Inhibitors of NEK7 kinase

Abstract

Compounds having activity as inhibitors of NEK7 are provided. The compounds have the structure (I): (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof wherein A, X, Y, R1, R2, R3, R4 and R5 are as defined herein. Methods associated with the preparation and use of such compounds, pharmaceutical compositions comprising such compounds, and methods of modulating the activity of NLRP3 inflammasomes are also provided.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180048858.3, filed on May 7, 2021, with the invention name “Inhibitors of NEK7 kinase”. background Technical Field

[0002]

[0014] Embodiments of the present disclosure are generally directed to compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example, for the treatment of inflammation.

[0003] Description of Related Technology

[0004] Inflammasomes are multiprotein complexes whose activation plays a central role in innate immunity and inflammation. To date, four inflammasomes have been described: NLRP1, NLRC4, NLRP3, and AIM2. The NLRP3 inflammasome is composed of NLRP3, ASC, and caspase-I. Its activation leads to the activation of caspase-I, which promotes the secretion of IL-1β and IL-18, cytokines that mediate inflammation in animal models of several autoimmune diseases, myocardial infarction, metabolic syndrome, inflammatory bowel disease, and macrophage activation syndrome.

[0005] NEK7 is a family member of NIMA-associated kinases (NEKs), which act as NLRP3 binding proteins that regulate their oligomerization and activation. NEK7 is a serine / threonine kinase required for mitotic entry, cell cycle progression, cell division, and mitotic progression. It is expressed in a variety of tissues, such as the brain, heart, lungs, liver, and spleen. Overexpression of NEK7 induces the generation of abnormal cells, which are closely associated with tumors such as retinoblastoma, gallbladder cancer, and head and neck cancer.

[0006] A large number of inhibitors have been widely used to interfere with the effector signaling pathways involving IL-1β or IL-18 without eliminating the inflammatory response. Inhibitors that block the activation of the NLRP3 inflammasome by the NLRP3-NEK7 interaction may have therapeutic or preventive activity in several human diseases, such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the precise mechanism of NLRP3-NEK7 is not yet fully understood.

[0007] Therefore, there is a need to develop inhibitors that will directly target NEK7 to affect the inflammatory response regulated by the NLRP3 inflammasome in several pathological diseases (e.g., gout, atherosclerosis, type 2 diabetes, metabolic syndrome, macular degeneration, Alzheimer's disease, multiple sclerosis, and inflammatory bowel disease). The embodiments of the present disclosure meet this need and provide other related advantages. Summary of the Invention

[0008] Briefly, embodiments of the present disclosure provide compounds capable of inhibiting NEK7 and / or modulating the activity of the NLRP3 inflammasome, including pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof.

[0009] In one aspect, the present invention provides compounds of structure (I):

[0010] (I)

[0011] Its pharmaceutically acceptable salt, stereoisomer or prodrug, wherein A, X, Y, R 1 、R 2 、R 3 、R 4 and R 5 Each is as defined below.

[0012] In another aspect, pharmaceutical compositions comprising the disclosed compounds and methods of use thereof for treating inflammation are also provided. DETAILED DESCRIPTION

[0013] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0014] Unless the context requires otherwise, throughout the specification and claims, the word "comprise" and variations thereof (e.g., "comprises" and "comprising") are to be construed in an open, inclusive sense, that is, to mean "including, but not limited to."

[0015] In this specification, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and include its fraction (such as one tenth and one hundredth of an integer) when appropriate, unless otherwise stated. As used herein, the terms "about" and "approximately" mean ± 20%, ± 10%, ± 5% or ± 1% of the range, value or structure shown, unless otherwise stated. It should be understood that the terms "one / a kind (a)" and "an" as used herein refer to "one / a kind or more / a variety" in the enumerated components. The use of alternatives (e.g., "or") should be understood to mean one or both or any combination thereof in the alternatives.

[0016] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0018] "Amino" refers to an NH2 group.

[0019] "Carboxy" (carboxy / carboxyl) is CO2H group.

[0020] "Cyano" refers to a -CN group.

[0021] "Hydroxy" or "hydroxyl" refers to an -OH group.

[0022] "Nitro" refers to a -NO2 group.

[0023] "Oxo" refers to a =0 substituent.

[0024] "Mercaptan" is SH substituent.

[0025] "Thio" refers to a =S substituent.

[0026] "Alkyl" refers to a saturated straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C 12 The alkyl group is optionally substituted with one to eight carbon atoms (C1-C8 alkyl), one to eight carbon atoms (C1-C8 alkyl), or one to six carbon atoms (C1-C6 alkyl), or any value within these ranges (e.g., C4-C6 alkyl, etc.), and is connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. The number of carbons mentioned relates to the main chain carbons and the branched carbons, but does not include the carbon atoms belonging to any substituent. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted.

[0027] "Alkenyl" refers to an unsaturated straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C 12 The carbon numbers mentioned relate to the main chain carbons and the side chain carbons, but do not include the carbon atoms belonging to any substituents. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted.

[0028] The term "alkynyl" refers to an unsaturated straight or branched chain hydrocarbon group having 2 to 12 carbon atoms (C2-C 12 The term "alkynyl" refers to a group having at least one carbon atom (C-C alkynyl), 2 to 9 carbon atoms (C-C alkynyl), or 2 to 6 carbon atoms (C-C alkynyl), or any value within these ranges, and having at least one carbon-carbon triple bond. Examples of alkynyl groups can be selected from ethynyl, propargyl, but-1-ynyl, but-2-ynyl, and the like. The number of carbons mentioned relates to the main chain carbons and the side chain carbons, but does not include the carbon atoms belonging to any substituent. Unless otherwise specifically stated in this specification, alkynyl groups are optionally substituted.

