disease, delaying or eliminating the onset of symptoms of the disease or disease, slowing, halting, or reversing the progression of the disease or disease, or any combination thereof. In certain embodiments, for prophylactic benefit, a composition is administered to a subject at risk of developing a particular disease or reporting one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0049] As used herein, the terms "co-administration," "administered in combination with," and grammatical equivalents include administering two or more agents to an animal (including a human) such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes administration at the same time in separate compositions, administration at different times in separate compositions, or administration in a composition that contains both agents.

[0050] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0051] A "pharmaceutically acceptable acid addition salt" refers to a salt that retains the biological effectiveness of the free base, is biologically acceptable, or is biologically suitable for administration to a subject. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are salts that are pharmacologically effective, suitable for contact with patient tissues, and do not produce undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts include those derived from inorganic acids (such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) and organic acids (such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0052] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effect of the free acid, is biologically acceptable, or is biologically suitable for administration to a subject. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective, suitable for contact with patient tissues, and do not cause undue toxicity, irritation, or allergic reactions. Pharmaceutically acceptable base addition salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins (such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dianol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like).Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0053] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide (eg, methyl bromide) salts.

[0054] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that inhibit the biological function of a target protein by inhibiting the activity or expression of the protein (e.g., NLRP3 inflammasome or NEK7 or NLRP3 inflammasome-NEK7 association). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but compounds that inhibit the biological activity of a target protein by interacting with other members of the signaling pathway in which the target protein is a member are also clearly included within this definition. Preferred biological activities inhibited by antagonists are associated with tumor development, growth, or spread.

[0055] The term "agonist" as used herein refers to a compound that has the ability to induce or enhance the biological function of a target protein by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. Preferred agonists herein specifically interact (e.g., bind) with the target, but compounds that induce or enhance the biological activity of a target polypeptide by interacting with other members of the signal transduction pathway in which the target polypeptide is a member are also clearly included within this definition.

[0056] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted into and within cells, resulting in an intracellular response.

[0057] The terms "selective inhibition" or "selectively inhibit" refer to the ability of a biologically active agent to preferentially reduce target signaling activity relative to off-target signaling activity, through direct or indirect interaction with the target.

[0058] "Subject" refers to an animal, such as a mammal, e.g., a human. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0059] "Mammals" includes humans and both domestic animals (such as laboratory animals and pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits)) and non-domestic animals (such as wild animals and the like).

[0060] The term "prodrug" is intended to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein (e.g., a compound of structure (I)). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Prodrugs are discussed in "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein are generally prepared by modifying functional groups in the active compound in such a way that the modification is cleaved to the parent active compound, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy, amino, or thiol group is bonded to any group that cleaves to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of hydroxy functional groups, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound.

[0061] The term "in vivo" refers to events that take place inside a subject's body.

[0062] The embodiments disclosed herein are also intended to encompass all pharmaceutically acceptable compounds of structure (I).

[0063] Certain embodiments are also intended to encompass in vivo metabolic products of the disclosed compounds. Such products may result primarily from enzymatic processes, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound. Accordingly, embodiments include compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are generally identified by administering to an animal (e.g., rat, mouse, guinea pig, monkey, etc.) or human a detectable dose of a radiolabeled compound of the present disclosure, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0064] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0065] Crystallization often results in a solvate of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate containing one or more compounds of the present disclosure together with one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as hydrates (such as monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like) and corresponding solvated forms. In some embodiments, the compounds of the present disclosure are true solvates, while in other cases, the compounds of the present disclosure merely retain added water or are merely a mixture of water and some added solvents.

[0066] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted aryl radicals and aryl radicals that have no substituents.

[0067] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure and a medium generally accepted in the art for the delivery of a compound of the present disclosure to a mammal, e.g., a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0068] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, additive, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0069] "Stereoisomers" refer to compounds consisting of the same atoms joined by the same bonds but with different three-dimensional structures, and are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0070] The compounds of the present disclosure (i.e., compounds of structure (I)) or pharmaceutically acceptable salts thereof may contain one or more centers of geometric asymmetry and may therefore give rise to stereoisomers (e.g., enantiomers, diastereomers, and other stereoisomers defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-). Embodiments therefore include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents and resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0071] Embodiments of the present disclosure include all types of rotamers and conformationally restricted states of the compounds of the present invention. Also included are atropisomers, which are stereoisomers resulting from restricted rotation about a single bond (energy differences due to steric strain or other factors create a barrier to rotation high enough to allow isolation of each conformer). For example, certain compounds of the present disclosure may exist as a mixture of atropisomers or may be purified or enriched for the presence of a single atropisomer.

[0072] In some embodiments, the compound of structure (I) is a mixture of enantiomers or diastereomers. In other embodiments, the compound of structure (I) is substantially one enantiomer or diastereomer.

[0073] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. The embodiments therefore include tautomers of the disclosed compounds.

[0074] The chemical nomenclature and chemical structure diagrams used herein are a modified form of the IUPAC nomenclature, using the ACD / Name Version 9.07 software program and / or the ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, a substituent is generally named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. Except as noted below, all bonds are revealed in the chemical structure diagrams herein, except for all bonds on some carbon atoms (which are assumed to be attached to sufficient hydrogen atoms to satisfy valences).

[0075] compound The present disclosure provides compounds (including pharmaceutically acceptable salts, stereoisomers and prodrugs thereof) that can inhibit NEK7 and / or modulate the activity of the NLRP3 inflammasome.

[0076] An embodiment of the present disclosure provides a compound having the following structure (I): [ka] [In the formula, A is C6-C 10 Aryl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, each of which is selected from the group consisting of one or more R 6 may be optionally substituted with; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl; R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4 is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C halo ... optionally substituted with one or more substituents selected from aryl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof; R 5is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 6 are each independently halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0077] In some embodiments of structure (I), A is C6-C 10 Aryl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, each of which is selected from the group consisting of one or more R 6 may be optionally substituted with; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl; R 3is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4 is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, and C-C halocycloalkyl; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 6 are each independently halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0078] Some further particular embodiments have the following structure (I): [ka] [In the formula, A is C6-C 10 Aryl, C3-C 10cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, each of which is selected from the group consisting of one or more R 6 may be optionally substituted with; X is CH or N; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl; R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl ... optionally substituted with one or more substituents selected from C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 6 are each independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl. or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0079] In one embodiment, R 1 is H. In other embodiments, R 1 is C1-C6 alkyl, such as methyl.

[0080] In one embodiment, a compound of structure (I), wherein R 2 is a branched C4-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5- or 6-membered heteroaryl, each of which may be optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl.

[0081] In another embodiment, compounds of structure (I) 2 is a branched C4-C6 alkyl, C3-C4 cycloalkyl, or C3-C8 heterocyclyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl.

[0082] In certain embodiments, R 2 is cyclopropyl or oxetanyl, each of which may be optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, and 3- to 8-membered heterocyclyl. 2 is cyclopropyl. In other embodiments, R 2 is oxetanyl. In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanyl.

[0083] In certain embodiments, R 2is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which may be optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, and 3- to 8-membered heterocyclyl. 2 is cyclopropyl. In other embodiments, R 2 is oxetanyl. In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R 2 is N-methyl substituted pyrrolidinyl. In certain embodiments, R 2 is unsubstituted cyclobutyl.

[0084] In a different embodiment, R 2 is a branched C4-C6 alkyl, optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl. For example, in some embodiments, R 2 is 2-methylpropyl, optionally substituted with hydroxyl.

[0085] In further particular embodiments, R 2 has the following structure: [ka] It has one of the following.

[0086] In some particular embodiments, R 2 has the following structure: [ka] It has one of the following.

[0087] In other embodiments, R3 is H. In other embodiments, R 3 is C1-C6 alkyl, such as methyl.

[0088] In any of the foregoing embodiments, R 4 is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, or 1,3,4-oxadiazolyl, each of which is optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof. For example, in certain embodiments, R 4 is isoxazolyl, optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, and C-C halocycloalkyl. 4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl.

[0089] In one embodiment, R 4is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1,3,4-oxadiazolyl, each of which is selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1 It may be optionally substituted with one or more substituents selected from -C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0090] In one embodiment, R 4 is isoxazolyl, and is optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof.

[0091] In one embodiment, R 4is thiazolyl, optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof.

[0092] In one embodiment, R 4 is isothiazolyl, optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof.

[0093] In one embodiment, R 4is 1,2,4-thiadiazolyl, optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof.

[0094] In one embodiment, R 4 is 1,3,4-thiadiazolyl, optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof.

[0095] In one embodiment, R 4is 1,2,4-triazolyl, optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof.

[0096] In one embodiment, R 4 is 1,3,4-oxadiazolyl, optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, 3- to 8-membered heterocyclyl, and C3-C8 halocycloalkyl, or combinations thereof.

[0097] In one embodiment, R 4 is substituted with C-C alkyl, C-C haloalkyl, C-C cycloalkyl, cyano, aminyl, C-C hydroxylalkyl, C-C cyanoalkyl, 3- to 8-membered heterocyclyl, C-C haloalkylcycloalkyl, C-C aminylalkylcycloalkyl, C-C alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C-C halocycloalkyl, and combinations thereof.

[0098] In various embodiments, R 4 has the following structure: [ka] It has one of the following.

[0099] In various other embodiments, R 4 has the following structure: [ka] It has one of the following.

[0100] In various other embodiments, R 4 has the following structure: [ka] It has one of the following.

[0101] In certain embodiments, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl; R 4 has the following structure: [ka] It has one of the following.

[0102] In certain embodiments, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl; R 4 has the following structure: [ka] It has one of the following.

[0103] In further particular embodiments, R 2 is C1-C6 alkyl and is substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0104] In other embodiments, R 5 is H. In other embodiments, R 5 is C1-C6 alkyl, such as methyl.

[0105] In some embodiments, Y is C(H)(OH). In other embodiments, Y is NH.

[0106] In various embodiments, A is C6-C 10 Aryl, C3-C 10 cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is selected from the group consisting of one or more R 6 It is understood that A is a divalent radical.

[0107] In one embodiment, A is divalent and is C6-C 10 In some embodiments, A is divalent and optionally substituted with a 3- to 8-membered, saturated or partially unsaturated carbocyclic ring. In some embodiments, A is divalent and optionally substituted with a 3- to 10-membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, A is divalent and optionally substituted with a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0108] In some embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl, each of which may be optionally substituted. In other embodiments, A is phenyl. In a different embodiment, A is saturated or unsaturated cyclohexyl. In a further embodiment, A is pyridinyl.

[0109] In certain embodiments, A is pyrimidinyl, optionally substituted.

[0110] In any of the foregoing embodiments, A is unsubstituted. In different of the foregoing embodiments, A is selected from one or more R 6 For example, in some embodiments, R 6 is halo. In some embodiments, R 6 is chloro or fluoro. In other embodiments, R 6 is fluoro.

[0111] In some embodiments, R 6 is C1-C6 hydroxylalkyl. In some embodiments, the C1-C6 hydroxylalkyl is -CH2CH2OH. In other embodiments, R 6 is cyano. In some embodiments, R 6 is C1-C6 alkoxy. In a further particular embodiment, said C1-C6 alkoxy is methoxy.

[0112] In certain embodiments, A is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl. , benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, Isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthryl Phenanthrolyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,A divalent group selected from 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl, each of which may be optionally substituted.

[0113] In certain embodiments, A has the following structure: [ka] It has one of the following.

[0114] In some particular embodiments, A has the following structure: [ka] It has one of the following.

[0115] In some particular embodiments, A has the following structure: [ka] It has one of the following.

[0116] In one embodiment, the compound has the following structure (IA): [ka] [In the formula, R 2a is C1-C6 alkyl or C3-C8 cycloalkyl, optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; R 4ais isoxazolyl, optionally substituted with one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkylcycloalkyl. or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0117] In further particular embodiments, R 2a is a branched C1-C6 alkyl substituted with hydroxyl. In some embodiments, R 2a is C-C cycloalkyl. In further particular embodiments, R 2a has the following structure: [ka] It has one of the following.

[0118] In one embodiment, R 4a is isoxazolyl substituted with C-C haloalkylcycloalkyl. In some embodiments, R 4a is C-C fluoroalkylcycloalkyl. In further particular embodiments, R 4a is fluoroalkylcyclopropyl or fluoroalkylcyclobutyl. In further particular embodiments, R 4a has the following structure: [ka] It has one of the following.

[0119] In some embodiments, X is CH. In some further embodiments, the compound has the following structure (IB): [ka] [In the formula, A is C6-C 10 Aryl, C3-C 10cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, each of which is selected from the group consisting of one or more R 6 may be optionally substituted with; X is CH or N; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl; R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is selected from halo, C-C alkyl, C-C alkenyl, C-C alkynyl ... optionally substituted with one or more substituents selected from C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 6 are each independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl. or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0120] In one embodiment, the compound of structure (I) is a modulator of the NLRP3 inflammasome.

[0121] In certain embodiments, the compounds of structure (I) are inhibitors of NEK7 in a patient or in a biological sample.

[0122] In various different embodiments, the compound has one of the structures set forth in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. The compounds of Table 1 may be prepared as described in the Examples or by methods known in the art, and analyzed by mass spectrometry and / or 1 It was analyzed by 1 H NMR. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17]

[0123] It is understood that combinations of substituents and / or variables of the depicted formulae are permissible in this description only if such combinations result in stable compounds.

