NEK7 kinase inhibitor

Abstract

A compound having inhibitory activity of NEK7 is provided. The compound is a compound of structure (I), a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof: In the above formula, A, X, Y, R1, R2, R3, R4, and R5 are as defined in this specification. Methods associated with the preparation and use of such compounds, pharmaceutical compositions comprising such compounds, and methods for controlling the activity of the NLRP3 inflammasome are also provided.

Description

Technology Field

[0001] Embodiments of the present invention generally relate to compounds and methods for manufacturing the same, and, for example, their use as therapeutic agents or preventive agents for treating inflammation. Background Technology

[0002] The inflammasome is a multi-protein complex 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 consists 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, inflammation-mediating cytokines, in animal disease models of various autoimmune diseases, myocardial infarction, metabolic syndrome, inflammatory bowel disease, and macrophage activation syndrome.

[0003] NEK7 is a member of the NIMA-associated kinase (NEK) family that acts as an NLRP3-binding protein to regulate 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 such as the brain, heart, lungs, liver, and spleen. Overexpression of NEK7 leads to the generation of abnormal cells, which are closely associated with tumors such as retinoblastoma, gallbladder cancer, and head and neck carcinoma.

[0004] Many inhibitors are widely used to disrupt effector signaling pathways involving IL-1β or IL-18 without abolishing the inflammatory response. Inhibitors of NLRP3 inflammasome activation that block NLRP3-NEK7 interactions may have therapeutic or preventive activity against various human diseases, such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the precise mechanism of NLRP-3-NEK7 is not well understood. The problem to be solved

[0005] Therefore, there is a need to develop inhibitors that directly target NEK7 and affect inflammatory responses regulated by the NLRP3 inflammasome in various 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 invention satisfy this need and provide additional related advantages. means of solving the problem

[0006] Briefly, embodiments of the present invention provide a compound comprising a pharmaceutically acceptable salt, stereoisomer, and prodrug thereof, which can inhibit NEK7 and / or modulate the activity of the NLRP3 inflammasome.

[0007] In one aspect, the present invention provides a compound of structure (I), a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof:

[0008]

[0009] In the above equation, each A, X, Y, R 1 , R 2 , R 3 , R4 and R 5 is as defined below.

[0010] In another aspect, a pharmaceutical composition comprising the disclosed compound and a method of using the same for treating inflammation are also provided.

[0011] In the following description, specific details are provided to provide a complete understanding of various embodiments of the present invention. However, those skilled in the art will understand that the invention can be practiced without these details.

[0012] Unless otherwise required by the context, throughout this specification and claims, the word “include” and its variations, e.g., “include (third-person singular)” and “includes”, shall be interpreted in an open, inclusive sense, namely, “includes but not limited thereto.”

[0013] In this detailed description, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range, and, in some cases, fractions thereof (e.g., tenths and hundredths of an integer). As used herein, unless otherwise indicated, the terms “about” and “approximately” mean ± 20%, ± 10%, ± 5%, or ± 1% of the stated range, value, or structure. As used herein, the terms “a” and “an” should be understood to refer to “one or more” of the listed components. The use of substitutes (e.g., “or”) should be understood to mean any one, both, or any combination thereof of the substitutes.

[0014] Throughout this specification, references to "one embodiment" or "an embodiment" mean that specific features, structures, or characteristics described in relation to said embodiment are included in at least one embodiment of the present invention. Accordingly, the appearance of the phrases "in one embodiment" or "in an embodiment" at various locations throughout this specification does not necessarily always refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which the present invention pertains. As used in the specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0016] "Amino" refers to the -NH2 radical.

[0017] "Carboxy" or "carboxyl" refers to the -CO2H radical.

[0018] "Cyano" refers to the -CN radical.

[0019] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0020] "Nitro" refers to the -NO2 radical.

[0021] "Oxo" refers to the =O substituent.

[0022] "Thiols" refer to -SH substituents.

[0023] "Thioxo" refers to an =S substituent.

[0024] "Alkyl" consists only of carbon and hydrogen atoms, with 1 to 12 carbon atoms (C1-C 12A saturated straight-chain or branched hydrocarbon radical attached to the remainder of the molecule by a single bond, having alkyl), 1 to 8 carbon atoms (C1-C8 alkyl) or 1 to 6 carbon atoms (C1-C6 alkyl), or any value within these ranges, e.g., C4-C6 alkyl, etc., e.g., methyl, ethyl n -propyl, 1-methylethyl( Iso -profile), n -butyl, n -pentyl, 1,1-dimethylethyl( t Refers to -butyl), 3-methylhexyl, 2-methylhexyl, etc. The number of carbons mentioned relates to the carbon skeleton and carbon branches, but does not include carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, alkyl groups are optionally substituted.

[0025] "Alkenyl" consists solely of carbon and hydrogen atoms containing one or more carbon-carbon double bonds, and 2 to 12 carbon atoms (C2-C 12 Refers to an unsaturated straight-chain or branched hydrocarbon radical attached to the remainder of the molecule by a single bond, having 2 to 8 carbon atoms (C2-C8 alkenyl) or 2 to 6 carbon atoms (C2-C6 alkenyl), or any value within these ranges, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. The number of carbons mentioned relates to the carbon skeleton and carbon branching, but does not include carbon atoms belonging to any substituents. Unless specifically otherwise stated in the specification, the alkenyl group is optionally substituted.

[0026] The term "alkynyl" refers to 2 to 12 carbon atoms (C2-C 12It refers to an unsaturated straight-chain or branched hydrocarbon radical having at least one carbon-carbon triple bond, having 2 to 9 carbon atoms (C2-C9 alkynyl), 2 to 6 carbon atoms (C2-C6 alkynyl), or any value within these ranges. Examples of alkynyl groups may be selected from the group consisting of ethinyl, propargyl, but-1-inyl, but-2-inyl, etc. The number of carbons mentioned relates to the carbon skeleton and carbon branching, but does not include carbon atoms belonging to any substituents. Unless specifically otherwise stated in the specification, the alkynyl group is optionally substituted.

[0027] "Alkoxy" is the chemical formula -OR a It refers to the radical of, where R a is 1 to 12 carbon atoms (C1-C 12 It is an alkyl radical as defined above containing 1 to 8 carbon atoms (C1-C8 alkoxy), 1 to 6 carbon atoms (C1-C6 alkoxy), or any value within these ranges. Unless specifically otherwise stated in the specification, the alkoxy group is optionally substituted.

[0028] "Aminyl" has the chemical formula -NR a R b It refers to the radical of, where R a and R b Each is independently H or a C1-C6 alkyl as defined above. R a and R b When both are H, the "aminyl" group is identical to the "amino" group as defined above. The C1-C6 alkyl portion of the aminyl group is optionally substituted unless otherwise noted.

[0029] "Aminylalkylcycloalkyl" has the chemical formula -R a R b NR c R d It refers to the radical of, where R ais a cycloalkyl as defined in this specification, and R b is a C1-C6 alkyl, and R c is H or C1-C6 alkyl, and R d is a C1-C6 alkyl as defined above. The cycloalkyl and each C1-C6 alkyl portion of the aminylalkylcycloalkyl group are optionally substituted unless otherwise noted.

[0030] "Aromatic ring" refers to a cyclic planar molecule or part of a molecule (i.e., a radical) having a ring of resonance bonds that has increased stability compared to other connectivity arrangements with the same set of atoms. Generally, an aromatic ring contains one set of covalently bonded coplanar atoms and includes a number of π electrons (e.g., alternating double and single bonds) that are even but not multiples of 4 (i.e., 4n + 2π 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 specifically stated otherwise in the specification, "aromatic ring" includes any optionally substituted radical.

[0031] "Aryl" refers to 6 to 18 carbon atoms, for example, 6 to 10 carbon atoms (C6-C 10 It refers to a carbocyclic ring system radical comprising an aryl group and at least one carbocyclic aromatic ring. For the purposes of embodiments of the present invention, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or cross-linked ring system. The aryl radical is acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as -Indasen, s- Includes, but is not limited to, aryl radicals derived from indacen, indan, indene, naphthalene, phenalene, phenanthrene, pleiaden, pyrene, and triphenylene. Unless specifically stated otherwise in the specification, the aryl group is optionally substituted.

[0032] "Cyanoalkyl" refers to an alkyl group comprising at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless specifically otherwise stated in the specification, the cyanoalkyl group is optionally substituted.

[0033] "Carbocyclic" or "carbocycle" refers to a ring system, where each ring atom is carbon.

[0034] "Cycloalkyl" consists only of carbon and hydrogen atoms and may include fused or cross-linked ring systems, and has 3 to 15 ring carbon atoms (C3-C 15 cycloalkyl), 3 to 10 ring carbon atoms (C3-C 10 It refers to a non-aromatic monocyclic or polycyclic carbocyclic radical having 3 to 8 cyclic carbon atoms (C3-C8 cycloalkyl), or any value within this range, e.g., 3 to 4 carbon atoms (C3-C4 cycloalkyl), saturated or partially unsaturated, and attached to the remainder 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, etc. Unless specifically otherwise stated in the specification, the cycloalkyl group is optionally substituted.

[0035] "Alkylcycloalkyl" has the chemical formula -R a R b It refers to the radical group of, where R ais a cycloalkyl group as defined above, and R b is an alkyl group. Unless specifically stated otherwise in the specification, an alkylcycloalkyl group is optionally substituted.

[0036] "Fused" refers to any ring structure described herein that is fused to another ring structure.

[0037] "Halo" refers to bromo, chloro, fluoro, or iodo.

[0038] "Haloalkyl" refers to an alkyl radical as defined above substituted by one or more halo radicals as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless specifically stated otherwise in the specification, the haloalkyl group is optionally substituted.

[0039] "Halocycloalkyl" refers to a cycloalkyl radical as defined above substituted by one or more halo radicals as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless specifically stated otherwise in the specification, the halocycloalkyl group is optionally substituted.

[0040] "Haloalkylcycloalkyl" has the chemical formula -R a R b It refers to the radical group of, where R a is a cycloalkyl group as defined above, and R b is a haloalkyl group. Unless specifically stated otherwise in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0041] "Hydroxyalkyl" refers to an alkyl radical as defined above, substituted by one or more hydroxyl radicals. The hydroxyalkyl radical is bonded to the main chain through an alkyl carbon atom. Unless specifically otherwise stated in the specification, the hydroxyalkyl group is optionally substituted.

[0042] "Heterocyclile" 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 specifically otherwise stated in the specification, a heterocyclile radical is a monocyclic, acyclic, tricyclic, or tetracyclic ring system that may include a partially or completely saturated, fused, spirocyclic, and / or cross-linked ring system. The nitrogen, carbon, and sulfur atoms within the heterocyclile radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Examples of such heterocyclil radicals include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolininyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolizine, 2-oxopiperadinyl, 2-oxopiperadinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranil, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomofolinyl, thiamofolinyl, Examples include, but are not limited to, 1-oxo-thiomolfolinyl and 1,1-dioxo-thiomolfolinyl. Unless specifically stated otherwise in the specification, the heterocyclyl group is optionally substituted.

[0043] "Haloheterocyclylalkyl" has the chemical formula -R a Rb It refers to the radical group of, where R a is an alkyl group as defined in this specification, and R b is a haloheterocyclyl group. Unless specifically stated otherwise in the specification, the haloheterocyclylalkyl group is optionally substituted.

[0044] "Heterocyclylalkyl" has the chemical formula -R a R b It refers to the radical group of, where R a is an alkyl group as defined in this specification, and R b is a heterocyclyl group. Unless specifically stated otherwise in the specification, the heterocyclylalkyl group is optionally substituted.

[0045] "Heteroaryl" refers to a 5- to 18-membered, e.g., 5- to 6-membered ring system radical comprising 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 may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include a fused or cross-linked ring system; the nitrogen, carbon, or sulfur atoms within the heteroaryl radical may optionally be oxidized; and the nitrogen atom may optionally be quaternized. Examples include azefinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[ b][1,4]dioxephinyl, 1,4-benzodioxanil, benzonaphthofranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzofuranil, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranil, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indoliginyl, isoxazolyl, naphthiridinyl, oxadiazolyl, 2-oxozephinyl, oxazolyl, 1-oxydopyridinyl, 1-Oxydopyrimidinyl, 1-Oxydopyrazinyl, 1-Oxydopyridazinyl, 1-Phenyl-1 H Examples include, but are not limited to, pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazollyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in the specification, the heteroaryl group is optionally substituted.

[0046] Oxazolil, isoxazolil, 1,2,3-oxadiazollil, 1,2,4-oxadiazollil, 1,2,5-oxadiazollil, 1,3,4-oxadiazollil, 1,2,3-triazolil, 1,2,4-triazolil, thiazolil, isothiazollil, 1,2,3-thiadiazolil, 1,2,4-thiadiazolil, 1,2,5-thiadiazolil, and 1,3,4-thiadiazolil each refer to the following structures:

[0047]

[0048] In the above formula, oxazolil, isoxazolil, 1,2,3-oxadiazollil, 1,2,4-oxadiazollil, 1,2,5-oxadiazollil, 1,3,4-oxadiazollil, 1,2,3-triazolil, 1,2,4-triazolil, thiazolil, isothiazollil, 1,2,3-thiadiazolil, 1,2,4-thiadiazolil, 1,2,5-thiadiazolil, and 1,3,4-thiadiazolil are oxazolil, isoxazolil, 1,2,3-oxadiazollil, 1,2,4-oxadiazollil, 1,2,5-oxadiazollil, 1,3,4-oxadiazollil, 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 attached to the rest of the molecule by a covalent bond to one of the carbon atoms within the ring.

[0049] The term "substituted" as used herein refers to any of the aforementioned groups in which at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) is replaced by bonding to a non-hydrogen substituent (e.g., It means alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclil, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl. 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, heterocyclil, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl substituents (each of which may optionally be substituted by one or more of the above substituents).

[0050] In some specific embodiments, any substituent is 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 It is independently selected from the group consisting of aryls, 5- or 6-membered heteroaryls, C1-C6 alkoxys, and 3-8 membered heterocyclils.

[0051] The terms “effective dose” or “therapeutic effective dose” refer to an amount of the compound described herein that is sufficient for an intended application, including but not limited to the treatment of a disease, to produce an effect, as defined below. The therapeutic effective dose may vary depending on the intended therapeutic application (in vivo) or the subject and disease condition to be treated, e.g., the subject’s body weight and age, the severity of the disease condition, the mode of administration, etc., which can be readily determined by a person skilled in the art. The term also applies to a dose that induces a specific response in target cells, e.g., a reduction in platelet adhesion and / or cell migration. The specific dose will vary depending on the specific compound selected, the administration regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system used therein.

[0052] As used herein, “treatment” or “treating” refers to an approach to obtain a favorable or desired result with respect to a disease, disorder, or medical condition, including but not limited to therapeutic effects and / or preventive effects. A therapeutic benefit means the eradication or alleviation of the underlying disorder to be treated. Additionally, a therapeutic benefit is achieved by the eradication or alleviation of one or more physiological symptoms associated with the underlying disorder such that improvement is observed in the subject, even though the subject still suffers from the underlying disorder. A preventive effect includes the delay or elimination of the onset of the disease or condition, the delay or elimination of the onset of symptoms of the disease or condition, the deceleration, cessation, or reversal of the progression of the disease or condition, or any combination thereof. In certain embodiments, for a preventive benefit, the composition is administered to a subject at risk of developing a specific disease, or to a subject in whom one or more physiological symptoms of the disease have been reported, even if the disease in question has not been diagnosed.

[0053] The terms “concurrent administration,” “combination administration,” and their grammatical equivalents as used herein encompass the administration of two or more agents to an animal, including humans, such that both agents and / or their metabolites are simultaneously present in the subject. Concurrent administration includes the simultaneous administration of separate compositions, administration of separate compositions at different times, or administration of a composition in which both agents are present.