[0029] "Alkoxy" means OR a A group in which R a is an alkyl group as defined above containing from one to twelve carbon atoms (C1-C 12 Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0030] "Amine" means NR a R b A group in which R a and R b Each independently is H or C1-C6 alkyl as defined above. a and R b When both are H, an "aminyl" group is the same as "amino" as defined above. Unless otherwise specified, the C1-C6 alkyl portion of the amino group is optionally substituted.

[0031] "Aminoalkylcycloalkyl" refers to an aminoalkyl group of the formula -R a R b NR c R dA group in which R a is a cycloalkyl group as defined herein, R b is a C1-C6 alkyl group, R c is H or C1-C6 alkyl, and R d is a C1-C6 alkyl group as defined above.Unless otherwise stated, the cycloalkyl group and each C1-C6 alkyl portion of the aminoalkylcycloalkyl group are optionally substituted.

[0032] "Aromatic ring" refers to a cyclic planar molecule or portion (i.e., group) of a ring with a resonant bond that exhibits increased stability relative to other connected arrangements with the same atomic group. Typically, an aromatic ring contains a set of covalently bonded coplanar atoms and comprises many π- electrons (e.g., alternating double bonds and single bonds), wherein the π- electrons are even numbers but not multiples of 4 (i.e., 4n + 2 π- electrons, wherein n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthyl, imidazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridyl, pyridazinyl, pyrimidyl. Unless otherwise specifically stated in the specification, "aromatic ring" includes all groups that are optionally substituted.

[0033] "Aryl" refers to a group containing 6 to 18 carbon atoms (e.g., 6 to 10 carbon atoms (C6-C 10 The term "aryl" refers to a carbocyclic ring system comprising an aryl group (an aryl group) and at least one carbocyclic aromatic ring. For the purposes of embodiments of the present invention, an aryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrene, acenaphthylene, acephenanthren, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrene, phenanthrene, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, aryl groups are optionally substituted.

[0034] "Cyanoalkyl" refers to an alkyl group that contains at least one cyano substituent. The -CN substituent can be on a primary, secondary, or tertiary carbon. Unless otherwise specifically stated in the specification, a cyanoalkyl group is optionally substituted.

[0035] "Carbocyclic" or "carbocycle" refers to a ring system in which every one of the ring atoms is carbon.

[0036] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic group consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C 15 Cycloalkyl), three to ten ring carbon atoms (C3-C 10The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.

[0037] "Alkylcycloalkyl" refers to a group of the formula -R a R b A group in which R a is a cyclic hydrocarbon group and R b is alkyl as defined above. Unless stated otherwise specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0038] "Fused" refers to any ring structure described herein that is fused to another ring structure.

[0039] "Halogen" refers to bromine, chlorine, fluorine or iodine.

[0040] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0041] "Halocycloalkyl" refers to a cycloalkyl as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0042] "Haloalkylcycloalkyl" refers to a group of the formula -R a R b The group, where R a is a cyclic hydrocarbon group and R b is a haloalkyl group as defined above. Unless stated otherwise specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0043] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. The hydroxyalkyl group is attached to the backbone through an alkyl carbon atom. Unless otherwise specifically stated in the specification, a hydroxyalkyl group is optionally substituted.

[0044] "Heterocyclyl" refers to a 3-18 membered, for example, 3-10 or 3-8 membered non-aromatic ring group having one to ten ring carbon atoms (e.g., two to ten) and one to six ring heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in this specification, a heterocyclyl is a partially or fully saturated, monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic, and / or bridged ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclyl are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolazine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, heterocyclic groups are optionally substituted.

[0045] "Haloheterocyclylalkyl" refers to a group of the formula -R a R b A group in which R a is an alkyl group and R b is a haloheterocyclyl group as defined herein.Unless stated otherwise specifically in the specification, a haloheterocyclylalkyl group is optionally substituted.

[0046] "Heterocyclylalkyl" refers to a group of the formula -R a R b A group in which R a is an alkyl group and R b is a heterocyclyl group as defined herein.Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0047] "Heteroaryl" refers to a 5-18, e.g., 5-6, ring system radical containing one to thirteen ring carbon atoms, one to six ring heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. A heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azaquinazole, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[ b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1, 2-a] pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindololinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridyl, 1-oxidopyrimidinyl, 1-oxidopyridazinyl, 1-phenyl-1- H -pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl (i.e., thiocyclopentadienyl). Unless otherwise specifically stated in the specification, heteroaryl groups are optionally substituted.

[0048] 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 refer to the following structures, respectively: ; ; ; ; ; ; ; ; ; ; ; ; and , wherein oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl are substituted by oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl. The 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 groups are attached to the rest of the molecule through a covalent bond to one of the carbon atoms in the ring.

[0049] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxyalkyl) in which at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxy, halogen, nitro, oxo, thiol, thio, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxyalkyl substituents, each of which may be optionally substituted with one or more of the above substituents.

[0050] In some embodiments, the optional substituents are independently selected from halogen, hydroxyl, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C 10 aryl, 5- or 6-membered heteroaryl, C1-C6 alkoxy and 3- to 8-membered heterocyclic group.

[0051] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound as described herein sufficient to achieve the intended application, including but not limited to the treatment of diseases as defined below. A therapeutically effective amount can vary depending on the intended therapeutic application (in vivo), or the individual and disease condition being treated, such as the weight and age of the individual, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to doses that induce a specific response in target cells, such as a decrease in platelet adhesion and / or cell migration. The specific dosage will vary depending on the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system it carries.