[0124] In further embodiments, various compounds of the present disclosure that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid in a manner known to those skilled in the art. Salts of compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0125] Methods for making the compounds described herein are set forth below. Generally, the starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or may be synthesized according to information known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or may be prepared as described herein.

[0126] The following general reaction scheme illustrates the reaction of a compound of structure (I): [ka] [In the formula, A, X, Y, R1 , R 2 , R 3 , R 4 and R 5 each of which is as defined below] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0127] General Reaction Scheme 1 The general reaction scheme below (wherein X 1 and X 2 are independently halogens, and X, R 1 , R 2 , R 3 and A has the meaning described herein) illustrates an example method for making amine intermediate D. [ka]

[0128] As shown in General Reaction Scheme 1, alkylation of pyrimidine / pyridine pyrroles (i.e., intermediate A) with cycloalkylboronates or suitable electrophiles in the presence of base affords intermediate B. Treatment of this precursor with ammonium hydroxide affords the pyrrolopyrimidine / pyridin-4-amine derivative (intermediate C). The resulting intermediate C then undergoes palladium-catalyzed arylation to afford intermediate D.

[0129] General Reaction Scheme 2 The following general reaction scheme illustrates an example of how to make the carbamate intermediate E. [ka]

[0130] As shown in General Reaction Scheme 2, intermediate E can be prepared by reacting phenyl chloroformate with a heteroarylamine (R 4 General Reaction Scheme 2 shows the reaction of R5 is H, where R 5 Compounds where is other than H can be prepared by adding R 5 or by an analogous method using an appropriately substituted heteroarylamine.

[0131] General Reaction Scheme 3 The following general reaction scheme illustrates an example of how to make compounds of structure (I). [ka]

[0132] Treatment of intermediates D and E with a base (eg, trimethylamine, DIPEA, DMAP, and the like) in THF provides compounds of structure (I).

[0133] General Reaction Scheme 4 The following general reaction scheme illustrates an example of how to make compounds of structure (I). [ka]

[0134] Intermediate D is reacted with the indicated phenyl carbonochloridate under appropriate conditions to provide intermediate E. Intermediate E is then coupled with an amine using a suitable base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to provide a compound of structure (I).

[0135] Any of the above reaction schemes can be modified at any step to add and / or change substituents, which may be added or changed as needed at any stage in the overall synthesis of the compound of interest.

[0136] Those skilled in the art will also recognize that during the preparation of the compounds described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable amino, amidino, and guanidino protecting groups include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable mercapto protecting groups include -C(O)-R" (where R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxylic acid protecting groups include alkyl, aryl, or arylalkyl esters. Protecting groups are known to those skilled in the art and are added or removed as appropriate according to conventional techniques, such as those described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one skilled in the art will recognize, the protecting group may also be a polymer resin (such as a Wang resin, a Rink resin, or a 2-chlorotrityl-chloride resin).

[0137] Those skilled in the art will also recognize that such protected derivatives of the disclosed compounds may not have pharmacological activity themselves, but may be administered to a mammal and then metabolized in the body to become pharmacologically active compounds of the disclosed compounds. Such derivatives may therefore be referred to as "prodrugs." Prodrugs of the disclosed compounds are included within the scope of embodiments of the present invention.

[0138] Pharmaceutical Composition Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In further embodiments, the pharmaceutical composition comprises a compound disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described herein below.

[0139] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0140] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner (e.g., by injecting the compound directly into an organ), often in a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the compounds are delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0141] In the methods of treatment described in embodiments of this invention, an effective amount of at least one compound of structure (I) is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. An effective amount or dose may be ascertained by methods such as modeling, dose escalation studies, or clinical trials, taking into account, for example, the method or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing treatments, the subject's health status and response to the drug, and the judgment of the treating physician.

[0142] The compound described in the present disclosure is effective in a wide range of dosage.For example, in the treatment of adult, the dosage of 10 to 5000mg, 100 to 5000mg, 1000mg to 4000mg and 1000 to 3000mg per day are examples of dosages that can be used in some embodiments.The exact dosage depends on the route of administration, the form that compound is administered, the subject that receives treatment, the body weight of the subject that receives treatment, and the preference and experience of the doctor in charge.

[0143] In some embodiments, the compound of the present disclosure is administered in a single dose. Generally, such administration will be by injection (e.g., intravenous injection) to rapidly introduce the drug. However, other routes may be used as needed. A single dose of the compound of the present disclosure may also be used to treat acute illnesses.

[0144] In some embodiments, the compound of the present disclosure is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present disclosure and another agent (e.g., an anticancer agent) are administered together about once a day to about six times a day. In another embodiment, administration of the compound of the present disclosure and the agent continues for less than about 7 days. In yet another embodiment, administration continues for about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year or more. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0145] Administration of the disclosed compound may be continued as long as necessary. In some embodiments, the disclosed compound is administered for 1, 2, 3, 4, 5, 6, 7, 14, or 28 days or more. In some embodiments, the disclosed compound is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the disclosed compound is administered continuously for an extended period of time, for example, to treat chronic effects.

[0146] In some embodiments, the compounds of the present disclosure are administered in individual dosage forms. It is known in the art that due to intersubject variability in the pharmacokinetics of compounds, individualization of dosing regimens is necessary for optimal therapy.

[0147] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including additives and auxiliaries that facilitate the processing of the disclosed compounds into pharmaceutically usable formulations. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable technology, carrier, and additive may be used as appropriate for formulating the pharmaceutical compositions described herein. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0148] Provided herein are pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0149] Provided herein are pharmaceutical compositions comprising one or more compounds selected from the compounds of structure (I) and pharmaceutically acceptable diluents, additives, and carriers. In some embodiments, the described compounds are administered as pharmaceutical compositions in which one or more compounds selected from the compounds of structure (I) are mixed with other active ingredients, such as in combination therapy. All combinations of active ingredients described in the combination therapy section below and throughout this disclosure are encompassed herein. In certain embodiments, the pharmaceutical compositions include one or more compounds of structure (I).

[0150] In certain embodiments, the pharmaceutical composition of the compound of structure (I) is a modulator of the NLRP3 inflammasome.

[0151] In certain embodiments, pharmaceutical compositions of compounds of structure (I) inhibit NEK7 when administered to a patient or biological sample.

[0152] As used herein, a pharmaceutical composition refers to a mixture of one or more compounds selected from the compounds of structure (I) with other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or additives). In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compounds of structure (I) provided herein is administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0153] In one embodiment, one or more compounds selected from the compounds of structure (I) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds selected from the compounds of structure (I) are formulated for transmucosal administration. In certain embodiments, transmucosal formulations include a penetrant appropriate for the barrier to be permeated. In yet other embodiments, where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions include physiologically compatible buffers and / or additives.

[0154] In another embodiment, the compound described herein is formulated for oral administration.The compound described herein is formulated by combining active compound with, for example, pharmaceutically acceptable carrier or additive.In various embodiments, the compound described herein is formulated in oral dosage form, and includes, for example, tablet, powder, pill, dragee, capsule, liquid, gel, syrup, elixir, slurry, suspension and the like.

[0155] In some embodiments, oral pharmaceutical preparations are prepared by mixing one or more solid additives with one or more of the compounds described herein, optionally grinding the resulting mixture, and optionally adding suitable additives to obtain tablets or dragee cores, followed by processing the resulting granular mixture. Suitable additives include, in particular, fillers (e.g., sugars such as lactose, sucrose, mannitol, or sorbitol), cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), or others (e.g., polyvinylpyrrolidone (PVP or povidone) or calcium phosphate, etc.). In certain embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate, etc.).

[0156] In one embodiment, dosage forms (e.g., dragee cores and tablets) are provided with one or more suitable coatings. In certain embodiments, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional ingredients (such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide), a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to characterize different combinations of active compound doses.

[0157] In some embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). In certain embodiments, the push-fit capsules contain the active ingredient in a mixture with one or more fillers. Fillers include, by way of example only, lactose, binders (e.g., starch), and / or lubricants (e.g., talc or magnesium stearate), and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0158] In yet other embodiments, the compounds described herein are formulated for parenteral injection (such as a formulation suitable for bolus injection or continuous infusion). In certain embodiments, the injectable formulation is provided in a single dosage form (e.g., in an ampule) or in a multi-dose container. Preservatives are added to the injectable formulation as appropriate. In still other embodiments, the pharmaceutical composition is formulated as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle in a form suitable for parenteral injection. Parenteral injection formulations include appropriate formulating agents (e.g., suspending agents, stabilizers, and / or dispersing agents, etc.). In certain embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of water-soluble forms of the active compound. In further embodiments, a suspension of one or more compounds selected from the compounds of structure (I) is prepared as a suitable oily suspension injection. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils (e.g., sesame oil, etc.), or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides, etc.), or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension (e.g., sodium carboxymethylcellulose, sorbitol, or dextran, etc.). Optionally, suspensions contain suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0159] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and one or more compounds selected from the compounds of structure (I) described herein as an active ingredient. The active ingredient may be in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein encompass unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, and the like). Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions may optionally include other medicinal or pharmaceutical agents, carriers, adjuvants (e.g., preservatives, stabilizers, wetting agents, or emulsifiers), solubility enhancers, salts for adjusting osmotic pressure, buffers, and / or other therapeutically useful substances.

[0160] Methods for preparing compositions containing the compounds described herein include formulating the compounds with one or more inert pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid forms. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein may be in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to use, or as emulsions. These compositions may also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, pH buffering agents, and the like.

[0161] In some embodiments, pharmaceutical compositions comprising one or more compounds selected from compounds of structure (I) are illustratively in the form of a liquid in which the drug is present in solution, suspension, or both. Generally, when the composition is administered as a suspension, a first portion of the drug is present in solution, and a second portion of the drug is present in the form of particles suspended in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is water-soluble.

[0162] In some embodiments, the aqueous suspension contains one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulose polymers (e.g., hydroxypropylmethylcellulose) and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain mucoadhesive polymers, such as carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylic acid), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0163] The pharmaceutical compositions also optionally include a solubilizing agent to aid in the dissolution of one or more compounds selected from the compounds of structure (I). The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers.

[0164] Additionally, pharmaceutical compositions may optionally contain one or more pH adjusting or buffering agents (such as acids, such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases, such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers, such as citrate / dextrose, sodium bicarbonate, and ammonium chloride). Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition, within acceptable limits.

[0165] The compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0166] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0167] The composition may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil), and polyoxyethylene alkyl ethers and alkylphenyl ethers (e.g., Octoxynol 10, Octoxynol 40).

[0168] The compositions may also include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0169] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, reclosable multi-dose containers are used, in which case a preservative is typically included in the composition.

[0170] In other embodiments, other delivery systems for hydrophobic pharmaceutical compounds are utilized. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In some embodiments, organic solvents, such as N-methylpyrrolidone, are also utilized. In further embodiments, the compounds described herein are delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for several weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are utilized.

[0171] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0172] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v or more.

[0173] In some embodiments, the concentration of one or more compounds selected from compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0. The range is from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% w / w, w / v or v / v.

[0174] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0175] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0176] Packaging materials used to package the pharmaceutical compositions described herein include, for example, those found in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended method of administration and treatment. For example, the container contains one or more compounds described herein, optionally in a composition or in combination with another drug disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). Such kits optionally include the compound along with an identifying description or label or instructions for its use in the methods described herein.

[0177] For example, kits typically include one or more additional containers, each containing one or more of a variety of materials (e.g., reagents and / or devices, optionally concentrated) that are desirable from a commercial and user perspective for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers describing the contents and / or instructions for use, packaging, containers, vial and / or tube labels, and package inserts with instructions. A set of instructions will also typically be included. The label may be on or associated with the container, as appropriate. For example, a label is on a container when letters, numbers, or other characters forming the label are affixed to, molded into, or etched into the container itself, whereas a label is associated with a container when the label is contained within a receptacle or carrier that also holds the container, e.g., as a package insert. Additionally, labels are used to indicate that the contents are to be used for a particular therapeutic application. Furthermore, the label indicates how to use the contents, such as the methods described herein. In some embodiments, the pharmaceutical compositions are present in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack may, for example, contain metal or plastic foil (e.g., a blister pack). Alternatively, the pack or dispenser device may be accompanied by instructions for administration. Alternatively, the pack or dispenser may have associated therewith a notice, associated with the container, in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the drug form for administration to humans or animals. Such notice may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs, i.e., an approved product insert. In some embodiments, compositions containing a compound described herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0178] method Embodiments of the present disclosure are useful as modulators of the NLRP3 inflammasome through inhibition of NEK7 in host animal species. Accordingly, compounds of structure (I) are also useful for treating diseases mediated by effector signaling molecules such as IL-β and IL-18.

[0179] The host or patient may belong to any mammalian species, such as primate species (especially humans), rodents (such as mice, rats and hamsters), rabbits, horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations and provide models for the treatment of human diseases.

[0180] In one embodiment, the present disclosure is useful as an inhibitor of the NLRP3 inflammasome activation mechanism. Accordingly, compounds of structure (I) are also useful for treating diseases resulting from its activation in a host animal species.

[0181] In another embodiment, the compounds of structure (I) are useful as inhibitors of the NLRP3 (protein)-NEK7 (protein) interaction. Thus, the compounds are also useful for treating diseases caused by NLRP3-NEK7 association in a host animal species.

[0182] In one embodiment, the compounds of structure (I) are useful for treating human diseases mediated by effectors selected from the group consisting of IL-β, IL-18, and caspase-1.