[0054] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0055] "Pharmaceutically acceptable acid addition salt" refers to a salt that retains the biological effects of a free base, which is biologically tolerable or otherwise biologically suitable for administration to a subject (generally, literature [SM Berge, et al. , “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, [See Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002]). Desirable pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with patient tissues without excessive toxicity, irritation, or allergic reactions. Pharmaceutically acceptable acid addition salts include inorganic acids including, but not limited to, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, etc., and acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphor acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactar acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, Hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic 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, parmoic acid, propionic acid, pyroglutamic acid, pyruvate, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanate, p - It is formed together with organic acids including, but not limited to, toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0056] "Pharmaceutically acceptable base addition salts" refers to salts that retain the biological effects of free acids, which are biologically tolerable or otherwise biologically suitable for administration to a subject (generally, literature [SM Berge, et al. , “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use,[Refer to Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002]. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with patient tissues without excessive toxicity, irritation, or allergic reactions. Pharmaceutically acceptable base addition salts are prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucarmin, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N - Salts such as ethylpiperidine and polyamine resins are included, but are not limited thereto. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0057] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (e.g., methyl bromide).

[0058] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds having the ability to inhibit the biological function of a target protein by inhibiting the activity or expression of a protein, e.g., the NLRP3 inflammasome or NEK7, or the NLRP3 inflammasome-NEK7 combination. Accordingly, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. In this specification, preferred antagonists are specifically included within this definition compounds that interact with (e.g., bind) to the target, but inhibit the biological activity of the target protein by interacting with other members of a signaling pathway to which the target protein is a member. The preferred biological activity inhibited by the antagonist is associated with the development, growth, or spread of a tumor.

[0059] The term "agent" as used herein refers to a compound having the ability to initiate or enhance the biological function of a target protein by inhibiting the activity or expression of the target protein. Accordingly, the term "agent" is defined in the context of the biological role of the target polypeptide. In this specification, preferred agents specifically interact (e.g., bind) with the target, but compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other members of the signaling pathway to which the target polypeptide is a member are also specifically included within this definition.

[0060] "Signal transduction" is the process by which stimulating or inhibitory signals are transmitted into and from a cell to elicit an intracellular response.

[0061] The terms "selective inhibition" or "to selectively inhibit" refer to the ability of a biologically active agent to preferentially reduce target signaling activity compared to off-target signaling activity through direct or indirect interaction with a target.

[0062] "Subject" refers to an animal, e.g., a mammal, e.g., a human. The method described herein may be useful in both human treatment and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0063] "Mammals" include both humans and domesticated animals, such as laboratory animals and pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-domesticated animals, such as wild animals.

[0064] "Prodrug" is considered to refer to a compound that can be converted into the biologically active compound described herein (e.g., the compound of structure (I)) under physiological conditions or by solvate degradation. Accordingly, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. In some embodiments, the prodrug is inactive when administered to a subject but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer the advantages of solubility, histocompatibility, or delayed release within mammalian organisms (e.g., see the literature [Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)]). The literature in which discussions of prodrugs are incorporated herein in their entirety by reference [Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. [14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987] is provided. The term “prodrug” is also considered to comprise any covalently bound carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. The prodrugs of the active compounds described herein are prepared by modifying a functional group typically present in the active compound in such a manner that the modified site degrades during routine processing or in vivo to form the parent active compound. The prodrug comprises a compound in which a hydroxyl, amino, or thiol group is bound to any group such that when the prodrug of the active compound is administered to a mammalian subject, it degrades to form a free hydroxyl, free amino, or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the hydroxyl functional group in the active compound, or acetamide, formamide, and benzamide derivatives of the amine functional group.

[0065] The term "in vivo" refers to events occurring within the body of a subject.

[0066] The embodiments disclosed herein are also considered to encompass all pharmaceutically acceptable compounds of structure (I).

[0067] A given embodiment is also considered to encompass in vivo metabolites of the disclosed compound. Such products may be obtained primarily from enzymatic processes of the administered compound, e.g., oxidation, reduction, hydrolysis, amidation, esterification, etc. Accordingly, an embodiment comprises a compound produced by a process comprising the step of administering the compound of the present invention to a mammal for a time sufficient to obtain its metabolites. Such products are typically identified by administering a radiolabeled compound of the present invention to an animal, e.g., a rat, mouse, guinea pig, monkey, or human, at a detectable dose, allowing sufficient time for metabolism to occur, and isolating its transformed products from urine, blood, or other biological samples.

[0068] "Stable compound" and "stable structure" are considered to refer to a compound robust enough to withstand separation from a reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent.

[0069] Often, crystallization produces solvates of the compounds disclosed herein. As used herein, the term “solvate” refers to an aggregate comprising one or more compounds of the present invention 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 invention may exist in hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., and corresponding solvates. In some embodiments, the compounds of the present invention are true solvates, but in other cases, the compounds of the present invention merely contain incident water or are merely a mixture of water and some incident solvent.

[0070] "Optional" or "opportunistically" means that a subsequent event or situation may or may not occur, and implies that the description includes cases where said event or situation occurs and cases where it does not occur. For example, "opportunistically substituted aryl" means that an aryl radical may or may not be substituted, and the description includes both substituted aryl radicals and unsubstituted aryl radicals.

[0071] "Pharmaceutical composition" refers to a formulation of the compound of the present invention and a medium generally accepted in the art for delivering the compound of the present invention to mammals, e.g., humans. Such a medium comprises any pharmaceutically acceptable carrier, diluent, or excipient.

[0072] "Pharmaceutically acceptable carriers, diluents, or excipients" include, without limitation, any adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0073] "Stereoisomer" refers to a compound composed of the same atoms bonded by the same bond but having different three-dimensional structures and being incompatible. The present invention considers various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed.

[0074] The compound of the present invention (i.e., the compound of structure (I)) or a pharmaceutically acceptable salt thereof may contain one or more geometrically asymmetric centers, and thus in terms of absolute stereochemistry, in the case of an amino acid ( R )- or ( S It may give rise to stereoisomers defined as )-, or (D)-, or (L)-, such as enantiomers, diastereomers, and other stereoisomer forms. Accordingly, embodiments include all such possible isomers, and their racemic and optically pure forms. Optically active (+) and (-), ( R )- and ( S )-, or (D)- and (L)- isomers may be prepared using chiral synthones or chiral reagents, or separated using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or, e.g., separation of racemic mixtures (or racemic mixtures of salts or derivatives) using chiral high-pressure liquid chromatography (HPLC). Unless otherwise specified, if a compound described herein contains an olefinic double bond or other geometrically asymmetric center, the compound is intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0075] Embodiments of the present invention include all modes of rotational isomers and stereolocated states of the compounds of the present invention. Atropic isomers, which are stereoisomers resulting from unfree rotation around a single bond, are also included where an energy difference caused by stereostrain or other factors creates a barrier to rotation sufficiently high to allow separation of the individual isomers. For example, a given compound of the present invention may exist as a mixture of atropic isomers, or in a purified or state rich in the presence of one atropic isomer.

[0076] 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.

[0077] "Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. Accordingly, the embodiments include tautomers of the disclosed compound.

[0078] The chemical naming protocols and structural diagrams used herein are a modified form of the IUPAC naming system 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, substituents are typically named before the group to which they are attached. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structural diagrams of this specification, and all bonds on some carbon atoms that are assumed to be bonded to hydrogen atoms sufficient to complete the valence are excluded.

[0079] compound

[0080] The present invention provides a compound comprising its pharmaceutically acceptable salt, stereoisomer, and prodrug, which can inhibit NEK7 and / or modulate the activity of the NLRP3 inflammasome.

[0081] Embodiments of the present invention provide a compound having the following structure (I), a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof:

[0082]

[0083] In the above formula

[0084] A is C6-C 10 Aryl, C3-C 10 It is a cycloalkyl, a 3-10-membered heterocyclile, or a 5-6-membered monocyclic heteroaryl, and each of these has one or more R 6 It is arbitrarily substituted into;

[0085] Y is CHOH or NH;

[0086] R 1 It is H or C1-C6 alkyl;

[0087] R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclyl, or 5- or 6-heteroaryl, each of which is optionally substituted by 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 heterocyclyl;

[0088] 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 by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0089] R 4 is a 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 halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxyalkyl, Optionally substituted by one or more substituents selected from 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;

[0090] R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 It is an aryl or a 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0091] R 6 In each case, it is independently a halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0092] In some embodiments of structure (I)

[0093] A is C6-C 10 Aryl, C3-C 10It is a cycloalkyl, a 3-10-membered heterocyclile, or a 5-6-membered monocyclic heteroaryl, and each of these has one or more R 6 It is arbitrarily substituted by;

[0094] Y is CHOH or NH;

[0095] R 1 It is H or C1-C6 alkyl;

[0096] R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclyl, or 5- or 6-heteroaryl, each of which is optionally substituted by 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 heterocyclyl;

[0097] 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 by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0098] R 4is a 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 substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl. Substituted;

[0099] R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 It is an aryl or a 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0100] R 6 In each case, it is independently a halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0101] Some more specific embodiments provide a compound having the following structure (I), a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof:

[0102]

[0103] In the above formula

[0104] A is C6-C 10 Aryl, C3-C 10 It is a cycloalkyl, a 3-10-membered heterocyclile, or a 5-6-membered monocyclic heteroaryl, and each of these has one or more R 6 It is arbitrarily substituted by;

[0105] X is CH or N;

[0106] Y is CHOH or NH;

[0107] R 1 is H or C1-C6 alkyl;

[0108] R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclyl, or 5- or 6-heteroaryl, each of which is optionally substituted by 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 heterocyclyl;

[0109] 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 by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0110] R 4is a 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 halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxyalkyl, Optionally substituted by one or more substituents selected from 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;

[0111] R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 It is an aryl or a 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0112] R 6 In each case, it is independently a halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl.

[0113] In a given embodiment, R 1 is H. In another embodiment, R 1 It is a C1-C6 alkyl, for example, methyl.

[0114] In one embodiment, a compound of structure (I) is provided, wherein R 2 is a branched C4-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted by 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.

[0115] In another embodiment, a compound of structure (I) is provided, wherein R 2 is a branched C4-C6 alkyl, C3-C4 cycloalkyl, or C3-C8 heterocyclile, each of which is optionally substituted by 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 heterocycliles.

[0116] In a specific embodiment, R 2 is cyclopropyl or oxetanyl, each of which is optionally substituted by 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 heterocyclil. In some embodiments, R 2 is cyclopropyl. In another embodiment, R 2 is oxetanil. In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanil.

[0117] In a specific embodiment, R 2is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is optionally substituted by 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 heterocyclil. In some embodiments, R 2 is cyclopropyl. In another embodiment, R 2 is oxetanil. In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R 2 is N-methyl-substituted pyrrolidinyl. In a specific embodiment, R 2 is unsubstituted cyclobutyl.

[0118] In different embodiments, R 2 is a branched C4-C6 alkyl optionally substituted by 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 heterocyclil. For example, in some embodiments, R 2 is 2-methylpropyl arbitrarily substituted by a hydroxyl group.

[0119] In a more specific embodiment, R 2 has one of the following structures:

[0120]

[0121] In some specific embodiments, R 2 has one of the following structures:

[0122] .

[0123] In another embodiment, R 3 is H. In another embodiment, R 3 is a C1-C6 alkyl, e.g., methyl.

[0124] In any of the aforementioned embodiments, R 4 is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, or 1,3,4-oxadiazolyl, each of which is optionally by 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, C1-C6 cyanoalkyl, 3- to 8-one heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-one heterocyclilalkyl, 3- to 8-one alkylheterocyclilcycloalkyl, 3- to 8-one haloheterocyclilalkyl, and C3-C8 halocycloalkyl, and combinations thereof. It is substituted. For example, in a given embodiment, R 4 is isoxazolyl optionally substituted by one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl. In further specific embodiments, R 4 is substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl.

[0125] In a given 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, and each of these is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-one heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-one heterocyclilalkyl, 3- to 8-one It is optionally substituted by one or more substituents selected from alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0126] In a given embodiment, R 4 is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-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 heterocyclilalkyl, 3- to 8-membered alkylheterocyclilcycloalkyl, 3- to 8-membered haloheterocyclilalkyl, and C3-C8 halocycloalkyl, and is optionally substituted by one or more substituents selected from combinations thereof.

[0127] In a given embodiment, R 4is a thiazolyl optionally substituted by one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-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 heterocyclilalkyl, 3- to 8-membered alkylheterocyclilcycloalkyl, 3- to 8-membered haloheterocyclilalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0128] In a given embodiment, R 4 is an isothiazolyl optionally substituted by one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-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 heterocyclilalkyl, 3- to 8-membered alkylheterocyclilcycloalkyl, 3- to 8-membered haloheterocyclilalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0129] In a given embodiment, R 4is 1,2,4-thiadiazolyl optionally substituted by one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-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 heterocyclilalkyl, 3- to 8-membered alkylheterocyclilcycloalkyl, 3- to 8-membered haloheterocyclilalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0130] In a given embodiment, R 4 is 1,3,4-thiadiazolyl optionally substituted by one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-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, and combinations thereof.

[0131] In a given embodiment, R 4is a 1,2,4-triazolyl optionally substituted by one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-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 heterocyclilalkyl, 3- to 8-membered alkylheterocyclilcycloalkyl, 3- to 8-membered haloheterocyclilalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0132] In a given embodiment, R 4 is a 1,3,4-oxadiazolyl optionally substituted by 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 heterocyclil, C3-C8 halocycloalkyl, or combinations thereof.

[0133] In a given embodiment, R 4 is substituted by C1-C6 alkyl, C1-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, and combinations thereof.

[0134] In various embodiments, R 4 has one of the following structures:

[0135] .

[0136] In various other embodiments, R 4has one of the following structures:

[0137] .

[0138] In various other embodiments, R 4 has one of the following structures:

[0139] .

[0140] In a specific embodiment, R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclyl, or 5- or 6-heteroaryl, each of which is optionally substituted by 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 heterocyclyl;

[0141] R 4 has one of the following structures:

[0142] .

[0143] In a specific embodiment, R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclyl, or 5- or 6-heteroaryl, each of which is optionally substituted by 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 heterocyclyl;

[0144] R 4 has one of the following structures:

[0145] .

[0146] In a more specific embodiment, R 2 is a C1-C6 alkyl substituted by a hydroxyl or a C1-C6 alkoxy. In some embodiments, R 2has one of the following structures:

[0147] .

[0148] In another embodiment, R 5 is H. In another embodiment, R 5 is a C1-C6 alkyl, e.g., methyl.

[0149] In a given embodiment, Y is C(H)(OH). In another embodiment, Y is NH.

[0150] In various embodiments, A is C6-C 10 Aryl, C3-C 10 It is a cycloalkyl or 5-6-membered monocyclic heteroaryl, and each of these has one or more R 6 It is arbitrarily substituted by. A is understood to be a divalent radical.

[0151] In a given embodiment, A is an arbitrarily substituted divalent C6- 10 It is an aryl. In a given embodiment, A is an optionally substituted divalent 3-8 member saturated or partially unsaturated carbocyclic ring. In a given embodiment, A is an optionally substituted divalent 3-10 member heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In a given embodiment, A is an optionally substituted divalent 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0152] In a given embodiment, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of these is optionally substituted. In another embodiment, A is phenyl. In a different embodiment, A is saturated or unsaturated cyclohexyl. In a further embodiment, A is pyridinyl.

[0153] In a given embodiment, A is pyrimidinyl, which is optionally substituted.

[0154] In any of the aforementioned embodiments, A is not substituted. In different prior embodiments, A is one or more R 6 It is replaced by. For example, in some embodiments, R 6 is a halo. In some embodiments, R 6 is chloro or fluoro. In other embodiments, R 6 is a fluoro.

[0155] In some embodiments, R 6 is a 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 a C1-C6 alkoxy. In a more specific embodiment, the C1-C6 alkoxy is a methoxy.