[0052] As used herein, "treatment" or "treat" refers to a method for obtaining a beneficial or desired result (including but not limited to a therapeutic effect and / or a preventive effect) with respect to a disease, disorder, or medical condition. A therapeutic benefit means a cure or improvement of the underlying disorder being treated. In addition, a therapeutic benefit is achieved by curing or improving one or more physiological symptoms associated with the underlying disorder, such that an improvement in the individual is observed, even though the individual may still be suffering from the underlying disorder. A preventive effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, preventing, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for a preventive benefit, a composition is administered to an individual at risk for a particular disease, or to an individual reporting one or more physiological symptoms of a disease, even though the disease may not yet have been diagnosed.

[0053] As used herein, the terms "co-administration," "combined administration," and grammatical equivalents thereof encompass the administration of two or more pharmaceutical agents to animals, including humans, such that both agents and / or their metabolites are present in the individual at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

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

[0055] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness of the free bases, are biologically tolerable, or are otherwise biologically suitable for administration to a subject. See generally, SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use,Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those which are pharmacologically effective and suitable for use in contact with patient tissues without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptylsulfonic acid, 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, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0056] "Pharmaceutically acceptable base addition salts" refers to those salts which retain the biological effectiveness of the free base, are biologically tolerable, or are otherwise biologically suitable for administration to a subject. See generally, SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use,Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for use in contact with patient tissues without undue toxicity, irritation, or allergic reactions. Pharmaceutically acceptable base addition salts are prepared by adding an inorganic base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, 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, dimethylethanolamine, 2-dimethylaminoethanol, 2-ethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N Ethylpiperidine, polyamine resin, etc. 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 ammonium alkyl halide salts (eg, methyl bromide).

[0058] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of a protein (e.g., NLRP3 inflammasome or NEK7) or by inhibiting the association of NLRP3 inflammasome with NEK7. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological action of the target protein. Although preferred antagonists herein particularly interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway in which the target protein is a member are also particularly included in this definition. The preferred biological activity inhibited by the antagonist is associated with the development, growth, or spread of a tumor.

[0059] As used herein, the term "agonist" refers to a compound that has the ability to induce or enhance the biological function of a target protein, whether or not by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological action of the target polypeptide. Although preferred agonists herein particularly interact with (e.g., bind to) the target, compounds that induce or enhance the biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also particularly included in this definition.

[0060] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted into and within cells to elicit intracellular responses.

[0061] The term "selective inhibition" or "selectively inhibits" refers to the ability of a biologically active agent, through direct or indirect interaction with the target, such that the agent preferentially reduces target signaling activity compared to off-target signaling activity.

[0062] "Subject" refers to an animal, such as a mammal, such as a human. The methods described herein can be used for human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0063] "Mammal" includes humans and livestock animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals, etc.

[0064] "Prodrug" is intended to mean a compound (e.g., a compound of structure (I)) that can be converted to a biologically active compound as described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. In some aspects, a prodrug is inert when administered to a subject, but is converted into an active compound in vivo, such as by hydrolysis. Prodrug compounds often provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), p. 79, p. 2124 (Elsevier, Amsterdam). In Higuchi, T., et al., "Prodrugs 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 A discussion of prodrugs is provided in Pharmacopoeia Press, 1987, both of which are incorporated herein by reference in their entirety. The term "prodrug" is also meant to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds as described herein are typically prepared by modifying functional groups present in the active compound in such a manner that the modifications are cleaved into the parent active compound during routine manipulation or in vivo. Prodrugs include compounds in which hydroxyl, amino, or thiol groups are attached to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form free hydroxyl, free amino, or free thiol groups, respectively. Examples of prodrugs include, but are not limited to, acetic acid, formic acid, and benzoic acid derivatives of hydroxyl functional groups in the active compound, or acetamide, formamide, and benzamide derivatives of amine functional groups, and the like.

[0065] The term "in vivo" refers to events that occur within the body of an individual.

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

[0067] Certain embodiments are also intended to include in vivo metabolites of the disclosed compounds. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Therefore, embodiments include compounds produced by methods comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to produce its metabolites. Typically, a radiolabeled compound of the present disclosure is administered in a detectable dose to an animal (e.g., rat, mouse, guinea pig, monkey) or to a human, allowing sufficient metabolic time to occur, and isolating its conversion products from urine, blood, or other biological samples to identify such products.

[0068] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0069] Typically, crystallization produces solvates of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the disclosure and 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 disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the disclosure may be true solvates, while in other cases, the compounds of the disclosure retain only adventitious water or are a mixture of water plus some adventitious solvent.

[0070] "Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstances occur and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups without substituents.

[0071] "Pharmaceutical composition" refers to a preparation of a compound of the present disclosure and a medium generally accepted in the art for delivering the compound of the present disclosure to a mammal (e.g., a human). Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0072] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

[0073] "Stereoisomers" refer to compounds composed of the same atoms bonded to the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0074] The compounds of the present disclosure (i.e., compounds of structure (I)) or pharmaceutically acceptable salts thereof may contain one or more centers of geometric asymmetry and may therefore give rise to stereoisomers, such as enantiomers, diastereomers, and other stereoisomeric forms, which are defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- of an amino acid. The embodiments therefore include all such possible isomers, as well as racemic and optically pure forms thereof. Optional active (+) and (), ( R )and( S ) or (D) and (L) isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, this is intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0075] Embodiments of the present disclosure include all forms and conformationally restricted states of rotational isomers of the compounds of the present invention. Also included are atropisomers, which are stereoisomers arising from hindered rotation about a single bond, where energy differences due to steric strain or other contributing factors create a rotational barrier high enough to allow separation of the individual conformers. As an example, certain compounds of the present disclosure may exist as a mixture of atropisomers, or may be purified or enriched to allow the presence of a single atropisomer.