[0183]

[0010] Embodiments of the present invention also relate to the use of a compound of structure (I) and / or a physiologically acceptable salt thereof for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or modulated by NLRP3 inflammasome activity. Furthermore, embodiments of the present invention relate to the use of a compound of structure (I) and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or modulated by NLRP3 inflammasome activity. In certain embodiments, the present invention provides the use of a compound of structure (I) or a physiologically acceptable salt thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment of NLRP3-mediated disorders.

[0184] In another embodiment, the present disclosure relates to a method of treating an NLRP3 inflammasome-mediated inflammatory disease or disorder by administering to a patient in need thereof a therapeutically effective amount of a compound of structure (I).

[0185] In certain embodiments, the diseases treatable with the compounds of structure (I) include type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage due to infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, and Muckle-Wells syndrome.

[0186] In certain other embodiments, the compounds of structure (I) are used in methods for treating a disorder or disease selected from autoimmune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, transplantation, sperm motility, red blood cell deficiency, graft rejection, pulmonary disorders, respiratory diseases, ischemic conditions, and cancer. In some further specific embodiments, the compounds of structure (I) are used in methods for treating myelodysplastic syndromes (MDS).

[0187] In some embodiments, said NEK7-associated disorder treatable with a compound of structure (I) is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulin D and periodic fever syndrome, cryopyrin-associated periodic fever syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer.

[0188] Also included herein are methods of treatment in which at least one compound of structure (I) is administered in combination with an anti-inflammatory or therapeutic agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, nonspecific and COX-2-specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants, and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

[0189] Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib and / or etoricoxib.

[0190] In some embodiments, the anti-inflammatory agent is a salicylate, including but not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

[0191] The anti-inflammatory agent may be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

[0192] In a further embodiment, the anti-inflammatory agent is a gold compound, such as gold sodium thiomalate or auranofin.

[0193] The present disclosure also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor (such as methotrexate) or a dihydroorotate dehydrogenase inhibitor (such as leflunomide).

[0194] Therapeutic agents include drugs for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by biotransformation of products of selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, analgesics and antipyretics, drugs that inhibit the synthesis of prostaglandins and thromboxanes, and selective inhibitors of inducible cyclooxygenase. Inhibitors, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, beta-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and leukotriene inhibitors may also be included.

[0195] Other embodiments of the present disclosure relate to combinations in which at least one anti-inflammatory compound is an anti-monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist (such as etanercept), or infliximab (an anti-TNF alpha monoclonal antibody).

[0196] Therapeutic agents used in combination with compounds of structure (I) can also include small molecule compounds that inhibit NLRP3 inflammasome activation, such as MCC950, sulforaphane, isoliquiritigenin, β-hydroxybutyrate, flufenamic acid, mefenamic acid, 3,4-methylenedioxy-β-nitrostyrene (MNS), and parthenolide.

[0197] Still other embodiments of the present disclosure relate to combinations in which at least one active agent is an immunosuppressant compound, such as an immunosuppressant compound selected from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0198] The disclosed compounds of structure (I) can be administered in combination with other known therapeutic agents, such as anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any agent administered to a cancer patient for the purpose of treating the cancer.

[0199] In some embodiments, the anti-cancer drug belongs to the following categories: Alkylating agents: such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834, etc.; Platinum compounds: for example, carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin, etc.; DNA acting agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine 1, 3, etc.; Topoisomerase inhibitors: for example, etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin, etc.; Microtubule polymerization modifiers: for example, cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabine, tesetaxel, etc.; Antimetabolites: for example, asparaginase 3, azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacitarabine, raltitrexed, sapacitabine, tegafur 2, 3, trimetrexate, etc. Anticancer antibiotics: for example, bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin; aclarubicin, peplomycin, pirarubicin, etc.; Hormones / antagonists: for example, abarelix, abiraterone, bicalutamide, buserelin, calucelone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide 1, 3, etc. Aromatase inhibitors: e.g., aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane, etc.; Small molecule kinase inhibitors: e.g., crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifamib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alanine ester, cediranib, etc.

[0200] In some embodiments, the drugs administered in combination with the compounds described herein include any suitable agent usefully delivered by inhalation, for example, analgesics (e.g., codeine, dihydromorphine, ergotamine, fentanyl, or morphine), antianginal medications (e.g., diltiazem), antiallergics (e.g., cromoglycate, ketotifen, or nedocromil), antiinfectives (e.g., cephalosporins, penicillin, streptomycin, sulfonamides, tetracycline, or pentamidine), antihistamines (e.g., methapyrilene), anti-inflammatory drugs (e.g., beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone), antitussives (e.g., noscapine), bronchodilators (e.g., ephedra), and the like. diuretics (e.g., amiloride), anticholinergics (e.g., ipratropium, atropine, or oxitropium), hormones (e.g., cortisone, hydrocortisone, or prednisolone), xanthines (e.g., aminophylline, choline theophylline, lysine ... These include therapeutic proteins and peptides (e.g., insulin or glucagon), as well as therapeutic agents such as benzodiazepines (e.g., theophyllinate or theophylline), and therapeutic proteins and peptides (e.g., insulin or glucagon). It will be apparent to those skilled in the art that, where appropriate, drugs are used in the form of a salt (e.g., as an alkali metal or amine salt, or as an acid addition salt), or as an ester (e.g., a lower alkyl ester), or as a solvate (e.g., a hydrate) to optimize the activity and / or stability of the drug.

[0201] The drugs disclosed herein or other suitable drugs are administered depending on the condition being treated. Thus, in some embodiments, the one or more compounds disclosed herein will be co-administered with other drugs as described above. When used in combination therapy, the compounds disclosed herein are administered simultaneously with the second drug or separately. This combination administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds disclosed herein and any of the drugs described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the drugs described above can be administered simultaneously, with both drugs being in separate formulations. In another alternative, the compounds disclosed herein can be administered immediately followed by any of the drugs described above, or vice versa. In some embodiments of the separate administration protocol, the compounds disclosed herein and any of the drugs described above can be administered minutes, hours, or days apart.

[0202] In some embodiments, the compound of structure (I) is administered as a monotherapy.

[0203] For the identification of signal transduction or mechanistic pathways and for the detection of interactions between various signal transduction pathways, various scientists have developed appropriate models or model systems, such as cell culture models and transgenic animal models. To quantify specific steps in the signal transduction cascade, interacting compounds can be used to modulate the signal. The compounds of the present embodiments can also be used as reagents for examining NEK7-dependent signal transduction pathways in animal and / or cell culture models or in clinical diseases mentioned in this application.

[0204] The method of the present invention can be carried out either in vitro or in vivo. The sensitivity of a particular cell to treatment with a compound of structure (I) can be determined, particularly in vitro, whether during research or clinical application. Generally, a culture of cells is combined with various concentrations of the compound for a period of time sufficient for the active agent to inhibit NEK7 activity, usually from about one hour to one week. In vitro treatment can be carried out using cultured cells derived from a biopsy sample or a cell line.

[0205] In some embodiments, the IC of a compound of structure (I) that inhibits NEK7 50 was determined by the concentration of compound required to inhibit 50% of the activity of NEK kinase. Compounds of structure (I) have an IC50 of less than about 5 mM, preferably less than about 1 mM, and even more preferably less than about 0.100 mM, as described in more detail in the Examples. 50 The efficacy values ​​were shown.

[0206] The examples and preparations described below further describe and demonstrate the compounds of the present disclosure, as well as methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, as well as throughout the specification and claims, molecules with only one stereocenter exist as racemic mixtures unless otherwise specified. Molecules with two or more stereocenters exist as racemic mixtures of diastereomers unless otherwise specified. Single enantiomers / diastereomers may be obtained by methods known to those skilled in the art. [Example]

[0207] The following examples are offered by way of illustration.

[0208] General Procedure All proton NMR experiments were recorded at 400 MHz on a Bruker NEO Spectrometer equipped with a BBFO probe. Deuterated solvents contained less than 0.05% v / v of tetramethylsilane, which was used as the reference signal (set at 0.00 ppm). When the deuterated solvent did not contain tetramethylsilane, the peak of the remaining non-deuterated solvent was used as the reference signal, following published guidelines (J. Org. Chem. 1997, 62(21), 7512-7515). Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in hertz (Hz). Splitting patterns are described by apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintet), or brs (broad singlet). LC / MS analysis was performed on an Agilent Technologies UHPLC 1290 Infinity II with a G6125 MS detector. Microwave reactions were carried out on a Monowave 300 from Anton Paar GmbH using standard protocols.

[0209] NEK7 enzyme assay Casein substrate (a hydrolyzed and partially dephosphorylated mixture of bovine milk-derived α-, β-, and κ-caseins, obtained from Sigma-Aldrich, catalog #C4765, diluted to a final concentration of 1 mg / mL with distilled water) and full-length recombinant human NEK7 (expressed by baculovirus in Sf9 insect cells with an N-terminal GST tag, obtained from SignalChem, catalog #N09-10G, 0.1 μg / μL) were mixed in assay buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO). Compounds of interest (serialized 3-fold dilutions in DMSO from 10 μM to 0.5 nM) or vehicle (1% DMSO) were dispensed into the kinase reaction mixture using Acoustic technology (Echo550; nanoliter range). After 20 min of incubation at room temperature,33 The kinase reaction was initiated by the addition of [P]-ATP (specific activity 10 μCi / μl), and the mixture was incubated for 2 hours at room temperature. The reaction was then stopped by spotting the reaction mixture onto a strip of phosphocellulose P81 paper. After washing, the radioactivity of the P81 paper was measured, and kinase activity data were expressed as a percentage of the remaining kinase activity in the test sample compared to the vehicle reaction. IC was calculated using Prism (GraphPad Software). 50 Values ​​and curve fits were obtained. IL-1β release assay Approximately 1.5 million THP-1 cells were seeded into each well of a 6-well TC plate and incubated with 40 nM PMA in RPMI (10% FBS, 1% Penstrep) for 24 hours. The medium was then removed, and the cells were rested in RPMI (10% FBS, 1% Penstrep) for 24 hours. The medium was then removed, and the cells were pretreated with various concentrations of the compound of interest (typically serially diluted 3-fold in RPMI + 5% FBS, ranging from 1 μM to 0.5 nM) for 2 hours in RPMI (5% FBS). The medium was again removed, and the cells were incubated with 250 ng / mL LPS and the compound of interest (concentrations as specified above) in RPMI (5% FBS) for 2 hours. Finally, the medium was removed, and the cells were incubated with 20 μM nigericin and the compound of interest (concentrations as specified above) in Opti-MEM for 30 minutes. The cell culture medium was then harvested, and the amount of cleaved IL-1β was determined using a JESS instrument (Protein Simple) and standard protocols. The cleaved IL-1β antibody was obtained from Cell Signaling (catalog #83186S) and used at a 1:20 dilution in antibody diluent 2. For chemiluminescence detection, Protein Simple 1x anti-Rabbit HRP secondary antibody was used with Protein Simple luminol and peroxide. Primary antibody incubation time was increased from 30 to 60 minutes.

[0210] Abbreviation °C (degrees Celsius); 1H NMR (proton nuclear magnetic resonance); ACN (acetonitrile); Boc (tert-butyloxycarbonyl); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (N,N-dimethylformamide); DMSO-d6 (deuterated Dimethyl sulfoxide; eq (equivalent); EtOAc (ethyl acetate); g (gram); h (hour); HPLC (high-performance liquid chromatography); LCMS (liquid chromatography mass spectrometry); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); mmol (millimol); n-BuOH (1-butanol); Pd(PPh3)4 (palladium-tetrakis(triphenylphosphine)); PdCl2(dppf) ([1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride); TBAF (tetra-n-butylammonium fluoride); TBDMS (tert-butyldimethylsilyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin-layer chromatography)

[0211] Preparation of synthetic intermediates [ka] N-Iodosuccinimide (1.465 g, 6.51 mmol) was added to a stirred solution (0 °C) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 6.51 mmol) in DMF (10 mL), and the resulting mixture was stirred at 25 °C for 12 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice-cold water (100 mL) and stirred at 25 °C for 15 min. The resulting solid was filtered, washed with water (2 x 25 mL), and dried to give the title compound as an off-white solid (1.7 g, 93% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 12.96 (bs, 1H), 8.60 (s, 1H), 7.95 (d, J = 2.40 Hz, 1H);LCMS:279.9 [M+H]

[0212] [ka] Copper(II) acetate (0.650 g, 3.58 mmol), 2,2'-bipyridine (0.559 g, 3.58 mmol), and sodium bicarbonate (0.601 g, 7.16 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A1, 1.000 g, 3.58 mmol) and cyclopropylboronic acid (0.615 g, 7.16 mmol) in dichloroethane (10 mL), and the resulting mixture was stirred at 70 °C under an oxygen atmosphere for 12 h. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite, which was then rinsed with DCM (2 x 20 mL). The combined filtrate was washed with water (20 mL) and brine (25 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to give the title compound as an off-white solid (0.7 g, 61% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 (s, 1H), 7.96 (s, 1H), 3.63-3.69 (m, 1H), 1.06-1.10 (m, 4H).LCMS:319.9 [M+H]

[0213] [ka] K2CO3 (0.40 g, 2.86 mmol) and 3-iodooxetane (0.32 g, 1.71 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 0.40 g, 1.43 mmol) in DMF (5 mL), and the resulting mixture was stirred in a sealed tube at 90 °C for 16 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured onto crushed ice (50 g) and stirred for 15 min. The resulting solid was filtered, washed with water (2 x 5 mL), and dried to give the title compound as an off-white solid (0.2 g, 42% yield). LCMS: 335.7 [M+H]

[0214] [ka] NaH2PO4 (0.105 g, 0.877 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A1, 0.250 g, 0.895 mmol), 2,2-dimethyloxirane (0.157 ml, 1.762 mmol), and K2CO3 (0.121 g, 0.877 mmol) in ACN (3 mL) and water (1 mL). The resulting mixture was subjected to microwave irradiation in a sealed tube at 150 °C for 1 h. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure, and the resulting crude material was purified by flash chromatography (silica gel 230-400 mesh, eluted with 18% EtOAc in petroleum ether) to give the title compound as a light brown solid (0.1 g, 17% yield). LCMS: 351.9 [M+H]

[0215] [ka] Triethylamine (0.905 g, 8.95 mmol) and copper(II) acetate (0.975 g, 5.37 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 1.000 g, 3.58 mmol) and 3-pyridinylboronic acid (0.880 g, 7.16 mmol) in DCM (25 mL), and the resulting mixture was stirred at 40 °C under an oxygen atmosphere for 40 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was filtered through a pad of Celite, which was then rinsed with DCM (2 x 50 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material. This was stirred with 30% diethyl ether in petroleum ether for 30 minutes at 25° C., filtered and dried to give the title compound as a brown solid (0.4 g, 29% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.05 (bs, 1H), 8.73 (s, 1H), 8.67 (bs, 1H), 8.48 (s, 1H), 8.26-8.28 (m, 1H), 7.64-7.67 (m, 1H).LCMS:356.8 [M+H]

[0216] [ka] Starting from 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 0.50 g, 1.789 mmol) and 4-pyridinylboronic acid (0.44 g, 3.580 mmol), the title compound was obtained as a brown solid (0.21 g, 29% yield) according to a procedure similar to that described in B4. LCMS: 356.9 [M+H]

[0217] [ka] The title compound was prepared as reported in PCT Publication No. WO2017 / 220477.