[0156] In a given embodiment, A is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2] Bicyclooctanyl, Fluorenyl, Indanyl, Tetrahydronaphthyl, Acridinyl, Azocinyl, Benzimidazolyl, Benzofuranil, Benzothiofuranil, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazollyl, Benzisoxazolyl, Benzisothiazolyl, Benzimidazolinyl, Carbazollyl, NH-Carbazollyl, Carvolinyl, Cromanyl, Cromenyl, Sinolinil, Decahydroquinolinil, Dithiazinyl, Tetrahydrofuranil, Furanyl, Furazanil, Imidazolidinyl, Imidazolinil, Imidazolyl, 1H-Indazollyl, Indolenyl, Indolinyl, Indolizinil, Indolyl, 3-Indolyl, Isoindolinyl, Isoindolenyl, Isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naftiridinyl, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolil, Oxazolidinyl, Pyrimidinyl, Fenanthridinyl, Fenanthrolinyl, Fenazinyl, Fenothiazinyl, Fenoxatiinyl, Fenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purinyl, Pyranil, Pyrazinyl, Pyrazolidinyl, Pyrazolinil, Pyrazolil, Pyridazinyl, Pyridoxazole, Pyridomidazole, Pyridothiaazole, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2-Pyrrolil, Pyrrolil, Quinazolinyl, Quinolinyl, 4H-Quinolidinyl, Quinoxalinyl, Quinuclidinyl, A divalent group selected from tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, 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 these is optionally substituted.

[0157] In a specific embodiment, A has one of the following structures:

[0158] .

[0159] In some specific embodiments, A has one of the following structures:

[0160] .

[0161] In some specific embodiments, A has one of the following structures:

[0162] .

[0163] In a given embodiment, the compound or its pharmaceutically acceptable salt, stereoisomer, or prodrug has the following structure (IA):

[0164]

[0165] In the above formula

[0166] R 2a is a C1-C6 alkyl or C3-C8 cycloalkyl optionally substituted by 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 heterocyclyl;

[0167] R 4a is a isoxazolyl optionally substituted by one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkyl cycloalkyl.

[0168] In a more specific embodiment, R 2a is a branched C1-C6 alkyl substituted by a hydroxyl group. In some embodiments, R 2a is a C3-C8 cycloalkyl. In a more specific embodiment, R 2a has one of the following structures:

[0169] .

[0170] In a given embodiment, R 4a is a isoxazolyl substituted by a C3-C8 haloalkylcycloalkyl group. In some embodiments, R 4a is a C3-C8 fluoroalkylcycloalkyl. In a more specific embodiment, R 4a is fluoroalkylcyclopropyl or fluoroalkylcyclobutyl. In a more specific embodiment, R 4a has one of the following structures:

[0171] .

[0172] In some embodiments, X is CH. In some more specific embodiments, the compound or its pharmaceutically acceptable salt, stereoisomer, or prodrug has the following structure (IB):

[0173]

[0174] In the above formula

[0175] A is C6-C 10 Aryl, C3-C 10 It is a cycloalkyl, a 3-10-membered heterocyclile, or a 5-6-membered monocyclic heteroaryl, and each of these has one or more R 6 It is arbitrarily substituted by;

[0176] X is CH or N;

[0177] Y is CHOH or NH;

[0178] R 1 is H or C1-C6 alkyl;

[0179] R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclyl, or 5- or 6-heteroaryl, each of which is optionally substituted by 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 heterocyclyl;

[0180] 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 by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0181] R 4 is a 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 halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxyalkyl, Optionally substituted by one or more substituents selected from 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;

[0182] R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 10 It is an aryl or a 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0183] R 6 In each case, it is independently a halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl.

[0184] In a given embodiment, the compound of structure (I) is a modulator of the NLRP3 inflammasome.

[0185] In a specific embodiment, the compound of structure (I) is an inhibitor of NEK7 in a patient or biological sample.

[0186] In various different embodiments, the compound, its pharmaceutically acceptable salt, stereoisomer, or prodrug has one of the structures listed in Table 1 below. The compounds in Table 1 were prepared as described in the examples or by methods known in the art and mass spectrometry and / or 1 It was analyzed by H NMR.

[0187] [Table 1]

[0188] Representative compound of structure (I)

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] In this specification, combinations of substituents and / or modifications of the illustrated formulas are understood to be acceptable only if such contribution results in a stable compound.

[0212] In additional embodiments, various compounds of the present invention existing in the form of free bases or acids may be converted into pharmaceutically acceptable salts thereof by treating with a suitable inorganic or organic base or acid by a method known to those skilled in the art. Salts of the compounds of the present invention may be converted into their free base or acid forms by standard techniques.

[0213] A method for preparing the compounds described herein is provided below. In general, the starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or synthesized according to sources known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared according to the method described herein.

[0214] The following general reaction scheme illustrates an inventive example of a compound of structure (I), its pharmaceutically acceptable salt, stereoisomer, or prodrug:

[0215]

[0216] In the above equation, each A, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 is as defined below.

[0217] General reaction equation 1

[0218] The following is the general reaction equation (where X 1 and X 2 is independently a halogen, and X, R 1 , R 2 , R 3 and A (having the meaning described herein) illustrates an example of a method for manufacturing amine intermediate D:

[0219]

[0220] As shown in General Reaction Scheme 1, alkylation of pyrimidine / pyridinpyrrole (i.e., intermediate A) using a cycloalkyl boronate or a suitable electrophile in the presence of a base yields intermediate B. This precursor is treated with ammonium hydroxide to form pyrrolopyrimidine / pyridin-4-amine derivative intermediate C. The resulting intermediate C is then subjected to palladium-catalyzed arylation to form intermediate D.

[0221] General reaction equation 2

[0222] The following general reaction scheme illustrates an example of a method for preparing carbamate intermediate E:

[0223]

[0224] As shown in General Reaction Scheme 2, intermediate E is phenylchloroformate and the indicated heteroaryl amine (R) in the presence of a base. 4 It can be prepared by the reaction of an amine-substituted analogue of). General reaction scheme 2 is R 5 Illustrates the preparation of a compound in which is H, but; R 5 For compounds where g is something other than hydrogen, R is prepared after intermediate E. 5 It can be prepared in a similar manner by injecting or using a suitably substituted heteroaryl amine.

[0225] General reaction equation 3

[0226] The following general reaction scheme illustrates an example of a method for preparing a compound of structure (I):

[0227]

[0228] Intermediate D and intermediate E are treated with a base (e.g., trimethylamine, DIPEA, DMAP, etc.) in THF to obtain the compound of structure (I).

[0229] General reaction equation 4

[0230] The following general reaction scheme illustrates an example of a method for preparing a compound of structure (I):

[0231]

[0232] Intermediate D is reacted with the phenyl carbonochloridate shown under appropriate conditions to obtain intermediate E. Then, intermediate E is coupled with an amine using a suitable base (e.g., trimethylamine, DIPEA, DMAP, etc.) in THF to obtain a compound of structure (I).

[0233] Any of the above reaction formulas may be modified at any step during any step of the overall synthesis of the target compound to add and / or modify substituents as needed.

[0234] It will be recognized by those skilled in the art that in the manufacturing process of the compounds described herein, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxyl, amino, mercapto, and carboxylic acids. In the case of hydroxyl groups, suitable protecting groups are trialkylsilyl or diarylalkylsilyl (e.g., t -butyldimethylsilyl, t - Includes butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. For amino, amidino, and guanidino groups, suitable protecting groups t - Includes butoxycarbonyl, benzyloxycarbonyl, etc. In the case of mercapto, a suitable protecting group is -C(O)-R (where R" is alkyl, aryl, or arylalkyl), p - Includes methoxybenzyl, trityl, etc. In the case of carboxylic acids, suitable protecting groups include alkyl, aryl, or arylalkyl esters. Protecting groups are optionally added or removed in accordance with standard techniques known to those skilled in the art and as described herein. The use of protecting groups [Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (This is described in detail in [1999), 3rd Ed., Wiley]. As is recognized by those skilled in the art, the protecting group may also be a polymer resin, such as Wang resin, Rink resin, or 2-chlorotrityl-chloride resin.

[0235] Although such protected derivatives of the compounds of the present invention may not possess pharmacological activity, it will be recognized by those skilled in the art that they can be administered to mammals and subsequently metabolized in the body to form pharmacologically active compounds of the present invention. Accordingly, such derivatives may be described as "prodrugs." Prodrugs of the compounds of the present invention are included within the scope of embodiments of the present invention.

[0236] Pharmaceutical composition

[0237] Another embodiment relates to a pharmaceutical composition. The pharmaceutical composition comprises any one (or more) of the aforementioned 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 yet another embodiment, the pharmaceutical composition comprises the compounds disclosed herein and additional therapeutic agents (e.g., anticancer agents). Non-limiting examples of such therapeutic agents are described below in this specification.

[0238] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nose, and topical administration. Additionally, as merely an example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, and intravertebral, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0239] In certain embodiments, the compounds described herein are administered by a local rather than a systemic method, for example, by injecting the compounds directly into the trachea, often in a depot formulation or a sustained-release formulation. In specific embodiments, long-acting formulations are administered by transplantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Also, in other embodiments, the compounds are delivered by a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In these embodiments, the liposomes are targeted to the trachea and selectively taken by the trachea. In yet another embodiment, the compounds described herein are provided in the form of a rapid-release formulation, an extended-release formulation, or an intermediate-release formulation. In yet another embodiment, the compounds described herein are administered topically.

[0240] In a treatment method according to an embodiment of the present invention, an effective amount of a compound of at least one structure (I) is administered to a subject who is diagnosed as having or suffering from such disease, disorder, or medical condition. The effective amount or dose may be determined by modeling, dose escalation studies, or clinical trials, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to the drug, and the judgment of the treating physician.

[0241] The compound according to the present invention is effective over a wide range of dosages. For example, in the treatment of adult humans, dosages of 10 to 5000 mg, 100 to 5000 mg, 1000 mg to 4000 mg, and 1000 to 3000 mg per day are examples of dosages used in some embodiments. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0242] In some embodiments, the compound of the present invention is administered as a single dose. Typically, such administration will be made by injection, e.g., intravenous injection, to rapidly introduce the drug. However, other routes are used in some cases. A single dose of the compound of the present invention may also be used for the treatment of acute conditions.

[0243] In some embodiments, the compound of the present invention is administered in multiple doses. In some embodiments, administration is approximately once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is approximately once a month, once every two weeks, once a week, or once every other day. In other embodiments, the compound of the present invention and other agents (e.g., anticancer agents) are administered together approximately once a day to approximately six times a day. In other embodiments, administration of the compound and agents of the present invention 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 more than 1 year. In some cases, sustained administration is achieved and maintained for the required period.

[0244] Administration of the compound of the present invention may continue for as long as necessary. In some embodiments, the compound of the present invention is administered for 1, 2, 3, 4, 5, 6, 7, 14 days, or more than 28 days. In some embodiments, the compound of the present invention is administered for 28, 14, 7, 6, 5, 4, 3, 2, or less than 1 day. In some embodiments, the compound of the present invention is administered continuously, for example, for a long period to treat chronic effects.

[0245] In some embodiments, the compounds of the present invention are administered in an individual dosage form. It is known in the art that individualization of the dosage regimen is necessary for optimal therapy due to variability among subjects in the pharmacokinetics of compounds.

[0246] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the disclosed compounds into formulations that can be pharmaceutically used. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable technology, carrier, and excipient suitable for formulating the pharmaceutical compositions described herein are used [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 & Wilkins1999)].

[0247] The present specification provides a pharmaceutical composition comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0248] The present specification provides a pharmaceutical composition comprising one or more compounds selected from compounds of structure (I) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In a specific embodiment, the described compounds are administered as a combination therapy as a pharmaceutical composition in which one or more compounds selected from compounds of structure (I) are mixed with other active ingredients. The present specification covers all combinations of active substances described in the following combination therapy section and throughout the invention. In a specific embodiment, the pharmaceutical composition comprises one or more compounds of structure (I).

[0249] In a given embodiment, the pharmaceutical composition of the compound of structure (I) is a modulator of the NLRP3 inflammation complex.

[0250] In a specific embodiment, the pharmaceutical composition of the compound of structure (I) inhibits NEK7 when administered to a patient or biological sample.

[0251] As used herein, the pharmaceutical composition refers to a mixture of one or more compounds selected from the compounds of structure (I) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspenders, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates the administration of the compounds 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 as a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compounds used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0252] In one embodiment, one or more compounds selected from the compounds of structure (I) are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected, for example, from a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In another embodiment, one or more compounds selected from the compounds of structure (I) are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation comprises a penetrating agent suitable for the barrier to be permeated. In another embodiment in which the compounds described herein are formulated for other parenteral injections, the suitable formulation comprises an aqueous or non-aqueous solution. In a specific embodiment, such a solution comprises a physiologically compatible buffer and / or excipients.

[0253] In other embodiments, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated for oral administration, exemplarily comprising tablets, powders, pills, coated tablets, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0254] In a given embodiment, an oral pharmaceutical formulation is obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, adding a suitable auxiliary agent if necessary, and then processing the mixture of granules to obtain a tablet or a coated tablet core. Suitable excipients are, in particular, fillers, such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In a specific embodiment, a disintegrant is optionally added. Disintegrants include, for example, cross-linked sodium croscarmellose, polyvinylpyrrolidone, agar, or alginic acid or its salt, such as sodium alginate.

[0255] In one embodiment, a dosage form, e.g., a sugar-coated tablet core and a tablet, is provided accompanied by one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used for the coating of the dosage form. The sugar solution optionally contains additional components, e.g., 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. Additionally, dyes and / or pigments are optionally used to characterize different combinations of active compound dosages.

[0256] In a specific embodiment, a therapeutically effective amount of at least one compound described herein is formulated into other oral formulations. The oral formulations include a press-fit capsule made of gelatin, and a soft, sealed capsule made of gelatin and a plasticizer, such as glycerol or sorbitol. In a specific embodiment, the press-fit capsule contains an active ingredient mixed with one or more fillers. The fillers include, for example, lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In another embodiment, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. The suitable liquid includes, for example, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer is optionally added.

[0257] In another embodiment, the compound described herein is formulated into a parenteral injection comprising a formulation suitable for bolus injection or continuous infusion. In a specific embodiment, the injectable formulation is presented as a unit dose (e.g., in an ampoule) or in a multi-dose container. Optionally, a preservative is added to the injectable formulation. In another embodiment, the pharmaceutical composition is formulated into a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains a formulation agent, such as a suspending agent, a stabilizer, and / or a dispersing agent. In a specific embodiment, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active compound in a water-soluble form. In an additional embodiment, a suspension of one or more compounds selected from the compounds of structure (I) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein comprise, for example, fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains a suitable stabilizer or a agent that increases the solubility of the compound to allow for the preparation of a highly concentrated solution. Alternatively, in other embodiments, the active ingredient is in powder form to be composed with a suitable vehicle, for example, sterile pyrogenic substance-removing water, before use.

[0258] A pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, a diluent, or an excipient, and as an active ingredient, one or more compounds selected from compounds of structure (I) described herein. The active ingredient is in a free acid or free base form, or in a pharmaceutically acceptable salt form. Additionally, the method and pharmaceutical composition 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. Additionally, the compounds described herein encompass both solvated and non-solvated forms in pharmaceutically acceptable solvents, such as water, ethanol, etc. Solvented forms of the compounds presented herein are also considered to be disclosed herein. Additionally, the pharmaceutical composition optionally includes other drugs or pharmaceutical preparations, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizing propellants, osmotic pressure regulating salts, buffers, and / or other therapeutically useful substances.

[0259] A method for preparing a composition comprising a compound described herein comprises the step of formulating the compound with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cases, and suppositories. Liquid compositions include a solution in which the compound is dissolved, an emulsion containing the compound, or a solution containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of pharmaceutical compositions described herein include liquid solutions or suspensions, and solid forms suitable for use as solutions or suspensions in liquid before use or as emulsions. These compositions may also optionally contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc.