[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 a single enantiomer or diastereomer.

[0077] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments therefore include tautomers of the disclosed compounds.

[0078] The chemical naming schemes and structure diagrams used herein are modified versions of the IUPAC nomenclature system, which use ACD / named software program version 9.07 and / or ChemDraw Professional version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, the substituent is typically named before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Unless described below, all bonds are identified in the chemical structure diagrams herein, but it is assumed that all bonds on some carbon atoms are bonded to enough hydrogen atoms to complete the valence.

[0079] Compound

[0080] The present disclosure provides compounds capable of inhibiting NEK7 and / or modulating the activity of the NLRP3 inflammasome, including pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof.

[0081] Embodiments of the present disclosure provide compounds having the following structure (I):

[0082] (I)

[0083] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is each optionally replaced by one or more R 6 Substituted C6-C 10 Aryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group or 5-6 membered monocyclic heteroaryl; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; R 3 is H, a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4is a heteroaryl group selected from the group consisting of 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 optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or a combination thereof; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, or 5- or 6-membered heteroaryl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R 6 is independently at each occurrence halogen, C1-C6 alkyl, cyano, C1-C6 hydroxyalkyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0084] In some embodiments of Structure (I): A is each optionally replaced by one or more R 6 Substituted C6-C 10 Aryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group or 5-6 membered monocyclic heteroaryl; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; R 3is H, a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4 is a heteroaryl group selected from the group consisting of 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 optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, or 5- or 6-membered heteroaryl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R 6 is independently at each occurrence halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0085] Some more specific embodiments provide compounds having the following structure (I):

[0086] (I)

[0087] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is each optionally replaced by one or more R 6 Substituted C6-C 10 Aryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group or 5-6 membered monocyclic heteroaryl; X is CH or N; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; R 3 is H, a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4 is a heteroaryl group selected from the group consisting of 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 optionally substituted with one or more substituents selected from the group consisting of: halogen aliphatic, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, or 5- or 6-membered heteroaryl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R 6 is independently at each occurrence halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxyalkyl or C1-C6 haloalkyl.

[0088] In one embodiment, R 1 is H. In other embodiments, R 1 is a C1-C6 alkyl group, such as a methyl group.

[0089] In one embodiment, a compound of structure (I) is provided wherein R 2 It is a branched C4-C6 alkyl group, a C3-C4 cycloalkyl group, a C3-C8 heterocyclyl group, or a 5- or 6-membered heteroaryl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl.

[0090] In another embodiment, compounds of structure (I) are provided wherein R 2 It is a branched C4-C6 alkyl, C3-C4 cycloalkyl or C3-C8 heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl.

[0091] In a specific embodiment, R 2 is a cyclopropyl or oxetanyl group, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. In some embodiments, R 2 In other embodiments, R 2 In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanyl.

[0092] In a specific embodiment, R 2 is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. In some embodiments, R 2 In other embodiments, R 2 In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R 2 is N-methyl substituted pyrrolidinyl. In certain specific embodiments, R 2 is an unsubstituted cyclobutyl group.

[0093] In various embodiments, R 2is a branched C4-C6 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. For example, in some embodiments, R 2 is 2-methylpropyl optionally substituted by hydroxy.

[0094] In some more specific embodiments, R 2 Has one of the following structures: ; or .

[0095] In some specific embodiments, R 2 Has one of the following structures: ; ; ; ; ; ; ; ; or .

[0096] In other embodiments, R 3 is H. In other embodiments, R 3 is a C1-C6 alkyl group, such as a methyl group.

[0097] In any of the preceding embodiments, R 4 is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl or 1,3,4-oxadiazolyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof. For example, in certain embodiments, R 4 is isoxazolyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl. In other specific embodiments, R 4Substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 halocycloalkyl.

[0098] In certain embodiments, R 4 is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1,3,4-oxadiazolyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

[0099] In certain embodiments, R 4 is isoxazolyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

[0100] In certain embodiments, R 4 is a triazolyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

[0101] In certain embodiments, R 4is an isothiazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

[0102] In certain embodiments, R 4 It is a 1,2,4-thiadiazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

[0103] In certain embodiments, R 4 It is a 1,3,4-thiadiazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

[0104] In certain embodiments, R 4 It is a 1,2,4-triazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

[0105] In certain embodiments, R 4It is a 1,3,4-oxadiazolyl group optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amine, C1-C6 hydroxyalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl or a combination thereof.

[0106] In certain embodiments, R 4 Substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl and combinations thereof.

[0107] In various embodiments, R 4 Has one of the following structures: ; ; ; ; ; ; ; ; ; ; or .

[0108] In other various embodiments, R 4 Has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0109] In other various embodiments, R 4 Has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0110] In certain embodiments, R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; and

[0111] R 4 Has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0112] In certain embodiments, R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; and

[0113] R 4 Has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0114] In a more specific embodiment, R 2 is a C1-C6 alkyl group substituted with a hydroxyl group or a C1-C6 alkoxy group. 2 Has one of the following structures: or .

[0115] In other embodiments, R 5 is H. In other embodiments, R 5 is a C1-C6 alkyl group, such as a methyl group.