[0218] [ka] CsCO (0.583 g, 1.789 mmol) and 3-(benzyloxy)cyclobutyl methanesulfonate (prepared as reported in PCT Publication No. WO2019 / 092170, 0.459 g, 1.789 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 0.250 g, 0.895 mmol) in DMF (5 mL), and the resulting mixture was stirred at 90 °C for 12 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound as a colorless gum (0.14 g, 31% yield). LCMS: 440.0 [M+H]

[0219] [ka] K2CO3 (0.742 g, 5.37 mmol) and 2-bromoethan-1-ol (0.537 g, 4.29 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 1.000 g, 3.58 mmol) in DMF (6 mL), and the resulting suspension was stirred at 80 °C for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was poured onto crushed ice (25 g). The resulting solid was filtered, washed with water (20 mL), and dried to give the title compound as a yellow solid (0.84 g, 64% yield). LCMS: 323.9 [M+H]

[0220] [ka] Triethylamine (0.332 g, 3.280 mmol), copper(II) acetate (0.298 g, 1.638 mmol), and molecular sieves (powder, 0.050 g) were added to a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (0.250 g, 1.638 mmol) and cyclopropylboronic acid (0.279 g, 3.280 mmol) in DMF (10 mL), and the resulting suspension was stirred at 60 °C for 12 h in a sealed tube. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite, which was then rinsed with EtOAc. The combined filtrate was concentrated under reduced pressure to give the crude material, which was purified by Isolera (silica gel 230-400 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound as a yellow solid (0.19 g, 59% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.04 (d, J = 5.6 Hz, 1H), 7.56-7.60 (m, 2H), 6.52-6.53 (m, 1H), 3.55-3.58 (m, 1H), 1.00-1.13 (m, 4H).LCMS:193.1 [M+H]

[0221] [ka] N-Iodosuccinimide (0.350 g, 1.557 mmol) was added to a solution of 4-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine (0.200 g, 1.038 mmol) in DMF (5 mL), and the resulting mixture was stirred at 80° C. for 1 hour. After completion of the reaction (as indicated by LCMS), the reaction mixture was poured onto crushed ice (25 g) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the title product (0.2 g), which was used without further purification. LCMS: 319.0 [M+H]

[0222] [ka] A mixture of 4-chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (B1, 1.00 g, 2.191 mmol) and ammonium hydroxide (25% aqueous solution, 5 mL) was subjected to microwave irradiation at 150° C. for 1 hour. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give the title compound as an off-white solid (0.75 g, 80% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.12 (s, 1H), 7.39 (s, 1H), 6.57 (bs, 2H), 3.48-3.54 (m, 1H), 0.97-1.01 (m, 4H).LCMS:301.0 [M+H]

[0223] [ka] The title compound was prepared according to a procedure similar to that described in C1, starting from 4-chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (B2, 0.5 g, 1.49 mmol) and aqueous ammonium hydroxide (25% aqueous solution, 2.5 mL), and obtained as a light brown solid (0.27 g, 58% yield). LCMS: 316.8 [M+H]

[0224] [ka] Starting from 1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (B3, 0.1 g, 0.284 mmol) and ammonium hydroxide (25% aqueous solution, 0.5 mL), following a procedure similar to that described in C1, the title compound was obtained as an off-white solid (0.08 g, 85% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.12 (s, 1H), 7.38 (s, 1H), 4.81 (s, 1H), 4.04 (s, 2H), 1.03 (s, 6H).LCMS:333.0 [M+H]

[0225] [ka] Ammonium hydroxide (25% aqueous solution, 1 mL) was added to a solution of 4-chloro-5-iodo-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (B4, 0.30 g, 0.841 mmol) in dioxane (10 mL), and the resulting mixture was subjected to microwave irradiation at 150° C. for 2 hours. After completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was washed with methyl tert-butyl ether and dried to give the title compound as an off-white solid (0.21 g, 63% yield). LCMS: 337.8 [M+H]

[0226] [ka] Starting from 4-chloro-5-iodo-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (B5, 0.21 g, 0.589 mmol) and ammonium hydroxide (25% aqueous solution, 1 mL), following a procedure similar to that described in C4, the title compound was obtained as an off-white solid (0.16 g, 69% yield). LCMS: 337.9 [M+H]

[0227] [ka] The title compound was prepared as reported in PCT Publication No. WO2017 / 220477.

[0228] [ka] Starting from 7-(3-(benzyloxy)cyclobutyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (B7, 0.140 g, 0.318 mmol) and ammonium hydroxide (25% aqueous solution, 1.4 mL), following a procedure similar to that described in C4, the title compound was obtained as an off-white solid (0.06 g, 45% yield). LCMS: 421.1 [M+H]

[0229] [ka] The title compound was prepared as reported in PCT Publication No. WO2014 / 184069A1.

[0230] [ka] Starting from 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (B8, 0.84 g, 2.61 mmol) and ammonium hydroxide (25% aqueous solution, 8 mL), following a procedure similar to that described in C4, the title compound was obtained as an off-white solid (0.94 g, 69% yield). LCMS: 305.0 [M+H]

[0231] [ka] The title compound was prepared as reported in PCT Publication No. WO2016 / 075224.

[0232] [ka] The title compound was prepared as reported in PCT Publication No. WO2016 / 075224.

[0233] [ka] A mixture of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 minutes. Pd(PPh3)4 (0.062 g, 0.053 mmol) was then added, and the reaction mixture was stirred at 100 °C for 12 hours. After the reaction was complete (as indicated by TLC), the mixture was filtered through a pad of Celite, which was then rinsed with EtOAc (2 x 10 mL). The combined filtrate was concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 3% MeOH in DCM) to give the title compound as a yellow solid (0.110 g, 73% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.13 (s, 1H), 7.05-7.09 (m, 1H), 6.95-6.98 (m, 1H), 6.82-6.86 (m, 1H), 6.10 (bs, 2H), 5.22 (bs, 2H), 3.52-3.58 (m, 1H), 1.00-1.04 (m, 4H). LCMS:284.1 [M+H]

[0234] [ka] Starting from 4-chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (C2, 0.252 g, 0.797 mmol) and (4-nitrophenyl)boronic acid (0.200 g, 1.198 mmol), the title compound was prepared according to a procedure similar to that described in D1 and obtained as a light brown solid (0.143 g, 58% yield). LCMS: 312.1 [M+H]

[0235] [ka] Iron powder (0.251 g, 4.5 mmol) and ammonium chloride (0.240 g, 4.5 mmol) were added to a solution of 5-(4-nitrophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.14 g, 0.45 mmol) in ethanol (5 mL) and water (2 mL), and the resulting mixture was stirred at 80 °C for 3 h. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite, which was then rinsed with EtOAc (2 x 5 mL). The combined filtrate was concentrated under reduced pressure to give a residue, which was dissolved in EtOAc (25 mL), washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound as a brown solid (0.12 g, quantitative yield), which was used without further purification. LCMS: 281.9 [M+H]

[0236] [ka] The title compound was prepared according to a similar procedure as described in D1 starting from 1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (C3 (0.100 g, 0.301 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.086 g, 0.361 mmol) and obtained as a pale yellow gum (0.05 g, 53% yield). LCMS: 316.1 [M+H]

[0237] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.18 g, 0.60 mmol) and (4-nitrophenyl)boronic acid (0.12 g, 0.72 mmol), the title compound was obtained as a light brown solid (0.10 g, 56% yield) according to a procedure similar to that described in D1. 1H NMR (400 MHz, DMSO-d6) δ = 8.28-8.32 (m, 2H), 8.21 (s, 1H), 7.77 (s, 1H), 7.70-7.73 (m, 2H), 7.55 (s, 1H), 5.69 (bs, 2H), 3.61-3.64 (m, 1H), 1.04-1.09 (m, 4H). LCMS:296.1 [M+H]

[0238] [ka] Starting from 7-cyclopropyl-5-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.10 g, 0.33 mmol) and Fe / NH4Cl, following a procedure similar to that described in step 2 of D2, the title compound was obtained as a brown gum (0.08 g, 90% yield), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.04-7.11 (m, 2H), 7.04 (s, 1H), 6.63-6.67 (m, 2H), 6.05 (bs, 2H), 5.27 (bs, 2H), 3.51-3.57 (m, 1H), 0.99-1.04 (m, 4H).LCMS:266.0 [M+H]

[0239] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.21 g, 0.69 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.20 g, 0.83 mmol), the title compound was obtained as a pale yellow gum (0.15 g, 76% yield) according to a procedure similar to that described in D1. LCMS: 284.1 [M+H]

[0240] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.28 g, 0.94 mmol) and 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.28 g, 1.13 mmol), the title compound was obtained as a light brown solid (0.16 g, 57% yield) according to a procedure similar to that described in D1. 1 H NMR (400 MHz, DMSO-d6) δ = 8.73 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.23 ​​(s, 1H), 8.17-8.20 (m, 1H), 7.67 (s, 1H), 6.49 (bs, 2H), 3.61-3.67 (m, 1H), 1.06-1.09 (m, 4H).LCMS:297.1 [M+H]

[0241] [ka] Starting from 7-cyclopropyl-5-(6-nitropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.16 g, 0.54 mmol) and Fe / NH4Cl, the title compound was obtained as a light brown solid (0.1 g, 70% yield) as described in step 2 of D2, which was used without further purification. LCMS: 267.0 [M+H]

[0242] [ka] K2CO3 (0.318 g, 2.299 mmol) was added to a solution of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.230 g, 0.766 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (0.372 g, 1.150 mmol) in dioxane (1 mL) and water (0.3 mL). The solution was purged with N2 for 10 min, then Pd(PPh3)4 (0.044 g, 0.038 mmol) was added, and the resulting mixture was subjected to microwave irradiation at 100 °C for 1 h. After the reaction was complete (as indicated by TLC), the reaction mixture was filtered through a pad of Celite, which was then rinsed with EtOAc (2 x 10 mL). The combined filtrate was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC (mass-based, gradient elution with aqueous ammonium acetate and ACN) to give the title product as a pale yellow gum (0.18 g, 62% yield). LCMS: 370.2 [M+H]

[0243] [ka] TFA (0.012 g, 0.108 mmol) was added to a solution of tert-butyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohex-3-en-1-yl)carbamate (0.040 g, 0.108 mmol) in DCM (2 mL) at 0° C., and the resulting solution was stirred at room temperature for 12 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give the title product as a brown gum (0.029 g), which was used without further purification. LCMS: 270.1 [M+H]

[0244] [ka] A mixture of 5-iodo-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C4, 0.160 g, 0.475 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.169 g, 0.712 mmol), and K2CO3 (0.131 g, 0.949 mmol) in dioxane (5 mL), water (2 mL), and ethanol (3 mL) was purged with N2 for 10 minutes. PdCl2(dppf) (0.017 g, 0.024 mmol) was added, and the resulting mixture was subjected to microwave irradiation at 100 °C for 1 hour. After completion of the reaction (as indicated by LCMS), the reaction mixture was filtered through a pad of Celite, which was then rinsed with EtOAc (5 mL). The combined filtrate was concentrated under reduced pressure to give a residue that was taken up in EtOAc (50 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by GRACE (silica gel 230-400 mesh, eluted with 4% MeOH in DCM) to give the title compound as a brown solid (0.2 g, 70% yield). LCMS: 321.0 [M+H]

[0245] [ka] Starting from 5-iodo-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C5, 0.160 g, 0.475 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.169 g, 0.712 mmol), the title compound was obtained as a brown solid (0.08 g, 51% yield) following a procedure similar to that described in D8. LCMS: 321.0 [M+H]