[0260] In some embodiments, a pharmaceutical composition comprising one or more compounds selected from the compounds of structure (I) takes the form of a liquid in which the drug is present in a solution, in a suspension, or both, exemplarily. Typically, when the composition is administered as a suspension, a first portion of the drug is present in the solution and a second portion of the drug is present in the suspension within the liquid matrix in the form of particulates. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0261] In a given embodiment, the aqueous suspension contains one or more polymers as suspending agents. The polymers include water-soluble polymers, such as cellulose-based polymers, such as hydroxypropyl methylcellulose, and water-insoluble polymers, such as cross-linked carboxyl-containing polymers. A given pharmaceutical composition described herein comprises, for example, a mucoadhesive polymer selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0262] The pharmaceutical composition also optionally comprises a solubilizing agent that aids in the solubility of one or more compounds selected from the compounds of structure (I). The term “solubilizing agent” generally comprises a formulation that causes the formation of a micelle solution or a true solution of the pharmaceutical. Certain acceptable nonionic surfactants, e.g., polysorbate 80, are useful as solubilizing agents as ophthalmologically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0263] Additionally, the pharmaceutical composition optionally comprises one or more pH adjusters or buffers, including 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 tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. These acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0264] The composition also optionally comprises one or more salts in an amount necessary to bring the osmotic concentration of the composition to an acceptable range. Such salts include those 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.

[0265] Other pharmaceutical compositions optionally include one or more preservatives that inhibit microbial activity. Suitable preservatives include mercury-containing substances, e.g., merphene and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds, e.g., benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0266] The composition may include one or more surfactants to improve physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, for example, octoxynol 10, octoxynol 40.

[0267] The composition may include one or more antioxidants to improve chemical stability if necessary. Suitable antioxidants include, for example, ascorbic acid and sodium metabisulfite.

[0268] In a given embodiment, the aqueous suspension composition is packaged in a single-volume non-resealable container. Alternatively, a multi-volume resealable container is used, in which case the composition typically contains a preservative.

[0269] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents, such as N-methylpyrrolidone, are also employed. In additional embodiments, the compounds described herein are delivered via a sustained-release system, such as the use of a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound over a period of several weeks to up to 100 days. Depending on the chemical properties and biological stability of the therapeutic agent, additional strategies for protein stabilization are employed.

[0270] In a given embodiment, the formulation described herein comprises one or more antioxidants, metal chelating agents, thiol-containing compounds and / or other common stabilizers. Examples of such stabilizers include (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 of these are possible, but are not limited thereto.

[0271] In some embodiments, the concentration of one or more compounds selected from compounds of structure (I) provided in the pharmaceutical composition of the present invention 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%, 1.25%, 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 greater than.

[0272] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical composition of the present invention is approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, and approximately 0.5% to approximately The range is 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, and approximately 1% to approximately 10% w / w, w / v, or v / v.

[0273] In some embodiments, the amount of one or more compounds selected from compounds of structure (I) provided in the pharmaceutical composition of the present invention 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, 0.3 g, 0.25 g, 0.2 g, It is equal to or less than 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0274] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical composition of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0275] Packaging materials for use in packaging the pharmaceutical compositions described herein include, for example, those described in the literature [U.S. Patents No. 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 the intended mode of administration and treatment. For example, the container(s) may comprise one or more compounds described herein, optionally as a composition with or in combination with other pharmaceuticals disclosed herein. The container(s) may optionally have a sterile access port (for example, the container is a vial or intravenous solution bag with a stopper that can be punctured with a subcutaneous injection needle). Such kits may optionally contain the compounds along with identification markings, labels, or instructions related to use in the methods described herein.

[0276] For example, the kit typically comprises one or more additional containers, each having one or more various materials (e.g., optionally concentrated forms of reagents, and / or devices) that are commercially and user-desirable for the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, and syringes; carriers, packaging, containers, vial and / or tube labels listing usage and / or instructions, and packaging inserts containing instructions for use. A set of instructions will also typically be included. The label is optionally on or associated with the container. For example, the label is on the container where the letters, numbers, or other characters forming the label are attached to, molded, or etched onto the container itself, and the label is associated with the container where it is present, for example, as a packaging insert in a receptacle or carrier containing the container. Additionally, the label is used to indicate that the contents are intended for use in a specific therapeutic application. Also, for example in the method described herein, the label indicates instructions for the use of the contents. In a given embodiment, the pharmaceutical composition is presented in a pack or dispenser device containing one or more unit dosage forms containing the compound provided herein. For example, the pack contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied by instructions associated with a container of a form prescribed by a government agency regulating the manufacture, use, or sale of the medicine, and such instructions reflect agency approval of the form of the medicine for human or veterinary administration. Such instructions are, for example, a label approved by the U.S. Food and Drug Administration for a prescription drug, or an approved product insert.In some embodiments, a composition containing the compound provided herein, formulated in a suitable pharmaceutical carrier, is prepared, placed in a suitable container, and labeled for the treatment of an indicated pathological condition.

[0277] method

[0278] Embodiments of the present invention are useful as modulators of the NLRP3 inflammasome through inhibition of NEK7 in host species. Thus, the compound of structure (I) is also useful for the treatment of pathological conditions mediated by effector signaling molecules such as Il-β and IL-18.

[0279] The host or patient may belong to any mammalian species, for example, primates, particularly humans; rodents, such as mice, rats, and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are subjects of interest in experimental research and provide models for the treatment of human diseases.

[0280] In one embodiment, the present invention is useful as an inhibitor of the NLRP3 inflammasome activation mechanism. Accordingly, the compound of structure (I) is also useful for treating pathological conditions caused by said activation in host species.

[0281] In another embodiment, the compound of structure (I) is useful as an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction. Thus, the compound is also useful for treating pathological conditions caused by the linkage of NLRP3-NEK7 in host species.

[0282] In a given embodiment, the compound of structure (I) is useful for treating human pathological conditions mediated by an effector selected from the group consisting of IL-β, IL-18, and caspase-1.

[0283] Embodiments of the present invention also relate to the use of a compound according to structure (I) and / or a physiologically acceptable salt thereof for the prophylactic or therapeutic treatment and / or surveillance of a disease caused by, or / or mediated by, or regulated by NLRP3 inflammasome activity. Furthermore, embodiments of the present invention relate to the use of a compound according to structure (I) and / or a physiologically acceptable salt thereof for the production of a drug for the prophylactic or therapeutic treatment and / or surveillance of a disease caused by, or / or mediated by, or regulated by NLRP3 inflammasome activity. In a given embodiment, the present invention provides the use of a compound according to structure (I) or a physiologically acceptable salt thereof for the production of a drug for the prophylactic or therapeutic treatment of an NLRP3-mediated disorder.

[0284] In another embodiment, the present invention relates to a method for treating an inflammatory disease or pathological condition mediated by the NLRP3 inflammasome by administering a therapeutically effective amount of a compound of structure (I) to a patient in need thereof.

[0285] In a given embodiment, diseases that can be treated by the compound of structure (I) include type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, and Muckle-Wells syndrome.

[0286] In some other embodiments, the compound of structure (I) is used in a method for treating a disorder or disease selected from autoimmune, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, bacterial and viral infection, allergy, asthma, pancreatitis, multi-organ failure, kidney disease, platelet aggregation, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injury, respiratory disease, ischemic condition, and cancer. In some more specific embodiments, the compound of structure (I) is used in a method for treating myelodysplastic syndrome (MDS).

[0287] In some embodiments, disorders associated with NEK7 that are treatable with the compound of structure (I) are selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, scleroderma, multiple sclerosis, psoriasis, diabetes mellitus type I, diabetes mellitus type II, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and cyclic fever syndrome, cryopyrin-associated cyclic syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonists), Alzheimer's disease, Parkinson's disease, and cancer.

[0288] The present specification also includes a therapeutic method in which a compound of at least one structure (I) is administered in combination with an anti-inflammatory agent or therapeutic agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific 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, combinations of diclofenac, diclofenac sodium and misoprostol, sulindac, oxaprozine, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmethine sodium, and hydroxychloroquine.

[0289] Examples of NSAIDs also include COX-2 specific inhibitors, such as celecoxib, valdecoxib, lumiracoxib and / or etoricoxib.

[0290] In some embodiments, the anti-inflammatory agent is a salicylate. The salicylate includes, but is not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylate.

[0291] Anti-inflammatory agents can also be corticosteroids. For example, corticosteroids can be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

[0292] In an additional embodiment, the anti-inflammatory agent is a gold compound, such as gold sodium thiomaleate or auranofin.

[0293] The present invention 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.

[0294] Therapeutic agents also include agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by the in vivo conversion of selective hydrolysis products of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory drugs, analgesics and antipyretics, synthesis inhibitors of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, ortacoids, paracrine hormones, somatostatin, gastrin, cytokines mediating interactions involved in humoral and cellular immune responses, lipid-derived ortacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, Examples include sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0295] Another embodiment of the present invention relates to a combination in which at least one anti-inflammatory compound is an anti-monoclonal antibody (e.g., eculizumab or pexelizumab), a TNF antagonist that is an anti-TNF alpha monoclonal antibody, such as entanercept, or infliximab.

[0296] The therapeutic agent used in combination with the compound of structure (I) may also include small molecule compounds that inhibit the activation of the NLRP3 inflammasome, such as MCC950, sulforaphane, isoliquiritigenin, β-hydroxybutyrate, flufenamic acid, mefenamic acid, 3,4-methylenedioxy-β-nitrostyrene (MNS), and parthenolide.

[0297] Another embodiment of the present invention relates to a combination in which at least one active agent is an immunosuppressant compound selected from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0298] The compound of the disclosed structure (I) may be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term “anticancer agent” refers to any agent administered to a cancer patient for the purpose of treating cancer.

[0299] In some embodiments, the anticancer agent belongs to the following categories - alkylating agents: e.g., altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, threosulfan, mechlorethamine, carboquione; aphaziquione, potemustine, gluphosphamide, paliphosphamide, pipovoromide, trophosphamide, uramustine, TH-3024, VAL-0834;

[0300] Platinum compounds: e.g., carboplatin, cisplatin, eptaplatin, myriplatin hydrate, oxaliplatin, lovaplatin, nedaplatin, picoplatin, satraplatin; lovaplatin, nedaplatin, picoplatin, satraplatin;

[0301] DNA modifying agents: e.g., amrubicin, virsanthren, decitabine, mitoxantrone, procarbazine, travectedin, cloparabine; amsacrin, brostalysin, picantrone, laromustine 1,3;

[0302] Topoisomerase inhibitors: e.g., etoposide, irinotecan, razoxic acid, sobuzoxic acid, tenifoside, topotecan; amonapid, belotecan, eliftinium acetate, borreloxine;

[0303] Microtubule modulators: e.g., cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesin, vinflunine; phosphretabulin, tesetaxel;

[0304] Anmetabates: e.g., asparaginase 3, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enositabine, floruridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxyfluridine, elacytarabine, raltitrexed, sapacitabine, tegafur 2,3, trimetrexate;

[0305] Anticancer antibiotics: e.g., bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosin, mitomycin C, romidepsin, streptozosin, valubicin, genostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peflomycin, pyrarubicin;

[0306] Hormones / Antagonists: e.g., abarellix, abiraterone, bicalutamide, buserelin, calosterone, chlorotrianisene, degarellix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, naparelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trirostan, triptorelin, diethylstilbestrol; acolbifen, danazol, desrorelin, epithiostanol, orteronel, enzalutamide 1,3;

[0307] Aromatase inhibitors: e.g., aminoglutethimide, anastrozole, exemestane, padrozole, letrozole, testolactone; formestane;

[0308] Small molecule kinase inhibitors: e.g., crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, allicertip, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, lincitinib, macitinib, midostaurin, motesanib, neratinib, orantinib, perifosin, ponatinib, radotinib, rigocertip, tipifamib, tivantinib, tibozanib, trametinib, fimasertip, brivanib alaninate, cediranib.

[0309] In some embodiments, the medicine administered together with the compound described herein is any suitable drug that is usefully delivered by inhalation, e.g., analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl, or morphine; angina agents, e.g., diltiazem; anti-allergic drugs, e.g., cromoglycate, ketotifen, or nedocromil; anti-infectives, e.g., cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, or pentamidine; antihistamines, e.g., metapyrylene; anti-inflammatory agents, e.g., beclomethasone, flunisolide, budesonide, tipredan, triamcinolone acetonide, or fluticasone; antitussives, e.g., noscapine; Bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, leproterol, limiterol, salbutamol, salmeterol, terbutaline, isoethaline, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g., amyloride; anticholinergics, e.g., ipratropium, atropine, or oxytropium; hormones, e.g., cortisone, hydrocortisone, or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate, or theophylline; and therapeutic proteins and peptides, e.g., insulin or glucagon. It will be obvious to those skilled in the art that, in some cases, to optimize the activity and / or stability of the medicine, the medicine is used in the form of a salt (e.g., as an alkali metal or amine salt or as an acid addition salt), an ester (e.g., a lower alkyl ester), or a solvate (e.g., a hydrate).

[0310] The agents described herein or other suitable agents are administered according to the condition being treated. Therefore, in some embodiments, one or more compounds of the present invention will be administered in combination with other agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously with or separately from the second agent. Such combination administration may include simultaneous administration of two agents within the same dosage form, simultaneous administration of separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any of the agents described above may be administered simultaneously, wherein both agents exist within separate dosage forms. In another alternative, any of the agents described above may be administered immediately after the compounds of the present invention are administered, or vice versa. In some embodiments of a separate administration protocol, the compounds of the present invention and any of the agents described above are administered at intervals of minutes, hours, or days.

[0311] In some embodiments, the compound of structure (I) is administered as monotherapy.

[0312] To identify signal transduction or mechanistic pathways and to detect interactions between various signal transduction pathways, many scientists have developed suitable models or model systems, e.g., cell culture models and genetically modified animal models. Signals can be modulated using interacting compounds to determine specific steps in a signal transduction cascade. Compounds of embodiments of the present invention can also be used as reagents to test NEK7-dependent signal transduction pathways in animal and / or cell culture models or in the clinical diseases mentioned herein.

[0313] The method of an embodiment of the present invention may be performed in vitro or in vivo. The susceptibility of specific cells to treatment with the compound of structure (I) may be specifically determined by in vitro testing during the course of research or clinical application. Typically, cell cultures are combined with the compound at various concentrations for a period sufficient for the activator to inhibit NEK7 activity, usually for about 1 hour to 1 week. In vitro treatment may be performed using cultured cells from biopsy samples or cell lines.

[0314] In some embodiments, the IC of a compound of structure (I) that inhibits NEK7 50 was determined as the concentration of the compound required to inhibit 50% of NEK kinase activity. The compound of structure (I) has an IC 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 value was shown.

[0315] The examples and preparation examples provided below further describe and illustrate the compounds of the present invention and methods for preparing and testing such compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparation examples. In the following examples, and throughout the specification and claims, molecules having a single stereocenter exist as a racemic mixture unless otherwise noted. Molecules having two or more stereocenters exist as a racemic mixture of diastereomers unless otherwise noted. A single enantiomer / diastereomer can be obtained by methods known to those skilled in the art. Specific details for implementing the invention

[0316] Examples

[0317] The following examples are provided for exemplary purposes.

[0318] General Procedure

[0319] All proton NMR experiments were recorded at 400 MHz on a Bruker NEO spectrometer equipped with a BBFO probe. The deuteration solvent contained less than 0.05% v / v tetramethylsilane, which was used as a reference signal (set to 0.00 ppm). If the deuteration solvent does not contain tetramethylsilane, the published guidelines (literature [ J. Org. Chem. 1997 According to [ , 62(21), 7512-7515]), the residual non-deuterated solvent peak was used as the reference signal. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in Hertz (Hz) units. The splitting pattern represents apparent multiplicity and is denoted as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), qt (pentruplet), or brs (wide singlet).