[0116] In certain embodiments, Y is C(H)(OH). In other embodiments, Y is NH.

[0117] In various embodiments, A is each optionally replaced by one or more R 6 Substituted C6-C 10 Aryl, C3-C 10 It should be understood that A is a divalent group.

[0118] In certain embodiments, A is a divalent optionally substituted C 6-10 Aryl. In certain embodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, A is a divalent optionally substituted 3-10 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0119] In certain embodiments, A is a divalent group selected from phenyl, pyridyl, cyclohexyl, and cyclohexenyl, each optionally substituted. In other embodiments, A is phenyl. In various embodiments, A is a saturated or unsaturated cyclohexyl. In further embodiments, A is pyridyl.

[0120] In certain embodiments, A is optionally substituted pyrimidinyl.

[0121] In any of the foregoing embodiments, A is unsubstituted. In different foregoing embodiments, A is replaced by one or more R 6 For example, in some embodiments, R 6 In some embodiments, R 6 is chloro or fluoro. In other embodiments, R 6 It's fluorine.

[0122] In some embodiments, R 6 In some embodiments, C1-C6 hydroxyalkyl is -CH2CH2OH. In other embodiments, R 6 In some embodiments, R 6 In a more specific embodiment, the C1-C6 alkoxy group is a methoxy group.

[0123] In certain embodiments, A is a divalent radical selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl, [2.2.2]bicyclooctyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, acridinyl, benzimidazolyl, benzofuranyl, benzothiathiophenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzo isoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazole oxadiazole, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazole quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl.

[0124] In specific embodiments, A has one of the following structures: ; ; ; or .

[0125] In some embodiments, A has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0126] In some embodiments, A has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0127] In certain embodiments, the compound has the following structure (IA):

[0128] (IA)

[0129] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: R 2a is a C1-C6 alkyl or C3-C8 cycloalkyl group, each optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R 4a isoxazolyl optionally substituted by one or more substituents selected from the group consisting of C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkylcycloalkyl.

[0130] In a more specific embodiment, R 2a is a branched C1-C6 alkyl group substituted with a hydroxyl group. 2ais a C3-C8 cycloalkyl. In a more specific embodiment, R 2a Has one of the following structures: or .

[0131] In certain embodiments, R 4a is an isoxazolyl group substituted with a C3-C8 haloalkylcycloalkyl group. 4a is a C3-C8 fluoroalkyl cycloalkyl. In a more specific embodiment, R 4a is fluoroalkylcyclopropyl or fluoroalkylcyclobutyl. In a more specific embodiment, R 4a Has one of the following structures: or .

[0132] In some embodiments, X is CH. In some more specific embodiments, the compound has the following structure (IB):

[0133] (IB)

[0134] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is each optionally replaced by one or more R 6 Substituted C6-C 10 Aryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group or 5-6 membered monocyclic heteroaryl; X is CH or N; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; R 3 is H, a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4is a heteroaryl group selected from the group consisting of 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 optionally substituted with one or more substituents selected from the group consisting of: halogen aliphatic, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, or 5- or 6-membered heteroaryl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R 6 is independently at each occurrence halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxyalkyl or C1-C6 haloalkyl.

[0135] In certain embodiments, the compound of structure (I) is a modulator of the NLRP3 inflammasome.

[0136] In specific embodiments, the compound of structure (I) is an inhibitor of NEK7 in a patient or biological sample.

[0137] In various embodiments, the compound has one of the structures set forth in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. The compounds in Table 1 were prepared as described in the Examples or methods known in the art and characterized by mass spectrometry and / or 1 H NMR analysis.

[0138] Table 1 Representative compounds of structure (I)

[0139] It is understood that in the present description, combinations of substituents and / or variables of the described formulae are permissible only if such combinations result in stable compounds.

[0140] In another embodiment, the various compounds of the present disclosure that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art with appropriate inorganic or organic bases or acids. The salts of the compounds of the present disclosure can be converted into their free base or acid forms by standard techniques.

[0141] Provided below are methods for producing the compounds described herein. Generally, starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or synthesized from 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 as described herein.

[0142] The following general reaction scheme illustrates examples of compounds of structure (I) of the present invention:

[0143] (I)

[0144] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, X, Y, R 1 、R 2 、R 3 、R 4 and R 5 Each is as defined below.

[0145] General reaction scheme 1

[0146] The following general reaction scheme (where X 1 and X 2 are independently halogen, and X, R 1 、R 2 、R 3 and A have the meanings described herein) illustrate an example of a method for preparing the amine intermediate D:

[0147] As shown in General Reaction Scheme 1, a pyrimidine / pyridinylpyrrole (i.e., intermediate A) is alkylated with a cyclic alkyl boronate or an appropriate electrophile in the presence of a base to provide intermediate B. This precursor is treated with ammonium hydroxide to form a pyrrolopyrimidine / pyridin-4-amine derivative intermediate C. The resulting intermediate C can then be subjected to palladium-catalyzed arylation to form intermediate D.

[0148] General Reaction Scheme 2

[0149] The following general reaction scheme illustrates an example of a method for preparing carbamate intermediate E:

[0150] As shown in General Reaction Scheme 2, intermediate E can be synthesized by reacting phenyl chloroformate with the heteroarylamine (R 4 General Reaction Scheme 2 describes the reaction of R 5 is the preparation of compounds wherein R 5 Compounds other than H can be prepared by a similar method by adding R after the preparation of intermediate E. 5 or by using appropriately substituted heteroarylamines.