[0246] [ka] Starting from 5-iodo-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C6, 0.180 g, 0.504 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.131 g, 0.554 mmol), the title compound was obtained as a brown gum (0.15 g, 80% yield) following a procedure similar to that described in D8. LCMS: 341.1 [M+H]

[0247] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.214 g, 0.916 mmol), the title compound was obtained as a brown gum (0.13 g, 56% yield) following a procedure similar to that described in D8. LCMS: 280.1 [M+H]

[0248] [ka] Starting from 7-(3-(benzyloxy)cyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C7, 0.060 g, 0.143 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.037 g, 0.157 mmol), the title compound was obtained as a brown solid (0.03 g, 53% yield) following a procedure similar to that described in D8. LCMS: 404.2 [M+H]

[0249] [ka] Potassium acetate (0.245 g, 2.499 mmol) was added to a solution of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and bis(pinacolato)diboron (0.317 g, 1.250 mmol) in DMSO (5 mL), and the resulting mixture was purged with N for 10 minutes. PdCl(dppf) (0.030 g, 0.042 mmol) was then added, and the reaction mixture was stirred at 85 °C for 12 hours. After the reaction was complete, the reaction mixture was filtered through a pad of Celite, which was then rinsed with DCM (2 x 20 mL). The combined filtrate was concentrated under reduced pressure to give the title compound as a black residue, which was used without further purification. LCMS: 300.9 [M+H]

[0250] [ka] Starting from 6-bromo-4-methylpyridin-3-amine (0.142 g, 0.759 mmol) and 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.251 g, 0.835 mmol), the title compound was obtained as a brown gum (0.05 g, 13% yield) following a procedure similar to that described in D8. LCMS: 281.0 [M+H]

[0251] [ka] Starting from 6-bromo-4-methylpyridin-3-amine (0.130 g, 0.751 mmol) and 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Step 1 of Intermediate D13, 0.248 g, 0.827 mmol), the title compound was obtained as a brown gum (0.03 g, 4.5% yield) following a procedure similar to that described in D8. LCMS: 267.0 [M+H]

[0252] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.500 g, 0.751 mmol) and 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.425 g, 1.666 mmol), the title compound was obtained as a pale yellow solid (0.10 g, 19% yield) according to a procedure similar to that described in D8. LCMS: 302.1 [M+H]

[0253] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.125 g, 0.417 mmol) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (prepared as reported in PCT Publication No. WO2017 / 172093, 0.106 g, 4.17 mmol), the title compound was obtained as a pale yellow solid (0.05 g, 40% yield) according to a procedure similar to that described in D8. LCMS: 302.1 [M+H]

[0254] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.055 g, 0.183 mmol) and 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (prepared as reported in PCT Publication No. WO2017 / 172093, 0.056 g, 0.220 mmol), following a procedure similar to that described in D8, the title compound was obtained as a light brown gum (0.046 g), which was used without further purification. LCMS: 301.9 [M+H]

[0255] [ka] Starting from 1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (C3, 0.280 g, 0.733 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.161 g, 0.733 mmol), the title compound was obtained as a yellow gum (0.12 g, 50% yield) following a procedure similar to that described in D8. LCMS: 299.1 [M+H]

[0256] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.25 g, 0.833 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.184 g, 0.833 mmol), the title compound was obtained as a colorless gum (0.08 g, 34% yield) according to a procedure similar to that described in D8. LCMS: 268.2 [M+H]

[0257] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.200 g, 0.666 mmol) and (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanol (prepared as reported in PCT Publication No. WO2011 / 130628, 0.184 g, 0.733 mmol), the title compound was obtained as a pale yellow gum (0.025 g, 13% yield) according to a procedure similar to that described in D8. LCMS: 296.0 [M+H]

[0258] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.203 g, 0.833 mmol), the title compound was obtained as a pale yellow gum (0.13 g, 34% yield) following a procedure similar to that described in D8. LCMS: 291.2 [M+H]

[0259] [ka] Starting from 5-iodo-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C8, 0.200 g, 0.629 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.149 g, 0.629 mmol), the title compound was obtained as a light brown solid (0.12 g, 42% yield) following a procedure similar to that described in D8. LCMS: 302.2 [M+H]

[0260] [ka] Starting from 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (C9, 0.50 g, 1.644 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.39 g, 1.644 mmol), the title compound was obtained as a brown solid (0.3 g, 63% yield) following a procedure similar to that described in D8. LCMS: 288.1 [M+H]

[0261] [ka] Starting from 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C10, 0.410 g, 1.305 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.309 g, 1.305 mmol), following a procedure similar to that described in D8, the title compound was obtained as a brown solid (0.18 g, 37% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.51 (s, 1H), 7.09-7.13 (m, 1H), 6.98-7.01 (m, 1H), 6.84-6.88 (m, 1H), 6.21 (bs, 2H), 5.14-5.26 (m, 3H), 2.67-2.68 (m, 2H), 2.38-2.39 (m, 2H), 1.85-1.86 (m, 2H).LCMS:298.0 [M+H]

[0262] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.211 g, 0.833 mmol), the title compound was obtained as a yellow solid (0.03 g, 12% yield) according to a procedure similar to that described in D8. LCMS: 300.1 [M+H]

[0263] [ka] Starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.208 g, 0.833 mmol), the title compound was obtained as a pale yellow gum (0.04 g, 16% yield) according to a procedure similar to that described in D8. LCMS: 296.1 [M+H]

[0264] [ka] Starting from 5-iodo-7-(1-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C11, 0.155 g, 0.452 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.107 g, 0.452 mmol), the title compound was obtained as a brown solid (0.084 g, 27% yield) according to a procedure similar to that described in D8. LCMS: 327.2 [M+H]

[0265] Intermediate E1-E25 General procedure for the synthesis of carbamate intermediate E Pyridine (1.2 eq) and phenyl chloroformate (1.5 eq) were added to a solution of the amine (1.0 eq) in THF (10 vol) at 0 °C. The reaction mixture was allowed to warm to 25 °C and stirred for 12 h. After completion of the reaction (as indicated by TLC), the mixture was diluted with EtOAc (10 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 10 to 20% EtOAc in petroleum) to give the desired carbamate.

[0266] The following carbamates were prepared using the general procedure above: [Table 18] [Table 19] [Table 20]

[0267] All amines used in the synthesis of carbamate intermediate E are commercially available with the following exceptions:

[0268] 3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-amine (precursor of E6) and 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (precursor of E7) were synthesized as reported in Synthesis 2013, 45, 171-173.

[0269] 3-(1,1,1-Trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (precursor of E8) and 3-(2-fluoropropan-2-yl)isoxazol-5-amine (precursor of E9) were synthesized from methyl 3,3,3-trifluoro-2,2-dimethylpropanoate and methyl 2-fluoro-2-methylpropionate, respectively, according to the procedure reported in Synthesis 2013, 45, 171–173.

[0270] 3-(1-((Tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-amine (precursor to E16) was synthesized as reported in PCT Publication No. WO2010 / 036630.

[0271] 2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile (precursor of E22) and 3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-amine (precursor of E24) were synthesized as reported in J. Med. Chem. 2012, 55(3), 1082-1105.

[0272] 3-(((Tert-butyldiphenylsilyl)oxy)methyl)isoxazol-5-amine (precursor to E23) was synthesized as reported in PCT Publication No. WO2013 / 104561.

[0273] 5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-amine (precursor to E25) was synthesized as reported in PCT Publication No. WO2011 / 022473.

[0274] [ka] NH2OH·H2SO4 (0.520 g, 3.16 mmol) was added to a solution of 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile (prepared as reported in PCT Publication No. WO2019 / 192962, 0.400 g, 2.87 mmol) and sodium hydroxide (0.126 g, 3.16 mmol) in EtOH (10 mL) and water (10 mL). The pH of the resulting mixture was adjusted to 7.5 with aqueous NaOH (1 M), and the reaction mixture was stirred at 80 °C for 15 h. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue that was taken up in EtOAc (25 mL), washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title product as a light brown solid (0.09 g, 20% yield). 1 H NMR (400 MHz, CDCl3) δ = 5.21 (s, 1H), 4.90-4.93 (m, 2H), 4.56-4.59 (m, 2H), 1.70 (s, 3H).LCMS:155.1 [M+H]

[0275] [ka] NH2OH·H2SO4 (0.699 g, 4.25 mmol) was added to a solution of 3-(1-methylcyclobutyl)-3-oxopropanenitrile (prepared as reported in PCT Publication No. WO2017 / 060874, 0.500 g, 3.86 mmol) and sodium hydroxide (0.170 g, 4.25 mmol) in EtOH (10 mL) and water (10 mL). The pH of the resulting mixture was adjusted to 7.5 with aqueous NaOH (1 M), and the reaction mixture was stirred at 80 °C for 15 h. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue that was taken up in DCM (25 mL), washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (silica gel 230-400 mesh, eluted with 40% EtOAc in petroleum ether) to give the title product as an off-white solid (0.110 g, 19% yield). 1 H NMR (400 MHz, CDCl3) δ = 5.04 (s, 1H), 2.43-2.49 (m, 2H), 1.96-2.02 (m, 4H), 1.50 (s, 3H).LCMS:153.2 [M+H]

[0276] Preparation of Examples General Urea Formation Procedure for the Synthesis of Examples 1-62

[0277] Method A - Triethylamine (2.0 eq.) was added to a mixture of amine intermediate D (1.0 eq.) and carbamate intermediate E (1.0 eq.) in THF (10 Vol.), and the resulting mixture was stirred in a sealed tube at 60° C. for 12 hours. After completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by reverse-phase preparative HPLC to give the desired product.

[0278] Method B - DMAP (0.05 eq.) and DIPEA (1.5 eq.) were added to a solution of amine intermediate D (1.0 eq.) and carbamate intermediate E (1.0 eq.) in THF (10 Vol.), and the resulting mixture was stirred in a sealed tube at 60° C. for 12 hours. After completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by reverse-phase preparative HPLC to give the desired product.

[0279] The following compounds were prepared using the general procedures above.

[0280] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.16 g, 0.30 mmol) and obtained as an off-white solid (0.026 g, 9% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.48 (bs, 1H), 9.34 (bs, 1H), 8.15 (s, 1H), 7.70 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 6.08 (bs, 2H), 6.07 (s, 1H), 5.86-5.90 (m, 1H), 4.97-5.05 (m, 4H), 1.27 (s, 9H).LCMS:448.2 [M+H]

[0281] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.16 g, 0.30 mmol) and obtained as an off-white solid (0.026 g, 9% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.48 (bs, 1H), 9.34 (bs, 1H), 8.15 (s, 1H), 7.70 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 6.08 (bs, 2H), 6.07 (s, 1H), 5.86-5.90 (m, 1H), 4.97-5.05 (m, 4H), 1.27 (s, 9H).LCMS:448.2 [M+H]

[0282] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D6, 0.100 g, 0.376 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.098 g, 0.376 mmol) and obtained as an off-white solid (9.6 mg, 6% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.46-8.47 (m, 1H), 8.22 (s, 1H), 7.89-7.92 (m, 2H), 7.35-7.38 (m, 1H), 7.28 (s, 1H), 6.23 (s, 1H), 3.50-3.57 (m, 1H), 1.27 (s, 9H), 1.07-1.16 (m, 4H);LCMS:433.2 [M+H]

[0283] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (5-(tert-butyl)isoxazol-3-yl)carbamate (E2, 0.091 g, 0.35 mmol) and obtained as an off-white solid (0.021 g, 13% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.86 (bs, 1H), 8.87 (bs, 1H), 8.17-8.21 (m, 2H), 7.24-7.35 (m, 3H), 6.51 (s, 1H), 6.17 (bs, 2H), 3.56-3.60 (m, 1H), 1.31 (s, 9H), 1.02-1.07 (m, 4H).LCMS:450.2 [M+H]

[0284] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.088 g, 0.282 mmol) and obtained as a white solid (0.031 g, 22% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.59 (bs, 1H), 8.84 (bs, 1H), 8.11-8.17 (m, 2H), 7.26-7.37 (m, 3H), 6.20 (s, 1H), 6.16 (bs, 2H), 3.55-3.61 (m, 1H), 1.45-1.49 (m, 2H), 1.38-1.43 (m, 2H), 1.03-1.08 (m, 4H).LCMS:502.1 [M+H]

[0285] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.060 g, 0.180 mmol) and phenyl (5-cyclopropylisoxazol-3-yl)carbamate (E5, 0.044 g, 0.282 mmol) and obtained as an off-white solid (8.4 mg, 9% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.20-8.22 (m, 2H), 7.28-7.33 (m, 2H), 7.22 (s, 1H), 6.35 (s, 1H), 3.49-3.55 (m, 1H), 2.08-2.12 (m, 1H), 1.08-1.16 (m, 6H), 0.97-0.99 (m, 2H).LCMS:434.2 [M+H]

[0286] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (3-methylisoxazol-5-yl)carbamate (E3, 0.077 g, 0.35 mmol) and obtained as an off-white solid (0.024 g, 17% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.35 (bs, 1H), 8.84 (bs, 1H), 8.10-8.18 (m, 2H), 7.25-7.36 (m, 3H), 6.13 (bs, 2H), 5.99 (s, 1H), 3.55-3.61 (m, 1H), 2.18 (s, 3H), 1.00-1.08 (m, 4H).LCMS:408.1 [M+H]