[0320] LC / MS analysis was performed on an Agilent Technologies UHPLC 1290 Infinity II equipped with a G6125 MS detector.

[0321] Microwave reactions were performed using a Monowave 300 by Anton Paar GmbH using a standard protocol.

[0322] NEK7 Enzyme Test

[0323] Casein substrates (derived from cow's milk, a mixture of hydrolyzed and partially dephosphorized α, β, κ casein, obtained from Sigma Aldrich, catalog #C4765, diluted with distilled water to a final concentration of 1 mg / mL) and full-length recombinant human NEK7 (expressed by baculovirus in Sf9 insect cells using 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). The compound of interest (serially diluted 3-fold in DMSO from 10 μM to 0.5 nM) or vehicle (1% DMSO) was dispensed into the kinase reaction mixture using acoustic technology (Echo550; nanoliter range). After incubation at room temperature for 20 minutes, [ 33 The kinase reaction was initiated by adding [P]-ATP (inactive 10 μCi / μl) and the mixture was incubated at room temperature for 2 hours. Subsequently, the reaction mixture was stopped by spotting it onto a phosphocellulose P81 paper strip. After washing, the radioactivity of the P81 paper was measured, and the kinase activity data was expressed as the percentage of residual kinase activity in the test sample compared to the vehicle reaction. IC was measured using Prism (GraphPad Software). 50 Values ​​and curve fitting were obtained.

[0324] IL-1β Release Test

[0325] Approximately 1.5 million THP-1 cells were plated into each well of a 6-well TC plate and incubated with 40 nM PMA in RPMI (10% FBS, 1% Penstrep) for 24 hours. Subsequently, the medium was removed and the cells were rested in RPMI (10% FBS, 1% Penstrep) for 24 hours, then the medium was removed and the cells were pre-treated for 2 hours with various concentrations of the compound of interest in RPMI (5% FBS) (typically, serially diluted 3-fold with RPMI + 5% FBS, concentrations ranging from 1 μM to 0.5 nM). Again, the medium was removed and the cells were incubated for 2 hours with 250 ng / mL LPS and the compound of interest (concentrations as above) in RMPI (5% FBS). Finally, the medium was removed, and the cells were incubated in Opti-MEM with 20 μM nigericin and the compound of interest (concentrations as above) for 30 minutes. Subsequently, the cell medium was collected, and the amount of degraded IL-1β was determined using a JESS instrument (Protein Simple) and standard protocols. Degraded IL-1β antibodies were 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 hydrogen peroxide. The primary antibody incubation time was increased from 30 minutes to 60 minutes.

[0326] abbreviation:

[0327] ℃ (Celsius); 1 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- d 6 (deuterated dimethyl sulfoxide); eq (equivalent); EtOAc (ethyl acetate); g (gram); h (hour); HPLC (High Performance Liquid Chromatography); LCMS (Liquid Chromatographic Mass Spectrometry); MeOH (methanol); mg (milligram); min (min); mL (milliliter); mmol (millimole); 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(t ert -Butyldimethylsilyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin-layer chromatography)

[0328] Preparation of synthetic intermediates

[0329] Intermediate A

[0330] 4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]Pyrimidine

[0331]

[0332] N - Iodosuccinimide (1.465 g, 6.51 mmol) in 4-chloro-7 in DMF (10 mL) at 0 ℃ H -pyrrolo[2,3- d ]Pyrimidine (1.000 g, 6.51 mmol) was added to a stirred solution, and the resulting mixture was stirred at 25 °C for 12 h. After the reaction was complete (indicated by TLC), the reaction mixture was poured into ice-cold water (100 mL) and stirred at 25 °C for 15 minutes. The resulting solid was filtered, washed with water (2 x 25 mL), and dried to obtain the title compound as an off-white solid (1.7 g, 93% yield). 1 ¹H 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].

[0333] Intermediate B1

[0334] 4-chloro-7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d ]Pyrimidine

[0335]

[0336] 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) in 4-chloro-5-iodo-7 in dichloroethane (10 mL) H -pyrrolo[2,3- d ]Pyrimidine (A1, 1.000 g, 3.58 mmol) and cyclopropylboronic acid (0.615 g, 7.16 mmol) were added to a solution, and the resulting mixture was stirred at 70 °C under an oxygen atmosphere for 12 h. After the reaction was complete (indicated by TLC), the reaction mixture was filtered through a Celite pad and then rinsed with DCM (2 x 20 mL). The filtrates were combined, washed with water (20 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an unrefined material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to obtain the title compound as an off-white solid (0.7 g, 61% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0337] Intermediate B2

[0338] 4-chloro-5-iodo-7-(oxetane-3-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine

[0339]

[0340] K2CO3 (0.40 g, 2.86 mmol) and 3-iodooxetane (0.32 g, 1.71 mmol) in 4-chloro-5-iodo-7 in DMF (5 mL) H -pyrrolo[2,3- d ]Pyrimidine (A, 0.40 g, 1.43 mmol) was added to the solution, and the resulting mixture was stirred in a sealed tube at 90 °C for 16 h. After the reaction was complete (indicated by TLC), the reaction mixture was poured into an icebreaker (50 g) and stirred for 15 minutes. The resulting solid was filtered, washed with water (2 x 5 mL), and dried to obtain the title compound as an off-white solid (0.2 g, 42% yield). LCMS: 335.7 [M+H].

[0341] Intermediate B3

[0342] 1-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidine-7-yl)-2-methylpropan-2-ol

[0343]

[0344] 4-chloro-5-iodo-7 in ACN (3 mL) and water (1 mL) NaH2PO4 (0.105 g, 0.877 mmol) H -pyrrolo[2,3- dIt was added to a mixture of 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). The resulting mixture in a sealed tube was microwaved at 150 °C for 1 h. After the reaction was complete (indicated by TLC), the reaction mixture was concentrated under reduced pressure, and the resulting unrefined material was purified by flash chromatography (silica gel 230-400 mesh, eluted with 18% EtOAc in petroleum ether) to obtain the title compound as a light brown solid (0.1 g, 17% yield). LCMS: 351.9 [M+H].

[0345] Intermediate B4

[0346] 4-chloro-5-iodo-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine

[0347]

[0348] Triethylamine (0.905 g, 8.95 mmol) and copper(II) acetate (0.975 g, 5.37 mmol) in 4-chloro-5-iodo-7 in DCM (25 mL) H -pyrrolo[2,3- d ]pyrimidine (A, 1.000 g, 3.58 mmol) and 3-pyridinylboronic acid (0.880 g, 7.16 mmol) were added to a solution, and the resulting mixture was stirred at 40 °C for 40 h under an oxygen atmosphere. After the reaction was complete (indicated by LCMS), the reaction mixture was filtered through a Celite pad and then rinsed with DCM (2 x 50 mL). The filtrates were combined, washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an unrefined material. This was stirred with 30% diethyl ether in petroleum ether at 25 °C for 30 minutes, filtered, and dried to obtain the title compound as a brown solid (0.4 g, 29% yield). 1¹H NMR(400 MHz, DMSO- d 6) 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].

[0349] Intermediate B5

[0350] 4-chloro-5-iodo-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine

[0351]

[0352] 4-chloro-5-iodo-7 H -pyrrolo[2,3- d Starting from 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) following a procedure similar to that described for B4. LCMS: 356.9 [M+H].

[0353] Intermediate B6

[0354] 4-chloro-5-iodo-7-(1-methylpiperidine-4-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine

[0355]

[0356] The title compound was prepared as reported in PCT application publication No. WO 2017 / 220477.

[0357] Intermediate B7

[0358] 7-(3-(benzyloxy)cyclobutyl)-4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]Pyrimidine

[0359]

[0360] Cs2CO3 (0.583 g, 1.789 mmol) and 3-(benzyloxy)cyclobutyl methanesulfonate (prepared as reported in PCT Application Publication No. WO 2019 / 092170, 0.459 g, 1.789 mmol) in 4-chloro-5-iodo-7 in DMF (5 mL) H -pyrrolo[2,3- d ] was added to a solution of pyrimidine (A, 0.250 g, 0.895 mmol), and the resulting mixture was stirred at 90 °C for 12 h. After the reaction was complete (indicated by TLC), the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic extracts were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain an unrefined substance, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to obtain the title compound as a colorless gum (0.14 g, 31% yield). LCMS: 440.0 [M+H].

[0361] Intermediate B8

[0362] 2-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidine-7-yl)ethanol-1-ol

[0363]

[0364] K2CO3 (0.742 g, 5.37 mmol) and 2-bromoethanol-1-ol (0.537 g, 4.29 mmol) in 4-chloro-5-iodo-7 in DMF (6 mL) H -pyrrolo[2,3- d]Pyrimidine (A, 1.000 g, 3.58 mmol) was added to the solution, and the resulting suspension was stirred at 80 °C for 2 h. After the reaction was complete (indicated by TLC), the reaction mixture was poured onto an icebreaker (25 g). The resulting solid was filtered, washed with water (20 mL), and dried to obtain the title compound as a yellow solid (0.84 g, 64% yield). LCMS: 323.9 [M+H].

[0365] Intermediate B9

[0366] 4-chloro-1-cyclopropyl-3-iodo-1 H -pyrrolo[3,2- c ]Pyridin

[0367] Step 1: Synthesis of 4-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine

[0368]

[0369] Triethylamine (0.332 g, 3.280 mmol), copper(II) acetate (0.298 g, 1.638 mmol), and molecular sieve (powdered, 0.050 g) in 4-chloro-1 in DMF (10 mL) H -pyrrolo[3,2- c ]Pyridine (0.250 g, 1.638 mmol) and cyclopropyl boronic acid (0.279 g, 3.280 mmol) were added to a solution, and the resulting suspension was stirred in a sealed tube at 60 °C for 12 h. After the reaction was complete (indicated by TLC), the reaction mixture was filtered through a Celite pad and subsequently rinsed with EtOAc. The filtrates were combined and concentrated under reduced pressure to obtain an unrefined material, which was purified with Isolera (silica gel 230-400 mesh, eluted with 20% EtOAc in petroleum ether) to obtain the title compound as a yellow solid (0.19 g, 59% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0370] Step 2: Concentration of 4-chloro-1-cyclopropyl-3-iodo-1H-pyrrolo[3,2-c]pyridine castle

[0371]

[0372] N - Iodosuccinimide (0.350 g, 1.557 mmol) in 4-chloro-1-cyclopropyl-1 in DMF (5 mL) H -pyrrolo[3,2- c ]Pyridine (0.200 g, 1.038 mmol) was added to the solution, and the resulting mixture was stirred at 80 °C for 1 hour. After the reaction was complete (indicated by LCMS), the reaction mixture was poured onto a crushed ice (25 g) and extracted with EtOAc (2 x 25 mL). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title product (0.2 g), which was used without further purification. LCMS: 319.0 [M+H].

[0373] Intermediate C1

[0374] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0375]

[0376] 4-chloro-7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d A mixture of pyrimidine (B1, 1.00 g, 2.191 mmol) and ammonium hydroxide (25% in water, 5 mL) was microwaved at 150 °C for 1 h. After the reaction was complete (indicated by TLC), the reaction mixture was concentrated under reduced pressure to obtain the title compound as an off-white solid (0.75 g, 80% yield). 1¹H NMR(400 MHz, DMSO- d 6) 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].

[0377] Intermediate C2

[0378] 5-iodo-7-(oxetane-3-il)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0379]

[0380] Starting from 4-chloro-5-iodo-7-(oxetane-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (B2, 0.5 g, 1.49 mmol) and aqueous ammonium hydroxide (25% in water, 2.5 mL), the title compound was prepared according to a procedure similar to that described for C1 and obtained as a light brown solid (0.27 g, 58% yield). LCMS: 316.8 [M+H].

[0381] Intermediate C3

[0382] 1-(4-amino-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidine-7-yl)-2-methylpropan-2-ol

[0383]

[0384] 1-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d Starting from ]pyrimidine-7-yl)-2-methylpropan-2-ol (B3, 0.1 g, 0.284 mmol) and ammonium hydroxide (25% in water, 0.5 mL), the title compound was obtained as an off-white solid according to a procedure similar to that described for C1 (0.08 g, 85% yield). 1 ¹H 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].

[0385] Intermediate C4

[0386] 5-iodo-7-(pyridine-3-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0387]

[0388] 4-chloro-5-iodo-7-(pyridine-3-yl)-7 in dioxane (10 mL) ammonium hydroxide (25% in water, 1 mL) H -pyrrolo[2,3- d ]Pyrimidine (B4, 0.30 g, 0.841 mmol) was added to a solution, and the resulting mixture was microwaved at 150 °C for 2 h. After the reaction was complete (indicated by LCMS), the reaction mixture was concentrated under reduced pressure to obtain an unrefined material, which was then methyl tert-butyl The title compound was washed with ether and dried to obtain an off-white solid (0.21 g, 63% yield). LCMS: 337.8 [M+H].

[0389] Intermediate C5

[0390] 5-iodo-7-(pyridine-4-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0391]

[0392] 4-chloro-5-iodo-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d Starting from pyrimidine (B5, 0.21 g, 0.589 mmol) and ammonium hydroxide (25% in water, 1 mL), the title compound was obtained as an off-white solid (0.16 g, 69% yield) following a procedure similar to that described for C4. LCMS: 337.9 [M+H].

[0393] Intermediate C6

[0394] 5-iodo-7-(1-methylpiperidine-4-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0395]

[0396] The title compound was prepared as reported in PCT application publication No. WO 2017 / 220477.

[0397] Intermediate C7

[0398] 7-(3-(benzyloxy)cyclobutyl)-5-iodo-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0399]

[0400] 7-(3-(benzyloxy)cyclobutyl)-4-chloro-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine (B7, 0.140 g, 0.318 mmol) and ammonium hydroxide (25% in water, 1.4 mL), the title compound was obtained as an off-white solid (0.06 g, 45% yield) following a procedure similar to that described for C4. LCMS: 421.1 [M+H].

[0401] Intermediate C8

[0402] 5-iodo-7-(2-methoxyethyl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0403]

[0404] The title compound was prepared as reported in PCT application publication No. WO 2014 / 184069A1.

[0405] Intermediate C9

[0406] 2-(4-amino-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidine-7-yl)ethanol-1-ol

[0407]

[0408] 2-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d Starting from ]pyrimidine-7-yl)ethanol-1-ol (B8, 0.84 g, 2.61 mmol) and ammonium hydroxide (25% in water, 8 mL), the title compound was obtained as an off-white solid (0.94 g, 69% yield) according to a procedure similar to that described for C4. LCMS: 305.0 [M+H].

[0409] Intermediate C10

[0410] 7-cyclobutyl-5-iodo-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0411]

[0412] The title compound was prepared as reported in PCT application publication No. WO 2016 / 075224.

[0413] Intermediate C11

[0414] 5-iodo-7-(1-methylpyrrolidine-3-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0415]

[0416] The title compound was prepared as reported in PCT application publication No. WO 2016 / 075224.

[0417] Intermediate D1

[0418] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0419]

[0420] 7-cyclopropyl-5-iodo-7 in 1,4-dioxane (1 mL) and water (0.3 mL)H -pyrrolo[2,3- d A mixture of pyrimidine-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) was purged with N2 for 10 minutes. Subsequently, Pd(PPh3)4 (0.062 g, 0.053 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 h. After the reaction was complete (indicated by TLC), the mixture was filtered through a Celite pad and then rinsed with EtOAc (2 x 10 mL). The filtrates were combined and concentrated under reduced pressure to obtain an unrefined substance, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 3% MeOH in DCM) to obtain the title compound as a yellow solid (0.110 g, 73% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0421] Intermediate D2

[0422] 5-(4-aminophenyl)-7-(oxetane-3-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0423] Step 1: Synthesis of 5-(4-nitrophenyl)-7-(oxetane-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0424]

[0425] Starting from 4-chloro-5-iodo-7-(oxetane-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 for D1 and obtained as a light brown solid (0.143 g, 58% yield). LCMS: 312.1 [M+H].