[0151] General reaction scheme 3

[0152] The following general reaction scheme illustrates an example of a method for preparing compounds of structure (I):

[0153] Intermediate D and Intermediate E are treated with a base (eg, trimethylamine, DIPEA, DMAP, etc.) in THF to give compounds of structure (I).

[0154] General reaction scheme 4

[0155] The following general reaction scheme illustrates an example of a method for preparing compounds of structure (I):

[0156] Intermediate D is reacted with phenyl chloroformate as shown under appropriate conditions to provide intermediate E. Intermediate E is then coupled with an amine using a suitable base (e.g., trimethylamine, DIPEA, DMAP, etc.) in THF to provide compounds of structure (I).

[0157] Any of the above reaction schemes may be modified at any step to add and / or modify substituents, which may be added or modified as appropriate during any stage of the overall synthesis of the desired compound.

[0158] It will also be appreciated by those skilled in the art that in the methods for preparing 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, sulfhydryl, and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino, and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for sulfhydryl include C(O)R" (wherein R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, etc. Suitable protecting groups for carboxylic acid include alkyl esters, aryl esters, or arylalkyl esters. Protecting groups are optionally added or removed according to standard techniques known to those skilled in the art and as described herein. In Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd edition, Wiley. As will be appreciated by those skilled in the art, the protecting group may also be a polymer resin, such as a Wang resin, a Rink resin or a 2-chlorotrityl-chloride resin.

[0159] Those skilled in the art will also understand that, although such protected derivatives of the compounds of the present disclosure may not have pharmacological activity, they can, nevertheless, be administered to a mammal and thereafter metabolized in vivo to form pharmacologically active compounds of the present disclosure. Such derivatives can therefore be described as "prodrugs." Prodrugs of the compounds of the present disclosure are included within the scope of the embodiments of the present disclosure.

[0160] Pharmaceutical composition

[0161] Other embodiments relate to pharmaceutical compositions. 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 more embodiments, the pharmaceutical composition comprises a compound disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0162] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0163] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, typically in the form of a depot formulation or a sustained release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in the form of a rapid release formulation, an extended release formulation, or an intermediate release formulation. In other embodiments, the compounds described herein are administered topically.

[0164] In the therapeutic methods according to embodiments of the present invention, an effective amount of at least one compound of structure (I) is administered to an individual suffering from or diagnosed as suffering from such a disease, disorder or medical condition. The effective amount or dose can be determined by methods such as modeling, dose escalation studies or clinical trials, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder or condition, the individual's previous or ongoing therapy, the individual's health status and response to drugs, and the judgment of the treating physician.

[0165] The compounds according to the present disclosure are effective over a wide dosage range. For example, in the treatment of adults, dosages of 10 to 5000 mg / day, 100 to 5000 mg / day, 1000 to 4000 mg / day, and 1000 to 3000 mg / day are examples of dosages used in some embodiments. The exact dosage depends on the route of administration, the form of the compound administered, the subject to be treated, the weight of the subject to be treated, the preference and experience of the attending physician.

[0166] In some embodiments, the compounds of the present disclosure are administered in a single dose. Typically, this administration will be by injection, such as intravenous injection, to allow for rapid introduction of the agent. However, other routes may be used as appropriate. A single dose of a compound of the present disclosure may also be used to treat acute conditions.

[0167] In some embodiments, the compound of the present disclosure is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times or more than six times per day. In other embodiments, administration is about once a month, once every two weeks, once a week or once every other day. In another embodiment, the compound of the present disclosure and another agent (e.g., anticancer agent) are administered together about once a day to about 6 times a day. In another embodiment, administration of the compound of the present disclosure and the agent is continued for less than about 7 days. In another embodiment, administration is continued for greater than about 6 days, 10 days, 14 days, 28 days, two months, six months or one year. In some cases, if necessary, continuous administration is achieved and maintained.

[0168] The administration of a Compound of the Disclosure can be continued for as long as desired. In some embodiments, a Compound of the Disclosure is administered for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, or 28 days. In some embodiments, a Compound of the Disclosure is administered for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, a Compound of the Disclosure is administered on an ongoing basis for a long period of time, e.g., to treat chronic effects.

[0169] In some embodiments, the compounds of the present disclosure are administered in separate dosage forms. It is known in the art that due to inter-individual variability in compound pharmacokinetics, individualization of dosing regimens is necessary for optimal treatment.

[0170] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate processing of the disclosed compounds into pharmaceutically acceptable formulations. Appropriate formulations depend on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are suitable for preparing the pharmaceutical compositions described herein: 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 Edition, (Lippincott Williams & Wilkins 1999).

[0171] Provided herein are pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0172] Provided herein is a pharmaceutical composition comprising one or more compounds selected from the compound of structure (I) and a pharmaceutically acceptable diluent, excipient, and carrier. In certain embodiments, the compound is administered as a pharmaceutical composition, wherein one or more compounds selected from the compound of structure (I) are mixed with other active ingredients, such as in combination therapy. All combinations of the active substances described in the combination therapy section below and all combinations of the active substances described in the disclosure are contemplated herein. In a specific embodiment, the pharmaceutical composition includes one or more compounds of structure (I).

[0173] In a certain embodiment, the pharmaceutical composition of the compound of structure (I) is a modulator of the NLRP3 inflammasome.

[0174] In specific embodiments, pharmaceutical compositions of compounds of structure (I) inhibit NEK7 when administered to a patient or biological sample.