[0287] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.127 g, 0.44 mmol) and phenyl (5-methylisoxazol-3-yl)carbamate (E4, 0.097 g, 0.44 mmol) and obtained as a white solid (0.033 g, 18% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.88 (bs, 1H), 8.96 (bs, 1H), 8.15-8.19 (m, 2H), 7.24-7.35 (m, 3H), 6.54 (s, 1H), 6.15 (bs, 2H), 3.55-3.61 (m, 1H), 2.38 (s, 3H), 1.00-1.07 (m, 4H).LCMS:408.2 [M+H]

[0288] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.076 g, 0.26 mmol) and phenyl (3-(2-fluoropropan-2-yl)isoxazol-5-yl)carbamate (E9, 0.070 g, 0.26 mmol) and obtained as a white solid (0.018 g, 14% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.99 (bs, 1H), 8.17 (s, 1H), 8.09-8.14 (m, 1H), 7.25-7.36 (m, 3H), 6.18 (s, 1H), 6.09 (bs, 2H), 3.57-3.61 (m, 1H), 1.71 (s, 3H), 1.66 (s, 3H), 1.02-1.05 (m, 4H).LCMS:454.2 [M+H]

[0289] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.10 g, 0.35 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.11 g, 0.35 mmol) and obtained as an off-white solid (0.010 g, 6% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.99 (bs, 1H), 8.86 (bs, 1H), 8.14-8.18 (m, 2H), 7.24-7.36 (m, 3H), 6.90 (s, 1H), 6.15 (bs, 2H), 3.56-3.61 (m, 1H), 1.48-1.57 (m, 4H), 1.02-1.07 (m, 4H).LCMS:502.2 [M+H]

[0290] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D5, 0.070 g, 0.24 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.082 g, 0.24 mmol) and obtained as an off-white solid (0.011 g, 9% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.56 (bs, 1H), 9.29 (bs, 1H), 8.16 (s, 1H), 7.58-7.62 (m, 1H), 7.27-7.36 (m, 2H), 7.22 (s, 1H), 6.20 (s, 1H), 6.00 (bs, 2H), 3.55-3.60 (m, 1H), 1.38-1.48 (m, 4H), 1.02-1.06 (m, 4H).LCMS:502.2 [M+H]

[0291] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)carbamate (E8, 0.055 g, 0.176 mmol) and obtained as an off-white solid (9.9 mg, 11% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.59 (bs, 1H), 8.83 (bs, 1H), 8.18 (s, 1H), 8.12-8.17 (m, 1H), 7.25-7.36 (m, 3H), 6.22 (s, 1H), 6.17 (bs, 2H), 3.55-3.61 (m, 1H), 1.52 (s, 6H), 1.02-1.07 (m, 4H).LCMS:504.2 [M+H]

[0292] [ka] The title compound was prepared starting from 5-(4-aminophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D4, 0.080 g, 0.30 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.078 g, 0.30 mmol) following the general procedure for urea formation (Method A) and obtained as an off-white solid (0.036 g, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.13 (bs, 1H), 8.93 (bs, 1H), 8.16 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.22 (s, 1H), 6.08 (s, 1H), 6.00 (bs, 2H), 3.56-3.59 (m, 1H), 1.27 (s, 9H), 1.05-1.07 (m, 4H).LCMS:430.2 [MH]

[0293] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 1-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (D3, 0.086 g, 0.273 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.085 g, 0.273 mmol) and obtained as a light brown solid (0.011 g, 8% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.92 (bs, 1H), 9.06 (bs, 1H), 8.11-8.15 (m, 2H), 7.26-7.35 (m, 3H), 6.18 (s, 1H), 6.14 (bs, 2H), 4.86 (bs, 1H), 4.11 (bs, 2H), 1.37-1.46 (m, 4H), 1.06-1.08 (m, 6H).LCMS:534.1 [M+H]

[0294] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D7, 0.120 g, 0.446 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.116 g, 0.446 mmol) and obtained as an off-white solid (0.013 g, 7% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.83 (bs, 1H), 8.39 (bs, 1H), 7.47 (s, 1H), 6.54 (d, J = 7.6 Hz, 1H), 5.93 (s, 1H), 5.67 (bs, 1H), 3.88-3.90 (m, 2H), 3.61-3.67 (m, 2H), 2.08-2.14 (m, 1H), 1.92-1.95 (m, 1H), 1.69-1.73 (m, 1H), 1.24 (s, 9H), 1.05-1.08 (m, 4H).LCMS:436.2 [M+H]

[0295] [ka] Platinum oxide (0.016 g, 0.069 mmol) was added to a solution of 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohex-3-en-1-yl)-3-(3-(tert-butyl)isoxazol-5-yl)urea (Example 15, 0.100 g, 0.230 mmol) in EtOAc (5 mL), and the resulting suspension was stirred at room temperature under an atmosphere of H for 12 hours. After completion of the reaction (as indicated by LCMS), the reaction mixture was filtered through a pad of Celite, which was then rinsed with EtOAc (2 x 5 mL). The combined filtrates were concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC (mass-based, gradient elution with aqueous ammonium acetate and ACN) to give the title product as an off-white solid (2.0 mg, 2% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.12 (s, 1H), 6.92 (s, 1H), 6.02 (s, 1H), 3.50-3.51 (m, 1H), 2.87-2.90 (m, 1H), 2.13-2.18 (m, 6H), 1.51-1.57 (m, 3H), 1.33 (s, 9H), 0.90-1.20 (m, 4H).LCMS:436.2 [MH]

[0296] [ka] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1-methylcyclopropyl)isoxazol-5-yl)carbamate (E10, 0.046 g, 0.176 mmol) and obtained as an off-white solid (0.013 g, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.40 (bs, 1H), 8.84 (bs, 1H), 8.11-8.17 (m, 2H), 7.24-7.36 (m, 3H), 6.16 (bs, 2H), 5.84 (s, 1H), 3.55-3.61 (m, 1H), 1.38 (s, 3H), 1.02-1.07 (m, 4H), 0.94-0.96 (m, 2H), 0.83-0.84 (m, 2H).LCMS:448.2 [M+H]

[0297] [ka] Starting from phenyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 4-(tert-butyl)thiazol-2-amine (0.015 g, 0.099 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (7.0 mg, 15% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.99 (bs, 1H), 9.29 (bs, 1H), 8.46 (s, 1H), 8.26-8.30 (m, 1H), 7.67 (s, 1H), 7.38-7.41 (m, 1H), 7.27-7.30 (m, 1H), 6.70 (s, 1H), 3.71 (bs, 1H), 1.27 (s, 9H), 1.10-1.10 (m, 4H).LCMS:466.0 [M+H]

[0298] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (5-(tert-butyl)-1,3,4-thiadiazol-2-yl)carbamate (E12, 0.049 g, 0.176 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (2.0 mg, 2% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.19-8.23 (m, 2H), 7.30-7.35 (m, 2H), 7.23 (s, 1H), 3.50-3.54 (m, 1H), 1.49 (s, 9H), 1.08-1.17 (m, 4H).LCMS:466.9 [M+H]

[0299] [ka] Starting from phenyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 4-(tert-butyl)thiazol-2-amine (0.015 g, 0.099 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (2.0 mg, 4% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.21 (s, 1H), 8.11-8.17 (m, 1H), 7.30-7.34 (m, 2H), 7.23 (s, 1H), 6.78 (s, 1H), 3.50-3.54 (m, 1H), 1.35 (s, 9H), 1.08-1.30 (m, 4H).LCMS:466.0 [M+H]

[0300] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(tert-butyl)-1,2,4-thiadiazol-5-yl)carbamate (E13, 0.049 g, 0.176 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (8.0 mg, 10% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 11.54 (bs, 1H), 9.00 (bs, 1H), 8.09-8.18 (m, 2H), 7.28-7.39 (m, 3H), 6.19 (bs, 2H), 3.57-3.61 (m, 1H), 1.34 (s, 9H), 1.03-1.05 (m, 4H).LCMS:467.0 [M+H]

[0301] [ka] Starting from phenyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 1-(tert-butyl)-1H-1,2,4-triazol-3-amine (0.014 g, 0.099 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (3.0 mg, 6% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.70 (bs, 1H), 10.16 (bs, 1H), 8.54 (s, 1H), 8.31-8.35 (m, 1H), 8.16 (s, 1H), 7.25-7.37 (m, 3H), 6.17 (bs, 2H), 3.56-3.59 (m, 1H), 1.57 (s, 9H), 1.02-1.05 (m, 4H).LCMS:450.0 [M+H]

[0302] [ka] Starting from phenyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 5-(tert-butyl)-1,3,4-oxadiazol-2-amine (0.014 g, 0.099 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (2.0 mg, 4% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.35 (s, 1H), 8.26-8.30 (m, 1H), 7.48 (s, 1H), 7.31-7.40 (m, 2H), 3.69-3.71 (m, 1H), 1.45 (s, 9H), 1.17-1.22 (m, 4H).LCMS:451.0 [M+H]

[0303] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D8, 0.100 g, 0.312 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.107 g, 0.343 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (0.023 g, 14% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.69 (bs, 1H), 9.13 (bs, 1H), 8.97 (bs, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.31-8.36 (m, 2H), 8.20-8.24 (m, 1H), 7.95 (s, 1H), 7.62-7.65 (m, 1H), 7.38-7.50 (m, 2H), 6.76 (bs, 2H), 6.21 (s, 1H), 1.39-1.47 (m, 4H).LCMS:538.8 [M+H]

[0304] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D9, 0.080 g, 0.250 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.086 g, 0.275 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.046 g, 33% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.68 (bs, 1H), 9.00 (bs, 1H), 8.89 (d, J = 6.4 Hz, 2H), 8.58 (d, J = 6.4 Hz, 2H), 8.43 (s, 1H), 8.21-8.27 (m, 2H), 7.49-7.52 (m, 1H), 7.39-7.42 (m, 1H), 6.90 (bs, 2H), 6.22 (s, 1H), 1.39-1.49 (m, 4H).LCMS:538.9 [M+H]

[0305] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D10, 0.020 g, 0.059 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.018 g, 0.059 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (2.4 mg, 7% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.68 (bs, 1H), 8.96 (bs, 1H), 8.32 (s, 1H), 8.16-8.20 (m, 1H), 7.55 (s, 1H), 7.38-7.41 (m, 1H), 7.29-7.31 (m, 1H), 6.98 (bs, 2H), 6.21 (s, 1H), 4.85-4.91 (m, 1H), 3.59-3.62 (m, 4H), 2.85 (s, 3H), 2.21-2.34 (m, 4H), 1.38-1.49 (m, 4H).LCMS:559.2 [M+H]

[0306] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(3-methyloxetan-3-yl)isoxazol-5-yl)carbamate (E14, 0.048 g, 0.176 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (3.4 mg, 4% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.56 (s, 1H), 8.94 (bs, 1H), 8.42 (s, 1H), 8.19 (t, J = 8.4 Hz, 1H), 7.57 (bs, 3H), 7.38 (d, J = 10.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.22 (s, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.52 (d, J = 5.6 Hz, 2H), 3.68-3.69 (m, 1H), 1.63 (s, 3H), 1.09-1.10 (m, 4H).LCMS:464.1 [M+H]

[0307] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(trifluoromethyl)isoxazol-5-yl)carbamate (E15, 0.048 g, 0.176 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (2.9 mg, 4% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 11.03 (bs, 1H), 8.97 (bs, 1H), 8.19 (s, 1H), 8.10 (t, J = 8.4 Hz, 1H), 7.27-7.38 (m, 3H), 6.54 (s, 1H), 6.30 (bs, 2H), 3.56-3.60 (m, 1H), 1.03-1.05 (m, 4H).LCMS:461.9 [M+H]

[0308] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.131 g, 0.461 mmol) and phenyl (3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-yl)carbamate (E16, 0.180 g, 0.461 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.013 g, 5% yield). LCMS: 580.0 [M+H]

[0309] [ka] TBAF (1 M in THF, 0.067 ml) was added to a solution of 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-yl)urea (0.013 g, 0.022 mmol) in THF (2 ml) at 0° C., and the resulting solution was stirred at 25° C. for 4 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give the title product as a white solid (TFA salt, 2.2 mg, 21% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.36 (s, 1H), 8.23 ​​(t, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.30-7.38 (m, 2H), 6.20 (s, 1H), 3.69-3.72 (m, 1H), 3.61 (s, 2H), 1.32 (s, 6H), 1.18-1.24 (m, 4H).LCMS:466.2 [M+H]

[0310] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.055 g, 0.194 mmol) and phenyl (3-(sec-butyl)isoxazol-5-yl)carbamate (E17, 0.051 g, 0.194 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (0.012 g, 14% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.39 (bs, 1H), 8.84 (bs, 1H), 8.12-8.14 (m, 2H), 7.25-7.36 (m, 3H), 6.16 (bs, 2H), 6.02 (s, 1H), 3.56-3.59 (m, 1H), 2.68-2.73 (m, 1H), 1.56-1.60 (m, 2H), 1.18-1.20 (m, 3H), 1.01-1.10 (m, 4H), 0.81-0.89 (m, 3H).LCMS:450.0 [M+H]

[0311] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(pentan-3-yl)isoxazol-5-yl)carbamate (E18, 0.048 g, 0.176 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.016 g, 19% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.65 (bs, 1H), 9.06 (bs, 1H), 8.37 (s, 1H), 8.18 (t, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.35-7.38 (m, 1H), 7.26-7.28 (m, 3H), 5.98 (s, 1H), 3.65-3.68 (m, 1H), 1.49-1.68 (m, 4H), 1.07-1.09 (m, 4H), 0.79-0.82 (m, 6H).LCMS:464.0 [M+H]