[0426] Step 2: Synthesis of 5-(4-aminophenyl)-7-(oxetane-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0427]

[0428] Iron powder (0.251 g, 4.5 mmol) and ammonium chloride (0.240 g, 4.5 mmol) in ethanol (5 mL) and water (2 mL) 5-(4-nitrophenyl)-7-(oxetane-3-yl)-7 H -pyrrolo[2,3- d ] It was added to a solution of pyrimidine-4-amine (0.14 g, 0.45 mmol), and the resulting mixture was stirred at 80 °C for 3 h. After the reaction was complete (indicated by TLC), the reaction mixture was filtered through a Celite pad and subsequently rinsed with EtOAc (2 x 5 mL). The filtrates were combined and concentrated under reduced pressure to obtain the residue, which was dissolved in EtOAc (25 mL), washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a brown solid (0.12 g, quantitative yield), which was used without further purification. LCMS: 281.9 [M+H].

[0429] Intermediate D3

[0430] 1-(4-amino-5-(4-amino-3-fluorophenyl)-7 H -pyrrolo[2,3- d ]pyrimidine-7-yl)-2-methylpropan-2-ol

[0431]

[0432] 1-(4-amino-5-iodo-7 H -pyrrolo[2,3-d Starting from ]pyrimidine-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), the title compound was prepared according to a procedure similar to that described for D1 and obtained as a pale yellow gum (0.05 g, 53% yield). LCMS: 316.1 [M+H].

[0433] Intermediate D4

[0434] 5-(4-aminophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0435] Step 1: Synthesis of 7-cyclopropyl-5-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0436]

[0437] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 for D1. 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0438] Step 2: Synthesis of 5-(4-aminophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0439]

[0440] 7-cyclopropyl-5-(4-nitrophenyl)-7 H -pyrrolo[2,3- dStarting from pyrimidine-4-amine (0.10 g, 0.33 mmol) and Fe / NH4Cl, the title compound was obtained as a brown gum (0.08 g, 90% yield) following a procedure similar to that described for step 2 of D2, and used without further purification. 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0441] Intermediate D5

[0442] 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0443]

[0444] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 for D1. LCMS: 284.1 [M+H].

[0445] Intermediate D6

[0446] 5-(6-aminopyridine-3-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0447] Step 1: Synthesis of 7-cyclopropyl-5-(6-nitropyridine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0448]

[0449] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 for D1. 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0450] Step 2: Synthesis of 5-(6-aminopyridine-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0451]

[0452] 7-cyclopropyl-5-(6-nitropyridine-3-yl)-7 H -pyrrolo[2,3- d Starting from pyrimidine-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) following a procedure similar to that described for Step 2 of D2, and this was used without further purification. LCMS: 267.0 [M+H].

[0453] Intermediate D7

[0454] 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0455] Step 1: Synthesis of tert-butyl(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)cyclohex-3-en-1-yl)carbamate

[0456]

[0457] K2CO3 (0.318 g, 2.299 mmol) in 7-cyclopropyl-5-iodo-7 in dioxane (1 mL) and water (0.3 mL) H -pyrrolo[2,3- d ]pyrimidine-4-amine (C1, 0.230 g, 0.766 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-en-1-yl)carbamate (0.372 g, 1.150 mmol) was added to the solution. The solution was purged with N2 for 10 minutes, followed by the addition of Pd(PPh3)4 (0.044 g, 0.038 mmol), and the resulting mixture was microwaved at 100 °C for 1 h. After the reaction was complete (indicated by TLC), the reaction mixture was filtered through a Celite pad and then rinsed with EtOAc (2 x 10 mL). The filtrates were combined and concentrated under reduced pressure to obtain an unrefined material, which was purified by preparative HPLC (mass-based, eluted via an ammonium acetate gradient in water and ACN) to obtain the title product as a light-yellow gum (0.18 g, 62% yield). LCMS: 370.2 [M+H].

[0458] Step 2: Synthesis of 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0459]

[0460] TFA (0.012 g, 0.108 mmol) in DCM (2 mL) at 0 ℃ tert-butyl (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)cyclohex-3-en-1-yl)carbamate (0.040 g, 0.108 mmol) was added to the solution, and the resulting solution was stirred at room temperature for 12 h. After the reaction was complete (indicated by TLC), the reaction mixture was concentrated under reduced pressure to obtain the title product as a brown gum (0.029 g), which was used without further purification. LCMS: 270.1 [M+H].

[0461] Intermediate D8

[0462] 5-(4-amino-3-fluorophenyl)-7-(pyridine-3-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0463]

[0464] 5-iodo-7-(pyridin-3-yl)-7 in dioxane (5 mL), water (2 mL), and ethanol (3 mL) H -pyrrolo[2,3- d A mixture of pyrimidine-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) was purged with N2 for 10 minutes. PdCl2 (dppf) (0.017 g, 0.024 mmol) was added, and the resulting mixture was microwaved at 100 °C for 1 h. After the reaction was complete (indicated by LCMS), the reaction mixture was filtered through a Celite pad and then rinsed with EtOAc (5 mL). The filtrates were combined and concentrated under reduced pressure to obtain the residue. This residue was taken in EtOAc (50 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting unrefined material was purified with GRACE (silica gel 230-400 mesh, eluted with 4% MeOH in DCM) to obtain the title compound as a brown solid (0.2 g, 70% yield). LCMS: 321.0 [M+H].

[0465] Intermediate D9

[0466] 5-(4-amino-3-fluorophenyl)-7-(pyridine-4-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0467]

[0468] 5-iodo-7-(pyridine-4-yl)-7 H -pyrrolo[2,3- d Starting from pyrimidine-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) according to a procedure similar to that described for D8. LCMS: 321.0 [M+H].

[0469] Intermediate D10

[0470] 5-(4-amino-3-fluorophenyl)-7-(1-methylpiperidine-4-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0471]

[0472] 5-iodo-7-(1-methylpiperidine-4-yl)-7 H -pyrrolo[2,3- d Starting from pyrimidine-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) according to a procedure similar to that described for D8. LCMS: 341.1 [M+H].

[0473] Intermediate D11

[0474] 5-(4-amino-3-methylphenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0475]

[0476] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- dStarting from pyrimidine-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) according to a procedure similar to that described for D8. LCMS: 280.1 [M+H].

[0477] Intermediate D12

[0478] 5-(4-amino-3-fluorophenyl)-7-(3-(benzyloxy)cyclobutyl)-7H-pyrrolo[2,3- d ]Pyrimidine-4-amine

[0479]

[0480] 7-(3-(benzyloxy)cyclobutyl)-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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) according to a procedure similar to that described for D8. LCMS: 404.2 [M+H].

[0481] Intermediate D13

[0482] Step 1: Synthesis of 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0483]

[0484] Potassium acetate (0.245 g, 2.499 mmol) in 7-cyclopropyl-5-iodo-7 in DMSO (5 mL) H -pyrrolo[2,3- d]Pyrimidine-4-amine (C1, 0.250 g, 0.833 mmol) and bis(pinacolato)diborone (0.317 g, 1.250 mmol) were added to a solution, and the resulting mixture was purged with N2 for 10 minutes. Subsequently, PdCl2 (dppf) (0.030 g, 0.042 mmol) was added, and the reaction mixture was stirred at 85 °C for 2 h. After the reaction was complete, the reaction mixture was filtered through a Celite pad and then rinsed with DCM (2 x 20 mL). The filtrates were combined and concentrated under reduced pressure to obtain the title compound as a black residue, which was used without further purification. LCMS: 300.9 [M+H].

[0485] Step 2: Synthesis of 5-(5-amino-4-methylpyridine-2-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0486]

[0487] 6-bromo-4-methylpyridine-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 Starting from pyrimidine-4-amine (0.251 g, 0.835 mmol), the title compound was obtained as a brown gum following a procedure similar to that described for D8 (0.05 g, 13% yield). LCMS: 281.0 [M+H].

[0488] Intermediate D14

[0489] 5-(5-aminopyridine-2-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0490]

[0491] 6-bromo-4-methylpyridine-3-amine (0.130 g, 0.751 mmol) and 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7 H -pyrrolo[2,3- dStarting from pyrimidine-4-amine (step 1 of intermediate D13, 0.248 g, 0.827 mmol), the title compound was obtained as a brown gum following a procedure similar to that described for D8 (0.03 g, 4.5% yield). LCMS: 267.0 [M+H].

[0492] Intermediate D15

[0493] 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0494]

[0495] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 for D8. LCMS: 302.1 [M+H].

[0496] Intermediate D16

[0497] 5-(4-amino-2,5-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0498]

[0499] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- dStarting from pyrimidine-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 Application Publication No. WO 2017 / 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 for D8. LCMS: 302.1 [M+H].

[0500] Intermediate D17

[0501] 5-(4-amino-2,6-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0502]

[0503] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 Application Publication No. WO 2017 / 172093, 0.056 g, 0.220 mmol), the title compound was obtained as a light brown gum (0.046 g) following a procedure similar to that described for D8 and used without further purification. LCMS: 301.9 [M+H].

[0504] Intermediate D18

[0505] 1-(4-amino-5-(6-aminopyridine-3-yl)-7H-pyrrolo[2,3- d ]pyrimidine-7-yl)-2-methylpropan-2-ol

[0506]

[0507] 1-(4-amino-5-iodo-7 H -pyrrolo[2,3- dStarting from ]pyrimidine-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)pyridine-2-amine (0.161 g, 0.733 mmol), the title compound was obtained as a yellow gum (0.12 g, 50% yield) according to a procedure similar to that described for D8. LCMS: 299.1 [M+H].

[0508] Intermediate D19

[0509] 5-(2-aminopyrimidine-5-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0510]

[0511] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-4-amine (C1, 0.25 g, 0.833 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-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 for D8. LCMS: 268.2 [M+H].

[0512] Intermediate D20

[0513] (2-amino-5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)phenyl)methanol

[0514]

[0515] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- dStarting from ]pyrimidine-4-amine (C1, 0.200 g, 0.666 mmol) and (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)phenyl)methanol (prepared as reported in PCT Application Publication No. WO 2011 / 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 for D8. LCMS: 296.0 [M+H].

[0516] Intermediate D21

[0517] 2-amino-5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)benzonitrile

[0518]

[0519] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 yellow gum (0.13 g, 34% yield) according to a procedure similar to that described for D8. LCMS: 291.2 [M+H].

[0520] Intermediate D22

[0521] 5-(4-amino-3-fluorophenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3- d ]Pyrimidine-4-amine

[0522]

[0523] 5-iodo-7-(2-methoxyethyl)-7H-pyrrolo[2,3- dStarting from pyrimidine-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) according to a procedure similar to that described for D8. LCMS: 302.2 [M+H].

[0524] Intermediate D23

[0525] 2-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3- d ]pyrimidine-7-yl)ethanol-1-ol

[0526]

[0527] 2-(4-amino-5-iodo-7 H -pyrrolo[2,3- d Starting from ]pyrimidine-7-yl)ethanol-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) according to a procedure similar to that described for D8. LCMS: 288.1 [M+H].

[0528] Intermediate D24

[0529] 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0530]

[0531] 7-cyclobutyl-5-iodo-7 H -pyrrolo[2,3- dStarting from pyrimidine-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), the title compound was obtained as a brown solid (0.18 g, 37% yield) according to a procedure similar to that described for D8. 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0532] Intermediate D25

[0533] 5-(4-amino-3-chlorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0534]

[0535] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 for D8. LCMS: 300.1 [M+H].

[0536] Intermediate D26

[0537] 5-(4-amino-3-methoxyphenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0538]

[0539] 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 for D8. LCMS: 296.1 [M+H].

[0540] Intermediate D27

[0541] 5-(4-amino-3-fluorophenyl)-7-(1-methylpyrrolidine-3-yl)-7 H -pyrrolo[2,3- d ]Pyrimidine-4-amine

[0542]

[0543] 5-iodo-7-(1-methylpyrrolidine-3-yl)-7 H -pyrrolo[2,3- d Starting from pyrimidine-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 for D8. LCMS: 327.2 [M+H].

[0544] Intermediate E1-E25

[0545] General procedure for the synthesis of carbamate intermediate E:

[0546] Pyridine (1.2 eq) and phenyl chloroformate (1.5 eq) were added to a solution of amine (1.0 eq) in THF (10 vol) at 0 °C. The reaction mixture was heated to 25 °C and stirred for 12 h. After the reaction was complete (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 obtain an unrefined material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 10 to 20% EtOAc in petroleum) to obtain the desired carbamate.

[0547] The following carbamate was prepared using the above general procedure:

[0548]

[0549]

[0550]

[0551]

[0552] Except for the following, all amines used in the synthesis of carbamate intermediate E are available for purchase:

[0553] 3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-amine (precursor for E6) and 5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-amine (precursor for E7) in the literature [ Synthesis It was synthesized as reported in [2013, 45, 171-173].

[0554] 3-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-5-amine (precursor for E8) and 3-(2-fluoropropane-2-yl)isoxazole-5-amine (precursor for E9) were derived from methyl 3,3,3-trifluoro-2,2-dimethylpropanoate and methyl 2-fluoro-2-methylpropionate, respectively, from the literature [ Synthesis Synthesized according to the procedure reported in [2013, 45, 171-173].

[0555] 3-(1-(( Tert- Butyldimethylsilyl)oxy)-2-methylpropane-2-yl)isoxazole-5-amine (a precursor for E16) was synthesized as reported in PCT application publication No. WO 2010 / 036630.

[0556] 2-(5-aminoisoxazole-3-yl)-2-methylpropanenitrile (precursor for E22) and 3-(1-(trifluoromethyl)cyclobutyl)isoxazole-5-amine (precursor for E24) in the literature [ J. Med. Chem. It was synthesized as reported in [2012, 55(3), 1082-1105].

[0557] 3-((( Tert- Butyldiphenylsilyl)oxy)methyl)isoxazole-5-amine (a precursor for E23) was synthesized as reported in PCT application publication No. WO 2013 / 104561.

[0558] 5-(1-(trifluoromethyl)cyclobutyl)isoxazole-3-amine (a precursor to E25) was synthesized as reported in PCT application publication No. WO 2011 / 022473.

[0559] Synthesis of 3-(3-methyloxetane-3-yl)isoxazole-5-amine (precursor to E14):

[0560]

[0561] NH2OH·H2SO4 (0.520 g, 3.16 mmol) was added to a solution of 3-(3-methyloxetane-3-yl)-3-oxopropanenitrile (prepared as reported in PCT Application Publication No. WO 2019 / 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 using aqueous NaOH (1 M), and the reaction mixture was stirred at 80 °C for 15 h. After the reaction was complete (indicated by TLC), the reaction mixture was concentrated under reduced pressure to obtain the residue, which was taken in EtOAc (25 mL), washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The generated unrefined material was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to obtain 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].

[0562] Synthesis of 3-(1-methylcyclobutyl)isoxazole-5-amine (precursor to E21):

[0563]

[0564] NH2OH·H2SO4 (0.699 g, 4.25 mmol) was added to a solution of 3-(1-methylcyclobutyl)-3-oxopropanenitrile (prepared as reported in PCT Application Publication No. WO 2017 / 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 using aqueous NaOH (1 M), and the reaction mixture was stirred at 80 °C for 15 h. After the reaction was complete (indicated by TLC), the reaction mixture was concentrated under reduced pressure to obtain the residue, which was taken into DCM (25 mL), washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The generated unrefined material was purified by flash chromatography (silica gel 230-400 mesh, eluted with 40% EtOAc in petroleum ether) to obtain 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].

[0565] Example Preparation

[0566] General urea formation procedure for the synthesis of Examples 1-62

[0567] 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 h. After the reaction was complete (indicated by LCMS), the reaction mixture was concentrated under reduced pressure to obtain an unrefined material, which was then purified by reverse-phase preparative HPLC to obtain the target product.