[0175] As used herein, pharmaceutical composition refers to a mixture of one or more compounds selected from the compound of structure (I) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. In certain embodiments, pharmaceutical composition promotes the administration of compound to organisms. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compound of structure (I) provided herein is applied to a mammal suffering from a disease to be treated, a disease or a medical condition in a pharmaceutical composition. In a specific embodiment, mammal is a human. In certain embodiments, a therapeutically effective amount varies according to the severity of the disease, the age and relative health of the individual, the efficacy of the compound used and other factors. Compounds as described herein are used as components of a mixture alone or in combination with one or more therapeutic agents.

[0176] In one embodiment, one or more compounds selected from the compounds of structure (I) are formulated into an aqueous solution. In specific embodiments, by way of example only, the aqueous solution is selected from a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or a physiological saline buffer. In other embodiments, one or more compounds selected from the compounds of structure (I) are formulated for transmucosal administration. In specific embodiments, the transmucosal formulation includes a penetrant suitable for the barrier to be permeated. In other embodiments, where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0177] In another embodiment, 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 into oral dosage forms including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0178] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if desired) to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other substances, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, a disintegrant is optionally added. By way of example only, disintegrants include cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0179] In one embodiment, dosage form, for example dragee core and tablet, is provided with one or more suitable coatings.In a specific embodiment, concentrated sugar solution is used for coated dosage form.Sugar solution optionally comprises other component, for example only as an example, gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.For the purpose of identification, dyestuff and / or pigment also optionally add in the coating.In addition, dyestuff and / or pigment are optionally used to characterize the different combinations of active compound dosage.

[0180] In certain embodiments, a therapeutically effective amount of at least one compound described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). In specific embodiments, push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, lactose, binders (e.g., starch), and / or lubricants (e.g., talc or magnesium stearate), and optionally, stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0181] In other embodiments, the compounds described herein are formulated for parenteral injection, including preparations suitable for rapid bolus injection or continuous infusion. In a specific embodiment, the preparation for injection is provided in unit dosage form (e.g., in an ampoule) or in a multidose container. Optionally, a preservative is added to the injection preparation. In other embodiments, 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. Parenteral injection preparations optionally contain a preparaton, such as a suspending agent, a stabilizer, and / or a dispersant. In a specific embodiment, the pharmaceutical preparation for parenteral administration includes an aqueous solution of the active compound in a water-soluble form. In another embodiment, a suspension of one or more compounds selected from the compound of structure (I) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include (as examples only) fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension contains a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution. Alternatively, in other embodiments, the active ingredient is in powder form for composition with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0182] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent or excipient, and one or more compounds selected from the compounds of structure (I) described herein as active ingredients. The active ingredient is in the form of a free acid or free base or a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. In addition, the compounds described herein include unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally includes other drugs or agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0183] Methods for preparing compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semisolid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semisolid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein may be in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or as emulsions. These compositions may also optionally contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, and the like.

[0184] In some embodiments, the pharmaceutical composition comprising one or more compounds selected from the compounds of structure (I) is illustratively in the form of a liquid, wherein the agent is present in a solution, a suspension, or both. Typically, when the composition is administered as a suspension, a first portion of the agent is present in solution, and a second portion of the agent is present in the form of particles suspended in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0185] In certain embodiments, the aqueous suspension contains one or more polymers as suspending agents. Polymers include water-soluble polymers, such as cellulosic polymers, e.g., hydroxypropyl methylcellulose; and water-insoluble polymers, such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0186] The pharmaceutical composition may also optionally include a solubilizing agent to aid in the solubility of one or more compounds selected from the group consisting of compounds of structure (I). The term "solubilizing agent" generally includes agents that result in the formation of micellar or true solutions of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, may be used as solubilizing agents, as may ophthalmically acceptable glycols, polyethylene glycols, such as polyethylene glycol 400, and glycol ethers.

[0187] In addition, the pharmaceutical composition optionally includes one or more pH adjusting agents 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; and buffers such as citrate / dextran, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts required to maintain the pH of the composition within an acceptable range.

[0188] Optionally, the composition further comprises one or more salts in an amount such that the osmotic pressure of the composition is within an acceptable range. Such salts include salts having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0189] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric nitrate and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0190] The composition may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10 and octoxynol 40.

[0191] The composition may contain one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0192] In certain embodiments, the aqueous suspension composition is enclosed in a single-dose non-reclosable container. Alternatively, a multiple-dose reclosable container is used, in which case a preservative is typically included in the composition.

[0193] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers that can be used herein. In certain embodiments, organic solvents, such as N-methylpyrrolidone, are also used. In other embodiments, sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents, are used to deliver the compounds described herein. Various sustained-release materials are useful in this article. In some embodiments, sustained-release capsules release the compound for several weeks up to more than 100 days. Depending on the chemical properties and biological stability of the therapeutic agent, additional protein stabilization strategies are employed.

[0194] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations, such as magnesium and zinc; or (n) combinations thereof.

[0195] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) in the pharmaceutical compositions of the present disclosure is provided at greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0196] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) in the pharmaceutical compositions of the present disclosure is provided at about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v, or v / v.

[0197] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) in the pharmaceutical compositions of the present disclosure is equal to or less than 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, 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, 0.0003g, 0.0002 g, or 0.0001 g.

[0198] In some embodiments, the amount of one or more compounds selected from compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is 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.

[0199] Packaging materials for packaging the pharmaceutical compositions described herein include those found in, for example, U.S. Pat. Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. For example, the container includes one or more compounds described herein, optionally in the form of a composition or in combination with another agent disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). Such kits optionally include a compound with an identifying description or label or instructions for use thereof in the methods described herein.