[0312] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.056 g, 0.198 mmol) and phenyl (3-isopropylisoxazol-5-yl)carbamate (E19, 0.049 g, 0.198 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.018 g, 21% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.34 (bs, 1H), 8.81 (bs, 1H), 8.12-8.16 (m, 2H), 7.25-7.36 (m, 3H), 6.15 (bs, 2H), 6.04 (s, 1H), 3.55-3.59 (m, 1H), 2.89-2.96 (m, 1H), 1.21-1.25 (m, 6H), 1.07-1.09 (m, 4H).LCMS:436.0 [M+H]

[0313] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.061 g, 0.215 mmol) and phenyl (3-ethylisoxazol-5-yl)carbamate (E20, 0.050 g, 0.215 mmol), the general procedure for urea formation (Method A) was followed to afford the title compound as an off-white solid (0.020 g, 22% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.31 (bs, 1H), 8.81 (bs, 1H), 8.12-8.17 (m, 2H), 7.25-7.36 (m, 3H), 6.15 (bs, 2H), 6.03 (s, 1H), 3.55-3.60 (m, 1H), 2.54-2.60 (m, 2H), 1.05-1.21 (m, 3H), 1.03-1.04 (m, 4H).LCMS:422.0 [M+H]

[0314] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.075 g, 0.265 mmol) and phenyl (3-(1-methylcyclobutyl)isoxazol-5-yl)carbamate (E21, 0.072 g, 0.265 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (6.8 mg, 5% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.42 (bs, 1H), 8.90 (bs, 1H), 8.42 (s, 1H), 8.18-8.22 (m, 1H), 7.58 (s, 1H), 7.37-7.40 (m, 1H), 7.27-7.29 (m, 1H), 6.06 (s, 1H), 3.67-3.71 (m, 1H), 2.34-2.38 (m, 2H), 1.85-2.08 (m, 4H), 1.42 (s, 3H), 1.07-1.11 (m, 4H).LCMS:462.2 [M+H]

[0315] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.070 g, 0.247 mmol) and phenyl (3-(2-cyanopropan-2-yl)isoxazol-5-yl)carbamate (E22, 0.067 g, 0.247 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (4.1 mg, 3% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.33 (s, 1H), 8.20-8.24 (m, 1H), 7.43 (s, 1H), 7.31-7.38 (m, 2H), 6.33 (s, 1H), 3.50-3.66 (m, 1H), 1.77 (s, 6H), 1.15-1.21 (m, 4H).LCMS:461.1 [M+H]

[0316] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.250 g, 0.882 mmol) and phenyl (3-(((tert-butyldimethylsilyl)oxy)methyl)isoxazol-5-yl)carbamate (E23, 0.308 g, 0.882 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.029 g, 8% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.43 (bs, 1H), 8.92 (bs, 1H), 8.40 (s, 1H), 8.18-8.22 (m, 1H), 7.56 (s, 1H), 7.37-7.40 (m, 1H), 7.27-7.29 (m, 1H), 6.12 (s, 1H), 4.43 (s, 2H), 3.66-3.71 (m, 1H), 1.08-1.11 (m, 4H).LCMS:422.0 [MH] Note: Cleavage of the TBDMS group was observed during purification using a gradient elution with 10 mM aqueous ammonium acetate and ACN.

[0317] [ka] Starting from 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D6, 0.300 g, 1.127 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.352 g, 1.127 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.018 g, 3% yield). 1H NMR (400 MHz, DMSO-d6) δ = 11.77 (bs, 1H), 9.85 (bs, 1H), 8.39-8.40 (m, 1H), 8.18 (s, 1H), 7.86-7.88 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 6.26 (s, 1H), 6.23 (bs, 2H), 3.58-3.61 (m, 1H), 1.40-1.49 (m, 4H), 1.03-1.06 (m, 4H).LCMS:485.0 [M+H]

[0318] [ka] Starting from 5-(4-amino-3-methylphenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D11, 0.270 g, 0.967 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.302 g, 0.967 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.080 g, 16% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.63 (bs, 1H), 8.29 (bs, 1H), 8.16 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.22-7.32 (m, 3H), 6.17 (s, 1H), 6.08 (bs, 2H), 3.55-3.60 (m, 1H), 2.29 (s, 3H), 1.37-1.48 (m, 4H), 1.00-1.05 (m, 4H).LCMS:498.1 [M+H]

[0319] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-(3-(benzyloxy)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D12, 0.033 g, 0.082 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.028 g, 0.090 mmol), following the general procedure for urea formation (Method B) gave the title compound as a yellow gum (0.038 g, 29% yield). LCMS: 622.3 [M+H]

[0320] [ka] Boron trichloride (1 M in DCM, 0.901 mL, 0.901 mmol) was added dropwise to a solution of 1-(4-(4-amino-7-(3-(benzyloxy)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.070 g, 0.113 mmol) in DCM (5 mL) at −60° C., and the resulting mixture was stirred at 0° C. for 3 h. After completion of the reaction (as indicated by TLC and LCMS), the reaction mixture was cooled to −70° C., neutralized with NH4OH (25% aqueous solution), and extracted with DCM (2 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC (gradient elution with 1% TFA in water and ACN) to give the title product as a white solid (0.012 g, 20% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.33 (s, 1H), 8.22-8.26 (m, 1H), 7.77 (s, 1H), 7.34-7.42 (m, 2H), 6.33 (s, 1H), 5.58-5.62 (m, 1H), 4.64-4.66 (m, 1H), 2.85-2.92 (m, 2H), 2.58-2.64 (m, 2H), 1.39-1.49 (m, 4H).LCMS:531.8 [M+H]

[0321] [ka] Starting from 5-(5-amino-4-methylpyridin-2-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D13, 0.050 g, 0.102 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.032 g, 0.102 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (8 mg, 16% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.81 (bs, 1H), 8.76 (s, 1H), 8.51 (bs, 1H), 8.08 (s, 1H), 7.93-7.94 (m, 2H), 7.12 (bs, 2H), 6.17 (s, 1H), 3.53-3.56 (m, 1H), 2.30 (s, 3H), 1.37-1.46 (m, 4H), 1.05-1.08 (m, 4H).LCMS:499.2 [M+H]

[0322] [ka] Starting from 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D15, 0.080 g, 0.266 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.083 g, 0.266 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (8 mg, 5.6% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.78 (bs, 1H), 8.71 (bs, 1H), 8.42 (bs, 1H), 7.67 (s, 1H), 7.56 (bs, 2H), 7.23-7.29 (m, 2H), 6.14 (s, 1H), 3.67-3.76 (m, 1H), 1.37-1.47 (m, 4H), 1.09-1.12 (m, 4H).LCMS:519.7 [M+H]

[0323] [ka] Starting from 5-(4-amino-2,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D16, 0.100 g, 0.332 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.104 g, 0.332 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (8 mg, 5% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.63 (bs, 1H), 9.01 (bs, 1H), 8.16 (s, 1H), 8.04-8.09 (m, 1H), 7.28-7.34 (m, 2H), 6.21 (s, 1H), 6.16 (bs, 2H), 3.55-3.61 (m, 1H), 1.36-1.49 (m, 4H), 1.00-1.04 (m, 4H).LCMS:520.1 [M+H]

[0324] [ka] Starting from 5-(4-amino-2,6-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D17, 0.0724 g, 0.240 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.075 g, 0.240 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (3 mg, 2% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.39-7.42 (m, 2H), 7.24 (s, 1H), 6.15 (s, 1H), 6.02 (bs, 2H), 3.58-3.59 (m, 1H), 1.36-1.44 (m, 4H), 1.03-1.05 (m, 4H).LCMS:520.2 [M+H]

[0325] [ka] Starting from 5-bromo-3-fluoropyridin-2-amine (0.040 g, 0.209 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.065 g, 0.209 mmol), and following the general procedure for urea formation (Method B), the title compound was obtained as a pale yellow solid (0.020 g, 23% yield). LCMS: 410.9 [M+H]

[0326] [ka] Starting from 1-(5-bromo-3-fluoropyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.020 g, 0.049 mmol) and tert-butyl (tert-butoxycarbonyl)(7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (prepared as reported in PCT Publication No. WO2018 / 015879, 0.024 g, 0.049 mmol), the title compound was obtained as an off-white solid (2 mg, 7% yield) according to a procedure similar to that described in Intermediate D8. 1 H NMR (400 MHz, CD3OD) δ = 8.32-8.33 (m, 2H), 7.81-7.84 (m, 1H), 7.50 (s, 1H), 6.42 (s, 1H), 3.60-3.68 (m, 1H), 1.41-1.50 (m, 4H), 1.13-1.23 (m, 4H). LCMS: 503.1 [M+H]. Note: Cleavage of the Boc group was observed during the reaction.

[0327] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-yl)carbamate (E24, 0.092 g, 0.282 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (0.035 g, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.66 (bs, 1H), 8.90 (bs, 1H), 8.21 (s, 1H), 8.12-8.16 (m, 1H), 7.26-7.36 (m, 3H), 6.41 (bs, 2H), 6.14 (s, 1H), 3.54-3.56 (m, 1H), 2.57-2.68 (m, 4H), 2.03-2.05 (m, 2H), 1.04-1.06 (m, 4H).LCMS:515.9 [M+H]

[0328] [ka] Starting from 1-(4-amino-5-(6-aminopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (D18, 0.100 g, 0.335 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.105 g, 0.335 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (0.010 g, 6% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 11.74 (bs, 1H), 9.91 (bs, 1H), 8.41-8.43 (m, 2H), 7.89-7.92 (m, 1H), 7.80 (bs, 2H), 7.68-7.71 (m, 1H), 7.59 (s, 1H), 6.26 (s, 1H), 4.20 (s, 2H), 1.38-1.50 (m, 4H), 1.11-1.12 (m, 6H).LCMS:516.9 [M+H]

[0329] [ka] Starting from 1-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (D3, 0.120 g, 0.381 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.119 g, 0.381 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (0.028 g, 13% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.04 (bs, 1H), 8.94 (bs, 1H), 8.41 (s, 1H), 8.23-8.27 (m, 1H), 7.55 (s, 1H), 7.36-7.40 (m, 1H), 7.27-7.30 (m, 1H), 6.91 (s, 1H), 4.18 (s, 2H), 1.51-1.58 (m, 4H), 1.07-1.11 (m, 6H).LCMS:534.2 [M+H]

[0330] [ka] Starting from 5-(2-aminopyrimidin-5-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D19, 0.080 g, 0.299 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.093 g, 0.299 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (4 mg, 3% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.76 (bs, 1H), 9.04 (bs, 1H), 8.65 (bs, 1H), 8.34 (bs, 2H), 7.61 (s, 1H), 6.66 (bs, 2H), 6.10 (s, 1H), 3.66-3.71 (m, 1H), 1.37-1.45 (m, 4H), 1.11-1.11 (m, 4H).LCMS:485.9 [M+H]

[0331] [ka] Starting from (2-amino-5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanol (D20, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.021 g, 0.068 mmol), following the general procedure for urea formation (Method A) gave the title compound as an off-white solid (3 mg, 8% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.96 (bs, 1H), 8.56 (bs, 1H), 8.17 (s, 1H), 7.91-7.93 (m, 1H), 7.34-7.42 (m, 2H), 7.21 (s, 1H), 6.04-6.17 (m, 3H), 5.49 (bs, 1H), 4.57 (bs, 2H), 3.56-3.61 (m, 1H), 1.37-1.47 (m, 4H), 1.00-1.06 (m, 4H).LCMS:514.1 [M+H]

[0332] [ka] Starting from 2-amino-5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (D21, 0.130 g, 0.287 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.089 g, 0.287 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (5 mg, 3% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.62 (s, 1H), 7.43-7.52 (m, 3H), 6.86 (s, 1H), 6.05 (s, 1H), 3.67-3.70 (m, 1H), 1.38-1.46 (m, 4H), 1.08-1.10 (m, 4H).LCMS:509.2 [M+H]

[0333] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D22, 0.075 g, 0.249 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.078 g, 0.249 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (0.037 g, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.63 (bs, 1H), 8.88 (bs, 1H), 8.13-8.18 (m, 2H), 7.42 (s, 1H), 7.26-7.36 (m, 2H), 6.35 (bs, 2H), 6.20 (s, 1H), 4.34 (t, J = 5.6 Hz, 2H), 3.72 (t, J = 5.2 Hz, 2H), 3.26 (s, 3H), 1.38-1.49 (m, 4H).LCMS:520.2 [M+H]

[0334] [ka] Starting from 2-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (D23, 0.080 g, 0.278 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.087 g, 0.278 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (0.011 g, 7% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.53 (bs, 1H), 8.78 (bs, 1H), 8.05-8.09 (m, 2H), 7.32 (s, 1H), 7.19-7.28 (m, 2H), 6.18 (bs, 2H), 6.13 (s, 1H), 4.90 (t, J = 5.2 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.66-3.69 (m, 2H), 1.31-1.41 (m, 4H).LCMS:506.2 [M+H]

[0335] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D24, 0.150 g, 0.504 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.158 g, 0.504 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (0.111 g, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.67 (bs, 1H), 8.96 (bs, 1H), 8.38 (s, 1H), 8.18-8.22 (m, 1H), 7.93 (s, 1H), 7.43 (bs, 2H), 7.41 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.21 (s, 1H), 5.23-5.27 (m, 1H), 2.51-2.68 (m, 4H), 1.84-1.89 (m, 2H), 1.38-1.49 (m, 4H).LCMS:516.1 [M+H]