[0568] 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 h. After the reaction was complete (indicated by LCMS), the reaction mixture was concentrated under reduced pressure to obtain an unrefined material, which was then purified by reverse-phase preparative HPLC to obtain the target product.

[0569] The following compounds were prepared using the above general procedure.

[0570] Example 1

[0571] 1-(4-(4-amino-7-(oxetane-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)phenyl)-3-(3-( tert -butyl)isoxazole-5-yl)urea

[0572]

[0573] 5-(4-aminophenyl)-7-(oxetane-3-yl)-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-( tert- The title compound was prepared from butyl)isoxazole-5-yl)carbamate (E1, 0.16 g, 0.30 mmol) and obtained as an off-white solid (0.026 g, 9% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0575] Example 2

[0576] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-( tert -butyl)isoxazole-5-yl)urea

[0577]

[0578] 5-(4-aminophenyl)-7-(oxetane-3-yl)-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-( tert- The title compound was prepared from butyl)isoxazole-5-yl)carbamate (E1, 0.16 g, 0.30 mmol) and obtained as an off-white solid (0.026 g, 9% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0579] Example 3

[0580] 1-(5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)pyridine-2-yl)-3-(3-( tert-Butyl)isoxazole-5-yl)urea

[0581]

[0582] According to the general procedure for urea formation (Method A), 5-(6-aminopyridine-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine (D6, 0.100 g, 0.376 mmol) and phenyl (3-( tert-butyl The title compound was prepared from )isoxazole-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].

[0583] Example 4

[0584] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-( tert- Butyl)isoxazole-3-yl)urea

[0585]

[0586] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (5-( tert- The title compound was prepared from butyl)isoxazole-3-yl)carbamate (E2, 0.091 g, 0.35 mmol) and obtained as an off-white solid (0.021 g, 13% yield). 1 ¹H NMR(400 MHz, DMSO-d 6) 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].

[0587] Example 5

[0588] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0589]

[0590] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was prepared from pyrimidine-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.088 g, 0.282 mmol) and obtained as a white solid (0.031 g, 22% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0591] Example 6

[0592] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3-d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0593]

[0594] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was prepared from pyrimidine-4-amine (D1, 0.060 g, 0.180 mmol) and phenyl (5-cyclopropylisoxazole-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].

[0595] Example 7

[0596] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-methylisoxazole-5-yl)urea

[0597]

[0598] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was prepared from pyrimidine-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (3-methylisoxazole-5-yl)carbamate (E3, 0.077 g, 0.35 mmol) and obtained as an off-white solid (0.024 g, 17% yield).1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0599] Example 8

[0600] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-methylisoxazole-3-yl)urea

[0601]

[0602] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was prepared from pyrimidine-4-amine (D1, 0.127 g, 0.44 mmol) and phenyl (5-methylisoxazole-3-yl)carbamate (E4, 0.097 g, 0.44 mmol) and obtained as a white solid (0.033 g, 18% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0603] Example 9

[0604] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(2-fluoropropane-2-yl)isoxazole-5-yl)urea

[0605]

[0606] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was prepared from pyrimidine-4-amine (D1, 0.076 g, 0.26 mmol) and phenyl (3-(2-fluoropropane-2-yl)isoxazole-5-yl)carbamate (E9, 0.070 g, 0.26 mmol) and obtained as a white solid (0.018 g, 14% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0607] Example 10

[0608] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)urea

[0609]

[0610] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- dThe title compound was prepared from pyrimidine-4-amine (D1, 0.10 g, 0.35 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)carbamate (E7, 0.11 g, 0.35 mmol) and obtained as an off-white solid (0.010 g, 6% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0611] Example 11

[0612] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-3-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0613]

[0614] 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was prepared from pyrimidine-4-amine (D5, 0.070 g, 0.24 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.082 g, 0.24 mmol) and obtained as an off-white solid (0.011 g, 9% yield). 1 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].

[0615] Example 12

[0616] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-5-yl)urea

[0617]

[0618] 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was prepared from pyrimidine-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-5-yl)carbamate (E8, 0.055 g, 0.176 mmol) and obtained as an off-white solid (9.9 mg, 11% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0619] Example 13

[0620] 1-(4-(4-amino-7-cyclopropyl-7H -pyrrolo[2,3- d ]pyrimidine-5-yl)phenyl)-3-(3-( tert- Butyl)isoxazole-5-yl)urea

[0621]

[0622] 5-(4-aminophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D4, 0.080 g, 0.30 mmol) and phenyl (3-( tert- The title compound was prepared from butyl)isoxazole-5-yl)carbamate (E1, 0.078 g, 0.30 mmol) and obtained as an off-white solid (0.036 g, 28% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0623] Example 14

[0624] 1-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0625]

[0626] According to the general procedure for urea formation (Method A), 1-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3- dThe title compound was prepared from ]pyrimidine-7-yl)-2-methylpropan-2-ol (D3, 0.086 g, 0.273 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.085 g, 0.273 mmol) and obtained as a light brown solid (0.011 g, 8% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0627] Example 15

[0628] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)cyclohex-3-en-1-yl)-3-(3-( tert- Butyl)isoxazole-5-yl)urea

[0629]

[0630] 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D7, 0.120 g, 0.446 mmol) and phenyl (3-( tert- The title compound was prepared from butyl)isoxazole-5-yl)carbamate (E1, 0.116 g, 0.446 mmol) and obtained as an off-white solid (0.013 g, 7% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0631] Example 16

[0632] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)cyclohexyl)-3-(3-( tert- Butyl)isoxazole-5-yl)urea

[0633]

[0634] Platinum oxide (0.016 g, 0.069 mmol) in 1-(4-(4-amino-7-cyclopropyl-7) in EtOAc (5 mL) H -pyrrolo[2,3- d ]pyrimidine-5-yl)cyclohex-3-en-1-yl)-3-(3-( tert- Butyl)isoxazole-5-yl)urea (Example 15, 0.100 g, 0.230 mmol) was added to the solution, and the resulting suspension was stirred at room temperature under H2 atmosphere for 12 h. After the reaction was complete (indicated by LCMS), the reaction mixture was filtered through a Celite pad and then rinsed with EtOAc (2 x 5 mL). The filtrates were combined and concentrated under reduced pressure to obtain an unrefined material, which was purified by preparative HPLC (mass-based, elution via an ammonium acetate gradient in water and ACN) to obtain the title product as an off-white solid (2.0 mg, 2% yield). 1H 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].

[0635] Example 17

[0636] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclopropyl)isoxazole-5-yl)urea

[0637]

[0638] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1-methylcyclopropyl)isoxazole-5-yl)carbamate (E10, 0.046 g, 0.176 mmol) (0.013 g, 16% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0639] Example 18

[0640] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3-d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(4-( tert- Butyl)thiazole-2-yl)urea

[0641]

[0642] According to the general procedure for urea formation (Method A), phenyl (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 4-( tert- The title compound was obtained as an off-white solid from butyl)thiazole-2-amine (0.015 g, 0.099 mmol) (7.0 mg, 15% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0643] Example 19

[0644] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-( tert- Butyl)-1,3,4-thiadiazole-2-yl)urea

[0645]

[0646] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (5-( tert-The title compound was obtained as an off-white solid from butyl)-1,3,4-thiadiazole-2-yl)carbamate (E12, 0.049 g, 0.176 mmol) (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].

[0647] Example 20

[0648] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-( tert- Butyl)isothiazole-5-yl)urea

[0649]

[0650] According to the general procedure for urea formation (Method A), phenyl (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 4-( tert- The title compound was obtained as an off-white solid from butyl)thiazole-2-amine (0.015 g, 0.099 mmol) (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].

[0651] Example 21

[0652] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3-d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-( tert- Butyl)-1,2,4-thiadiazole-5-yl)urea

[0653]

[0654] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-( tert- The title compound was obtained as an off-white solid from butyl)-1,2,4-thiadiazole-5-yl)carbamate (E13, 0.049 g, 0.176 mmol) (8.0 mg, 10% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0655] Example 22

[0656] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(1-( tert- Butyl)-1 H -1,2,4-triazole-3-yl)urea

[0657]

[0658] According to the general procedure for urea formation (Method A), phenyl (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 1-( tert- Butyl)-1H The title compound was obtained as an off-white solid from -1,2,4-triazole-3-amine (0.014 g, 0.099 mmol) (3.0 mg, 6% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0659] Example 23

[0660] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-( tert- Butyl)-1,3,4-oxadiazole-2-yl)urea

[0661]

[0662] According to the general procedure for urea formation (Method A), phenyl (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 5-( tert- The title compound was obtained as an off-white solid from butyl)-1,3,4-oxadiazole-2-amine (0.014 g, 0.099 mmol) (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].

[0663] Example 24

[0664] 1-(4-(4-amino-7-(pyridine-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0665]

[0666] 5-(4-amino-3-fluorophenyl)-7-(pyridine-3-yl)-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as a white solid from pyrimidine-4-amine (D8, 0.100 g, 0.312 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.107 g, 0.343 mmol) (0.023 g, 14% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0667] Example 25

[0668] 1-(4-(4-amino-7-(pyridine-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0669]

[0670] 5-(4-amino-3-fluorophenyl)-7-(pyridine-4-yl)-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D9, 0.080 g, 0.250 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.086 g, 0.275 mmol) (0.046 g, 33% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0671] Example 26

[0672] 1-(4-(4-amino-7-(1-methylpiperidine-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0673]

[0674] 5-(4-amino-3-fluorophenyl)-7-(1-methylpiperidine-4-yl)-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- dThe title compound was obtained as a white solid (2.4 mg, 7% yield) from pyrimidine-4-amine (D10, 0.020 g, 0.059 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.018 g, 0.059 mmol). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0675] Example 27

[0676] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(3-methyloxetane-3-yl)isoxazole-5-yl)urea

[0677]

[0678] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as a white solid (3.4 mg, 4% yield) from pyrimidine-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(3-methyloxetane-3-yl)isoxazole-5-yl)carbamate (E14, 0.048 g, 0.176 mmol). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0679] Example 28

[0680] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)isoxazole-5-yl)urea

[0681]

[0682] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as a white solid from pyrimidine-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(trifluoromethyl)isoxazole-5-yl)carbamate (E15, 0.048 g, 0.176 mmol) (2.9 mg, 4% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0683] Example 29

[0684] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-hydroxy-2-methylpropane-2-yl)isoxazole-5-yl)urea

[0685] Step 1: 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropane-2-yl) Speed ​​Soldier 5-1) Synthesis of urea

[0686]

[0687] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D1, 0.131 g, 0.461 mmol) and phenyl (3-(1-(( tert- The title compound was obtained as an off-white solid from butyldimethylsilyl)oxy)-2-methylpropane-2-yl)isoxazole-5-yl)carbamate (E16, 0.180 g, 0.461 mmol) (0.013 g, 5% yield). LCMS: 580.0 [M+H].

[0688] Step 2: Synthesis of 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-hydroxy-2-methylpropane-2-yl)isoxazole-5-yl)urea

[0689]

[0690] At 0 ℃, TBAF (1 M in THF, 0.067 ml) in 1-(4-(4-amino-7-cyclopropyl-7) in THF (2 ml) H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(( tert- Butyldimethylsilyl)oxy)-2-methylpropane-2-yl)isoxazole-5-yl)urea (0.013 g, 0.022 mmol) was added to the solution, and the resulting solution was stirred at 25 °C for 4 h. After the reaction was complete (indicated by TLC), the reaction mixture was concentrated under reduced pressure to obtain an unrefined substance, which was purified by preparative HPLC to obtain the title compound as a white solid (TFA salt, 2.2 mg, 21% yield). 1H 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].

[0691] Example 30

[0692] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(sec-butyl)isoxazole-5-yl)urea

[0693]

[0694] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D1, 0.055 g, 0.194 mmol) and phenyl (3-( sec The title compound was obtained as a white solid from -butyl)isoxazole-5-yl)carbamate (E17, 0.051 g, 0.194 mmol) (0.012 g, 14% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0695] Example 31

[0696] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(pentane-3-yl)isoxazole-5-yl)urea

[0697]

[0698] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(pentane-3-yl)isoxazole-5-yl)carbamate (E18, 0.048 g, 0.176 mmol) (0.016 g, 19% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0699] Example 32

[0700] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-isopropylisoxazole-5-yl)urea

[0701]

[0702] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- dThe title compound was obtained as an off-white solid from pyrimidine-4-amine (D1, 0.056 g, 0.198 mmol) and phenyl (3-isopropylisoxazole-5-yl)carbamate (E19, 0.049 g, 0.198 mmol) (0.018 g, 21% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0703] Example 33

[0704] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-ethylisoxazole-5-yl)urea

[0705]

[0706] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D1, 0.061 g, 0.215 mmol) and phenyl (3-ethylisoxazole-5-yl)carbamate (E20, 0.050 g, 0.215 mmol) (0.020 g, 22% yield). 1 ¹H 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].

[0707] Example 34

[0708] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclobutyl)isoxazole-5-yl)urea

[0709]

[0710] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as a white solid (6.8 mg, 5% yield) from pyrimidine-4-amine (D1, 0.075 g, 0.265 mmol) and phenyl (3-(1-methylcyclobutyl)isoxazole-5-yl)carbamate (E21, 0.072 g, 0.265 mmol). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0711] Example 35

[0712] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(2-cyanopropane-2-yl)isoxazole-5-yl)urea

[0713]

[0714] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as a white solid from pyrimidine-4-amine (D1, 0.070 g, 0.247 mmol) and phenyl (3-cyanopropane-2-yl)isoxazole-5-yl)carbamate (E22, 0.067 g, 0.247 mmol) (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].

[0715] Example 36

[0716] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(hydroxymethyl)isoxazole-5-yl)urea

[0717]

[0718] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d ]pyrimidine-4-amine (D1, 0.250 g, 0.882 mmol) and phenyl (3-((( tert-The title compound was obtained as an off-white solid from butyldimethylsilyl)oxy)methyl)isoxazole-5-yl)carbamate (E23, 0.308 g, 0.882 mmol) (0.029 g, 8% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0719] Note: Decomposition of TBDMS groups was observed during purification when eluting with a 10 mM ammonium acetate gradient in water and ACN.

[0720] Example 37

[0721] 1-(5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)pyridine-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0722]

[0723] 5-(6-aminopyridine-3-yl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D6, 0.300 g, 1.127 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.352 g, 1.127 mmol) (0.018 g, 3% yield). 1 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].

[0724] Example 38

[0725] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-methylphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0726]

[0727] 5-(4-amino-3-methylphenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D11, 0.270 g, 0.967 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.302 g, 0.967 mmol) (0.080 g, 16% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0728] Example 39

[0729] 1-(4-(4-amino-7-(3-hydroxycyclobutyl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0730] Step 1: 1-(4-(4-amino-7-(3-(benzyloxy)cyclobutyl)-7H- Pyrrolo[ Synthesis of 2,3-d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0731]

[0732] According to the general procedure for urea formation (Method B), 5-(4-amino-3-fluorophenyl)-7-(3-(benzyloxy)cyclobutyl)- 7H -pyrrolo[2,3- d The title compound was obtained as a yellow gum from pyrimidine-4-amine (D12, 0.033 g, 0.082 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.028 g, 0.090 mmol) (0.038 g, 29% yield). LCMS: 622.3 [M+H].

[0733] Step 2: Synthesis of 1-(4-(4-amino-7-(3-hydroxycyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0734]

[0735] At -60 ℃, boron trichloride (1 M in DCM, 0.901 mL, 0.901 mmol) in 1-(4-(4-amino-7-(3-(benzyloxy)cyclobutyl)-7 in DCM (5 mL) H -pyrrolo[2,3- d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea (0.070 g, 0.113 mmol) solution was added dropwise, and the resulting mixture was stirred at 0 °C for 3 h. After the reaction was complete (indicated by TLC and LCMS), the reaction mixture was cooled to -70 °C, neutralized with NH4OH (25% in water), and extracted with DCM (2 x 10 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an unrefined material, which was purified by preparative HPLC (eluting with a 1% TFA gradient in water and ACN) to obtain 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].

[0736] Example 40

[0737] 1-(6-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-4-methylpyridine-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0738]

[0739] 5-(5-amino-4-methylpyridine-2-yl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- dThe title compound was obtained as an off-white solid from pyrimidine-4-amine (D13, 0.050 g, 0.102 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.032 g, 0.102 mmol) (8 mg, 16% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0740] Example 41

[0741] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2,6-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0742]

[0743] 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D15, 0.080 g, 0.266 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.083 g, 0.266 mmol) (8 mg, 5.6% yield). 1 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].

[0744] Example 42

[0745] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0746]

[0747] 5-(4-amino-2,5-difluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D16, 0.100 g, 0.332 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.104 g, 0.332 mmol) (8 mg, 5% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0748] Example 43

[0749] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3-d ]pyrimidine-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0750]

[0751] 5-(4-amino-2,6-difluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D17, 0.0724 g, 0.240 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.075 g, 0.240 mmol) (3 mg, 2% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0752] Example 44

[0753] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0754] Step 1: Synthesis of 1-(5-bromo-3-fluoropyridine-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0755]

[0756] The title compound was obtained as a pale yellow solid from 5-bromo-3-fluoropyridine-2-amine (0.040 g, 0.209 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.065 g, 0.209 mmol) according to the general procedure for urea formation (Method B) (0.020 g, 23% yield). LCMS: 410.9 [M+H].

[0757] Step 2: Synthesis of 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0758]

[0759] According to a procedure similar to that described for intermediate D8, 1-(5-bromo-3-fluoropyridine-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-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)-7 H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from ]pyrimidine-4-yl)carbamate (prepared as reported in PCT Application Publication No. WO 2018 / 015879, 0.024 g, 0.049 mmol) (2 mg, 7% yield). 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].

[0760] Note: Decomposition of the Boc group was observed during the reaction.

[0761] Example 45

[0762] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclobutyl)isoxazole-5-yl)urea

[0763]

[0764] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclobutyl)isoxazole-5-yl)carbamate (E24, 0.092 g, 0.282 mmol) (0.035 g, 22% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0765] Example 46

[0766] 1-(5-(4-amino-7-(2-hydroxy-2-methylpropyl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)pyridine-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0767]

[0768] 1-(4-amino-5-(6-aminopyridine-3-yl)-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- dThe title compound was obtained as an off-white solid (0.010 g, 6% yield) from pyrimidine-7-yl)-2-methylpropan-2-ol (D18, 0.100 g, 0.335 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.105 g, 0.335 mmol). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0769] Example 47

[0770] 1-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)urea

[0771]

[0772] 1-(4-amino-5-(4-amino-3-fluorophenyl)-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from ]pyrimidine-7-yl)-2-methylpropan-2-ol (D3, 0.120 g, 0.381 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)carbamate (E7, 0.119 g, 0.381 mmol) (0.028 g, 13% yield). 1 ¹H 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].

[0773] Example 48

[0774] 1-(5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)pyrimidine-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0775]

[0776] 5-(2-aminopyrimidine-5-yl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D19, 0.080 g, 0.299 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.093 g, 0.299 mmol) (4 mg, 3% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0777] Example 49

[0778] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3-d ]pyrimidine-5-yl)-2-(hydroxymethyl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0779]

[0780] According to the general procedure for urea formation (Method A), (2-amino-5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-5-yl)phenyl)methanol (D20, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.021 g, 0.068 mmol) (3 mg, 8% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0781] Example 50

[0782] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-cyanophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0783]

[0784] 2-amino-5-(4-amino-7-cyclopropyl-7) according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- dThe title compound was obtained as an off-white solid from ]pyrimidine-5-yl)benzonitrile (D21, 0.130 g, 0.287 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.089 g, 0.287 mmol) (5 mg, 3% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0785] Example 51

[0786] 1-(4-(4-amino-7-(2-methoxyethyl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0787]

[0788] 5-(4-amino-3-fluorophenyl)-7-(2-methoxyethyl)-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D22, 0.075 g, 0.249 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.078 g, 0.249 mmol) (0.037 g, 28% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0789] Example 52

[0790] 1-(4-(4-amino-7-(2-hydroxyethyl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0791]

[0792] 2-(4-amino-5-(4-amino-3-fluorophenyl)-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-7-yl)ethanol-1-ol (D23, 0.080 g, 0.278 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.087 g, 0.278 mmol) (0.011 g, 7% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0793] Example 53

[0794] 1-(4-(4-amino-7-cyclobutyl-7 H -pyrrolo[2,3- d]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0795]

[0796] 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D24, 0.150 g, 0.504 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.158 g, 0.504 mmol) (0.111 g, 38% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0797] Example 54

[0798] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-chlorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0799]

[0800] 5-(4-amino-3-chlorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3-d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D25, 0.050 g, 0.167 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.052 g, 0.167 mmol) (6 mg, 7% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0801] Example 55

[0802] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-methoxyphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0803]

[0804] 5-(4-amino-3-methoxyphenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D26, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.021 g, 0.068 mmol) (7 mg, 19% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0805] Example 56

[0806] 1-(4-(4-amino-7-(1-methylpyrrolidine-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0807]

[0808] 5-(4-amino-3-fluorophenyl)-7-(1-methylpyrrolidine-3-yl)-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as a white solid from pyrimidine-4-amine (D27, 0.040 g, 0.123 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.036 g, 0.115 mmol) (0.015 mg, 24% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0809] Example 57

[0810] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclobutyl)isoxazole-3-yl)urea

[0811]

[0812] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as a white solid (0.081 mg, 28% yield) from pyrimidine-4-amine (D1, 0.160 g, 0.565 mmol) and phenyl (5-(1-(trifluoromethyl)cyclobutyl)isoxazole-3-yl)carbamate (E25, 0.184 g, 0.565 mmol). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0813] Example 58

[0814] 1-(4-(4-amino-7-cyclobutyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)urea

[0815]

[0816] 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- dThe title compound was obtained as an off-white solid from pyrimidine-4-amine (D24, 0.204 g, 0.686 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)carbamate (E7, 0.214 g, 0.686 mmol) (0.096 g, 27% yield). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0817] Example 59

[0818] 1-(6-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)pyridine-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0819]

[0820] 5-(5-aminopyridine-2-yl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as an off-white solid from pyrimidine-4-amine (D14, 0.030 g, 0.045 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.014 g, 0.045 mmol) (5 mg, 23% yield). 1 ¹H 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].

[0821] Example 60

[0822] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2,6-difluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)urea

[0823]

[0824] 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7 according to the general procedure for urea formation (Method A) H -pyrrolo[2,3- d The title compound was obtained as a white solid (0.015 g, 6% yield) from pyrimidine-4-amine (D15, 0.150 g, 0.498 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)carbamate (E7, 0.155 g, 0.498 mmol). 1 ¹H NMR(400 MHz, DMSO- d 6) 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].

[0825] Example 61

[0826] 1-(4-(4-amino-7-(2-hydroxyethyl)-7H -pyrrolo[2,3- d ]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)urea

[0827]

[0828] 2-(4-amino-5-(4-amino-3-fluorophenyl)-7 according to the general procedure for urea formation (Method B) H -pyrrolo[2,3- d The title compound was obtained as a white solid (0.035 mg, 20% yield) from pyrimidine-7-yl)ethanol-1-ol (D23, 0.100 g, 0.348 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)carbamate (E7, 0.109 g, 0.348 mmol). 1 H 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].

[0829] Example 62

[0830] 1-(4-(4-amino-1-cyclopropyl-1 H -pyrrolo[3,2- c ]pyridine-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0831] Step 1: Synthesis of 1-cyclopropyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine-4-amine

[0832]

[0833] n 4-chloro-1-cyclopropyl-3-iodo-1 in -BuOH (10 mL) H -pyrrolo[3,2- cA mixture of pyridine (B9, 0.300 g, 0.942 mmol) and (2,5-dimethoxyphenyl)methaneamine (0.429 mL, 2.83 mmol) was stirred at 110 °C for 12 h. After the reaction was complete (indicated by LCMS), the reaction mixture was concentrated under reduced pressure to obtain an unrefined material, which was purified with Isolera (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to obtain the title product as a yellow gum (0.10 g, 19% yield). LCMS: 450.0 [M+H].

[0834] Step 2: Synthesis of 3-(4-amino-3-fluorophenyl)-1-cyclopropyl-N-(2,4-dimethoxybenzyl)-1H-pyrrolo[3,2-c]pyridine-4-amine

[0835]

[0836] 1-cyclopropyl- according to a procedure similar to that described for intermediate D8 N -(2,4-dimethoxybenzyl)-3-iodo-1 H -pyrrolo[3,2- c The title compound was obtained as a brown gum from pyridine-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) (0.080 g, 41% yield). LCMS: 433.2 [M+H].

[0837] Step 3: 1-(4-(1-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)-1H-pyrrolo[3,2-c]pyridine-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0838]

[0839] 3-(4-amino-3-fluorophenyl)-1-cyclopropyl- according to the general procedure for urea formation (Method B) N -(2,4-dimethoxybenzyl)-1 H -pyrrolo[3,2- cThe title compound was obtained as an off-white solid from pyridine-4-amine (0.080 g, 0.185 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)carbamate (E6, 0.058 g, 0.185 mmol) (0.027 g, 17% yield). LCMS: 651.3 [M+H].

[0840] Step 4: Synthesis of 1-(4-(4-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea

[0841]

[0842] At 0 ℃, triethylsilane (4.8 mg, 0.041 mmol) and TFA (4.7 mg, 0.041 mmol) in 1-(4-(1-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)-1 in DCM (2 mL) H -pyrrolo[3,2- c ]pyridine-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazole-5-yl)urea (0.027 g, 0.041 mmol) was added to the solution, and the resulting mixture was stirred at 25 °C for 12 h. After the reaction was complete (indicated by LCMS), the reaction mixture was concentrated under reduced pressure to obtain an unrefined material, which was purified by preparative HPLC (eluting with a 0.1% TFA gradient in water) to obtain 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].

[0843] Biological Example 1

[0844] Biochemical testing of compounds

[0845] The inhibitory activity of representative compounds on NEK7 and IL-1β release was tested according to the procedure described above. The results are shown in the table below.

[0846] [Table 2]

[0847] Activity of representative compounds

[0848]

[0849] For NEK7, the IC in Table 2 50 Active:

[0850] * IC 50 A exceeds 1500 nM

[0851] ** IC 50 A range of 501 - 1500 nM

[0852] *** IC 50 Ga 301 - 500 nM range

[0853] **** IC 50 A range of 151 - 300 nM

[0854] ***** IC 50 Less than 150 nM

[0855] For IL-1β, the IC in Table 2 50 Active:

[0856] + IC 50 A exceeds 1000 nM

[0857] ++ IC 50 Ga 301 - 500 nM range

[0858] +++ IC 50 A range of 151 - 300 nM

[0859] ++++ IC 50 Less than 150 nM

[0860] - indicates that the value has not been determined

[0861] Additional embodiments may be provided by combining the various embodiments described above. All U.S. patents, U.S. patent publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to herein and listed in the application data sheet, including but not limited to U.S. Provisional Application No. 63 / 022,159 filed May 8, 2020, and U.S. Provisional Application No. 63 / 170,761 filed April 5, 2021, are incorporated herein by reference in their entirety. Where necessary, aspects of the embodiments may be modified to provide additional embodiments by adopting concepts from various patents, applications, and application publications.

[0862] In light of the detailed description above, variations and other modifications to the embodiments may be made. Generally, in the following claims, the terms used should not be interpreted as limiting the claims to the specific embodiments disclosed in this specification and claims, but should be interpreted to include equivalents of the full scope together with all possible embodiments falling within these claims. Accordingly, the claims are not limited by what is disclosed.

Claims

Claim 1 A compound having the following structure (I), a pharmaceutically acceptable salt or stereoisomer thereof: In the above formula, A is C6-C 10 Aryl, C3-C 10 It is a cycloalkyl, a 3-10-membered heterocyclile, or a 5-6-membered monocyclic heteroaryl, and each of these has one or more R 6 It is arbitrarily substituted by; X is CH or N; Y is NH; and R 1 is H and;R 2 is a C3-C4 cycloalkyl, a 3-8-membered heterocyclile, or a 5- or 6-membered heteroaryl, each of which is optionally substituted by 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 heterocyclile; R 3 is H and; R 4 is a 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 halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxyalkyl, Optionally substituted by one or more substituents selected from 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 and;R 6 In each case, it is independently a halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl. Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 In paragraph 1, R 2 A compound in which is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, and each of these is optionally substituted by 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. Claim 6 In paragraph 5, R 2 A compound that is unsubstituted. Claim 7 delete Claim 8 delete Claim 9 In paragraph 1, R 2 a compound having one of the following structures: ; ; ; ; ; ; ; ; or . Claim 10 delete Claim 11 In paragraph 1, R 4 a 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, and each of these is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-one heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-one heterocyclilalkyl, 3- to 8-one A compound optionally substituted by one or more substituents selected from alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. Claim 12 In Paragraph 11, R 4 A compound that is a isoxazolyl optionally substituted by one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-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, and combinations thereof. Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 In paragraph 1, R 4 A compound substituted by C1-C6 alkyl, C1-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, or C3-C8 halocycloalkyl, or a combination thereof. Claim 20 In paragraph 1, R 4 a compound having one of the following structures: . Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 A compound according to claim 1 in which A is phenyl, saturated or unsaturated cyclohexyl, pyridinyl, or pyrimidinyl. Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 In paragraph 1, a compound in which A is unsubstituted. Claim 33 A compound according to claim 1, wherein A is substituted by one or more substituents selected from halo, C1-C6 hydroxyalkyl, cyano, or C1-C6 alkoxy. Claim 34 delete Claim 35 In paragraph 33, a compound in which the halo is chloro or fluoro. Claim 36 delete Claim 37 In paragraph 33, a compound in which the C1-C6 hydroxylalkyl group is -CH2CH2OH. Claim 38 delete Claim 39 delete Claim 40 In paragraph 33, a compound in which the C1-C6 alkoxy methoxy is present. Claim 41 In paragraph 1, A is a compound having one of the following structures: . Claim 42 In claim 1, a compound having the following structure (IA), a pharmaceutically acceptable salt thereof, or a stereoisomer: In the above equation, R 2a is a C3-C4 cycloalkyl optionally substituted by 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 heterocyclyl; R 4a is a compound having one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or . Claim 43 In Paragraph 42, R 2a Compound having the following structure: . Claim 44 In Paragraph 42, R 4a a compound having one of the following structures: . Claim 45 In paragraph 1, a compound in which X is CH. Claim 46 In claim 1, a compound having one of the following structures, a pharmaceutically acceptable salt thereof, or a stereoisomer: . Claim 47 A compound that is an inhibitor of the NLRP3 inflammasome, NEK7, or a modulator of both, according to claim 1. Claim 48 delete Claim 49 delete Claim 50 A pharmaceutical composition for treating an NLRP3-mediated disorder comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the disorder is selected from autoimmune, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, bacterial and viral infection, allergy, multi-organ failure, kidney disease, platelet aggregation, cancer, transplantation, graft rejection, lung injury, respiratory disease, and ischemic condition;or a disorder selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue injury caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, multiple sclerosis, Muckle-Wells syndrome, platelet aggregation, pancreatitis, sperm motility, and erythrocyte deficiency Pharmaceutical composition.; Claim 51 A pharmaceutical composition according to claim 50, wherein the disorder is selected from autoimmune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, multi-organ failure, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection, lung injury, respiratory diseases, and ischemic conditions. Claim 52 A pharmaceutical composition according to claim 50, 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 caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced sunburn, contact hypersensitivity, sepsis, multiple sclerosis, Merkle-Wells syndrome, platelet aggregation, pancreatitis, sperm motility, and erythropoietin.

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