[0336] [ka] Starting from 5-(4-amino-3-chlorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D25, 0.050 g, 0.167 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.052 g, 0.167 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (6 mg, 7% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 11.04 (bs, 1H), 8.67 (bs, 1H), 8.40 (s, 1H), 8.23-8.25 (m, 1H), 7.58-7.60 (m, 2H), 7.42-7.44 (m, 1H), 6.21 (s, 1H), 3.67-3.73 (m, 1H), 1.46-2.33 (m, 2H), 1.37-1.38 (m, 2H), 1.11-1.13 (m, 4H).LCMS:518.2 [M+H]

[0337] [ka] Starting from 5-(4-amino-3-methoxyphenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D26, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.021 g, 0.068 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (7 mg, 19% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.96 (bs, 1H), 8.65 (bs, 1H), 8.23 ​​(s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.12-7.17 (m, 1H), 7.01-7.04 (m, 1H), 6.47 (bs, 2H), 6.19 (s, 1H), 3.94 (s, 3H), 3.60-3.62 (m, 1H), 1.45-1.48 (m, 2H), 1.36-1.38 (m, 2H), 1.04-1.07 (m, 4H).LCMS:513.9 [M+H]

[0338] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-(1-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D27, 0.040 g, 0.123 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.036 g, 0.115 mmol), following the general procedure for urea formation (Method B) gave the title compound as a white solid (0.015 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.82 (bs, 1H), 9.07 (bs, 1H), 8.39 (s, 1H), 8.19-8.23 (m, 1H), 7.84 (s, 1H), 7.14-7.40 (m, 2H), 6.21 (s, 1H), 5.55-5.66 (m, 1H), 3.90-4.09 (m, 2H), 2.95 (bs, 4H), 2.08 (s, 3H), 1.38-1.49 (m, 4H).LCMS:545.3 [M+H]

[0339] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.160 g, 0.565 mmol) and phenyl (5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-yl)carbamate (E25, 0.184 g, 0.565 mmol), following the general procedure for urea formation (Method B) gave the title compound as a white solid (0.081 mg, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.02 (bs, 1H), 8.87 (bs, 1H), 8.15-8.20 (m, 2H), 7.25-7.36 (m, 3H), 6.96 (s, 1H), 6.16 (bs, 2H), 3.55-3.61 (m, 1H), 2.59-2.68 (m, 4H), 2.03-2.11 (m, 2H), 1.02-1.11 (m, 4H).LCMS:516.2 [M+H]

[0340] [ka] Starting from 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D24, 0.204 g, 0.686 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.214 g, 0.686 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (0.096 g, 27% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.01 (bs, 1H), 8.87 (bs, 1H), 8.14-8.20 (m, 2H), 7.66 (s, 1H), 7.28-7.39 (m, 2H), 6.91 (s, 1H), 6.18 (bs, 2H), 5.18-5.23 (m, 1H), 2.39-2.41 (m, 4H), 1.81-1.90 (m, 2H), 1.54-1.55 (m, 4H).LCMS:516.2 [M+H]

[0341] [ka] Starting from 5-(5-aminopyridin-2-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D14, 0.030 g, 0.045 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.014 g, 0.045 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (5 mg, 23% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.67 (bs, 1H), 9.68 (bs, 1H), 9.12 (s, 1H), 8.59-8.60 (m, 1H), 8.09 (s, 1H), 7.92-8.00 (m, 2H), 7.17 (bs, 2H), 6.20 (s, 1H), 3.58-3.63 (m, 1H), 1.36-1.48 (m, 4H), 1.06-1.10 (m, 4H).LCMS:485.2 [M+H]

[0342] [ka] Starting from 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D15, 0.150 g, 0.498 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.155 g, 0.498 mmol), following the general procedure for urea formation (Method A) gave the title compound as a white solid (0.015 g, 6% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 11.47 (bs, 1H), 10.17 (bs, 1H), 8.18 (s, 1H), 7.42 (s, 1H), 7.18-7.22 (m, 2H), 6.82 (s, 1H), 6.27 (bs, 2H), 3.51-3.55 (m, 1H), 1.46-1.51 (m, 4H), 1.04-1.05 (m, 4H).LCMS:520.2 [M+H]

[0343] [ka] Starting from 2-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (D23, 0.100 g, 0.348 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.109 g, 0.348 mmol), following the general procedure for urea formation (Method B) gave the title compound as a white solid (0.035 mg, 20% yield). 1H NMR (400 MHz, CD3OD) δ = 8.35 (s, 1H), 8.23-8.27 (m, 1H), 7.58 (s, 1H), 7.32-7.39 (m, 2H), 6.81 (s, 1H), 4.47 (t, J = 10.8 Hz, 2H), 3.95-3.98 (m, 2H), 1.49-1.59 (m, 4H).LCMS:506.2 [M+H]

[0344] [ka] A mixture of 4-chloro-1-cyclopropyl-3-iodo-1H-pyrrolo[3,2-c]pyridine (B9, 0.300 g, 0.942 mmol) and (2,5-dimethoxyphenyl)methanamine (0.429 mL, 2.83 mmol) in n-BuOH (10 mL) was stirred at 110 °C for 12 hours. After completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by Isolera (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title product as a yellow gum (0.10 g, 19% yield). LCMS: 450.0 [M+H]

[0345] [ka] Starting from 1-cyclopropyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrrolo[3,2-c]pyridin-4-amine (0.190 g, 0.423 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.100 g, 0.423 mmol), the title compound was obtained as a brown gum (0.080 g, 41% yield) according to a procedure similar to that described in Intermediate D8. LCMS: 433.2 [M+H]

[0346] [ka] Starting from 3-(4-amino-3-fluorophenyl)-1-cyclopropyl-N-(2,4-dimethoxybenzyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (0.080 g, 0.185 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.058 g, 0.185 mmol), following the general procedure for urea formation (Method B) gave the title compound as an off-white solid (0.027 g, 17% yield). LCMS: 651.3 [M+H]

[0347] [ka] Triethylsilane (4.8 mg, 0.041 mmol) and TFA (4.7 mg, 0.041 mmol) were added to a solution of 1-(4-(1-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.027 g, 0.041 mmol) in DCM (2 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 12 hours. After completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC (gradient elution with 0.1% TFA in water and ) to give the title product as an off-white solid (5 mg, 24% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.21-8.25 (m, 1H), 7.64-7.66 (m, 1H), 7.51 (s, 1H), 7.30-7.38 (m, 3H), 6.33 (s, 1H), 3.59-3.62 (m, 1H), 1.39-1.49 (m, 4H), 1.13-1.26 (m, 4H).LCMS:501.2 [M+H]

[0348] Biological Example 1 Biochemical assay of compounds Following the procedures described above, representative compounds were tested for inhibitory activity against NEK7 and IL-1β release, and the results are shown in the table below. [Table 21] [Table 22] NEK7 IC in Table 2 50 Regarding activity: * I C 50 is greater than 1500nM ** I C 50 is between 501 and 1500 nM *** I C 50 is between 301 and 500 nM **** I C 50 is between 151 and 300 nM ***** I C 50 is less than 150nM Table 2 IL-1β IC 50 Regarding activity: + IC 50 is greater than 1000nM ++IC 50 is between 301 and 500 nM +++ IC 50 is between 151 and 300 nM ++++IC 50 is less than 150nM - indicates that the value was not determined

[0349] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature referenced herein and / or listed in application data sheets (including, but not limited to, U.S. Provisional Application Serial No. 63 / 022,159, filed May 8, 2020, and U.S. Provisional Application Serial No. 63 / 170,761, filed April 5, 2021) are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified as necessary to utilize concepts from various patents, applications, and publications to provide further embodiments.

[0350] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments along with the full range of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims

1. The following structure (I): 【Chemistry 1】 [In the formula, A is C ６ -C １０ Aryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, each of which is selected from one or more R ６ may be optionally substituted with; X is CH or N; Y is NH; R １ is H or C １ -C ６ is alkyl; R ２ is C ３ -C ４ cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is selected from the group consisting of halo, hydroxyl, cyano, aminyl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ optionally substituted with one or more substituents selected from alkoxy and 3- to 8-membered heterocyclyl; R ３ is H; R ４ is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, cyano, aminyl, C １ -C ６ Hydroxyl alkyl, C １ -C ６ cyanoalkyl, 3- to 8-membered heterocyclyl, C ３ -C ８ Haloalkylcycloalkyl, C ３ -C ８ Aminylalkylcycloalkyl, C ３ -C ８ alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C ３ -C ８ optionally substituted with one or more substituents selected from halocycloalkyl; R ５ is H; R ６ are each independently halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, cyano, C １ -C ６ Hydroxyl alkyl or C １ -C ６ haloalkyl] or a pharmaceutically acceptable salt, or stereoisomer thereof.

2. R １ The compound of claim 1 , wherein is H.

3. R ２ is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is halo, hydroxyl, cyano, aminyl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ 3. A compound according to any one of claims 1 or 2, optionally substituted with one or more substituents selected from alkoxy and 3- to 8-membered heterocyclyl.

4. R ２ The compound of claim 3 , wherein is unsubstituted.

5. R ２ but has the following structure: 【Chemistry 2】 5. The compound of claim 1, wherein

6. R ４ is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1,3,4-oxadiazolyl, each of which is selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, cyano, aminyl, C １ -C ６ Hydroxyl alkyl, C １ -C ６ cyanoalkyl, 3- to 8-membered heterocyclyl, C ３ -C ８ Haloalkylcycloalkyl, C ３ -C ８ Aminylalkylcycloalkyl, C ３ -C ８ alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C ３ -C ８ 6. The compound of any one of claims 1 to 5, optionally substituted with one or more substituents selected from halocycloalkyl, and combinations thereof.

7. R ４ is isoxazolyl, halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, cyano, aminyl, C １ -C ６ Hydroxyl alkyl, C １ -C ６ cyanoalkyl, 3- to 8-membered heterocyclyl, C ３ -C ８ Haloalkylcycloalkyl, C ３ -C ８ Aminylalkylcycloalkyl, C ３ -C ８ alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C ３ -C ８ 7. The compound of claim 6, which may be optionally substituted with one or more substituents selected from halocycloalkyl, and combinations thereof.

8. R ４ But C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, cyano, aminyl, C １ -C ６ Hydroxyl alkyl, C １ -C ６ cyanoalkyl, 3- to 8-membered heterocyclyl, C ３ -C ８ Haloalkylcycloalkyl, C ３ -C ８ Aminylalkylcycloalkyl, C ３ -C ８ alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C ３ -C ８ 8. The compound of any one of claims 1 to 7, substituted with halocycloalkyl, or combinations thereof.

9. R ４ but has the following structure: 【Transformation 3】 9. The compound of claim 1, wherein

10. 10. The compound of any one of claims 1 to 9, wherein A is phenyl, saturated or unsaturated cyclohexyl, pyridinyl, or pyrimidinyl.

11. 11. The compound of any one of claims 1 to 10, wherein A is unsubstituted.

12. A is halo, C １ -C ６ Hydroxyl alkyl, cyano, and C １ -C ６ 11. The compound of any one of claims 1 to 10, substituted with one or more substituents selected from alkoxy.

13. 13. The compound of claim 12, wherein halo is chloro or fluoro.

14. C １ -C ６ The hydroxyl alkyl is —CH ２ CH ２ 13. The compound of claim 12, wherein:

15. Said C １ -C ６ 13. The compound of claim 12, wherein the alkoxy is methoxy.

16. A has the following structure: 【Chemistry 4】 16. The compound of any one of claims 1 to 15, having one of the following:

17. The following structure (IA): 【Transformation 5】 [In the formula, R ２ａ is C ３ -C ４ cycloalkyl, halo, hydroxyl, cyano, aminyl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ optionally substituted with one or more substituents selected from alkoxy and 3- to 8-membered heterocyclyl; R ４ａ teeth, 【Transformation 6】 having one of the following structures:

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. R ２ａ but has the following structure: 【Transformation 7】 18. The compound of claim 17, having the formula:

19. R ４ａ but has the following structure: 【Transformation 8】 19. The compound of claim 17 or 18, having one of the following:

20. 17. The compound of any one of claims 1 to 16, wherein X is CH.

21. The following structure: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 10. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, having one of:

22. 22. A pharmaceutical composition for treating an NLRP3-mediated disorder or an NEK7-mediated disorder, or both, comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier, diluent, or excipient.

23. 23. The pharmaceutical composition of claim 22 for treating a NEK7-mediated disorder.

24. 24. The pharmaceutical composition of claim 23, wherein the disorder is selected from autoimmune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung disorders, respiratory diseases, and ischemic conditions.

25. 25. The pharmaceutical composition of any one of claims 22 to 24, wherein the disorder is selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage due to infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, and Muckle-Wells syndrome.

26. Use of a compound of any one of claims 1 to 21, or a pharmaceutical composition of any one of claims 22 to 25, in the manufacture of a medicament for treating an NLRP3-mediated disorder or an NEK7-mediated disorder, or both.

27. 27. The use of claim 26, wherein the disorder is selected from autoimmune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung disorders, respiratory diseases, and ischemic conditions.

28. 28. The use of any one of claims 26 or 27, wherein the disorder is selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage due to infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, and Muckle-Wells syndrome.

Images