[0200] For example, a kit typically includes one or more additional containers, each containing one or more of the various materials (e.g., reagents, optionally in concentrated form, and / or devices) desired from a commercial and user perspective for using the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packaging, container, vial, and / or tube labels listing the contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. The label is optionally located on or associated with the container. For example, when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, the label is located on the container; when the label is present within a container or carrier that also holds the container, the label is associated with the container, such as a package insert. In addition, the label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates instructions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is present in a package or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The package, for example, comprises metal or plastic foil, such as a blister pack. Alternatively, the package or dispenser device is accompanied by instructions for administration. Alternatively, the package or dispenser is also accompanied by a notice associated with the container by a governmental agency regulating the manufacture, use or sale of drugs, which reflects the agency's approval of the drug form for human or veterinary administration. Such a notice, for example, is a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. In some embodiments, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0201] method

[0202] Embodiments of the present disclosure may be used as modulators of the NLRP3 inflammasome by inhibiting NEK7 in host species. Thus, compounds of structure (I) may also be used to treat conditions mediated by effector signaling molecules such as IL-β and IL-18.

[0203] The host or patient can be of any mammalian species, such as primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are interesting for experimental research and provide models for treating human diseases.

[0204] In one embodiment, the present disclosure can be used as an inhibitor of the NLRP3 inflammasome activation mechanism. Therefore, compounds of structure (I) can also be used to treat conditions caused by activation in host species.

[0205] In another embodiment, the compounds of structure (I) are useful as inhibitors of NLRP3 (protein)-NEK7 (protein) interactions. Thus, the compounds are also useful for treating conditions caused by NLRP3-NEK7 association in host species.

[0206] In certain embodiments, compounds of structure (I) are useful for treating human conditions mediated by effectors selected from the group consisting of IL-β, IL-18, and caspase-1.

[0207] Embodiments of the present disclosure also relate to the use of compounds according to structure (I) and / or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated and / or regulated by NLRP3 inflammasome activity. In addition, embodiments of the present invention relate to the use of compounds according to structure (I) and / or physiologically acceptable salts thereof for the preparation of medicaments for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated and / or regulated by NLRP3 inflammasome activity. In certain embodiments, the present invention provides the use of compounds according to structure I or physiologically acceptable salts thereof for the preparation of medicaments for the prophylactic or therapeutic treatment of NLRP3-mediated disorders.

[0208] In another embodiment, the disclosure relates to a method of treating an inflammatory disease or condition mediated by the NLRP3 inflammasome by administering to a patient in need thereof a therapeutically effective amount of a compound of structure (I).

[0209] In certain embodiments, diseases that can be treated with compounds of structure (I) include type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver disease, 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.

[0210] In certain other embodiments, the compounds of structure (I) are used in a method of treating a condition or disease selected from autoimmune diseases, inflammatory conditions, cardiovascular diseases, neurodegenerative conditions, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases, ischemic conditions and cancer. In some more specific embodiments, the compounds of structure (I) are used in a method of treating myelodysplastic syndrome (MDS).

[0211] In some embodiments, the NEK7-related disorder treatable with a compound of structure (I) is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndromes, cryptopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease, and cancer.

[0212] Also included herein are methods of treatment in which at least one compound of 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 inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants, and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

[0213] Examples of NSAIDs also include COX-2 specific inhibitors, such as celecoxib, valdecoxib, lumiracoxib and / or etoricoxib.

[0214] In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include but are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylate.

[0215] The anti-inflammatory agent can also be a corticosteroid. For example, the corticosteroid can be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate or prednisone.

[0216] In further embodiments, the anti-inflammatory agent is a gold compound, such as gold sodium thiomalate or auranofin.

[0217] The present disclosure also encompasses embodiments in which the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor, eg, methotrexate, or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

[0218] Therapeutic agents may also include agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by biotransformation of products of selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesics and antipyretics, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, endocrines, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived endocrines, eicosanoids, beta-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0219] Other embodiments of the present disclosure relate to combinations wherein at least one anti-inflammatory compound is an anti-monoclonal antibody (eg, eculizumab or pembrolizumab), a TNF antagonist (eg, etanercept or infliximab, which are anti-TNFα monoclonal antibodies).

[0220] Therapeutic agents used in combination with the compounds of structure (I) may also include small molecule compounds that inhibit activation of the NLRP3 inflammasome, such as MCC950, sulforaphane, isoliquiritigenin, β-hydroxybutyrate, flufenamic acid, mefenamic acid, 3,4-methylenedioxy-β-nitrostyrene (MNS), and parthenolide.

[0221] Still other embodiments of the present disclosure are directed to combinations wherein at least one active agent is an immunosuppressive compound, such as an immunosuppressive compound selected from the group consisting of methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0222] The disclosed compounds of structure (I) can be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anticancer agent" refers to any agent that is administered to a patient suffering from cancer for the purpose of treating the cancer.

[0223] In some embodiments, the anticancer agent belongs to the following classes: Alkylating agents: e.g., altretamine, bendamustine, busulfan, carmustine, chlorambucil, mechlorethamine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tociloxetine, lomustine, melphalan, dibromomannitol, dibromodulcitol, nimustine, ranimustine, temozolomide, thiotepa, treoxazole, dichloromethyldiethylamine, carboquinone; apaziquin, fotemustine, glutamate, ifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834; Platinum compounds: e.g., carboplatin, cisplatin, epazoteplatin, imiplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin; DNA-altering agents: e.g., amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brolindane, pixantrone, laromustine 1,3; Topoisomerase inhibitors: etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amifide, belotecan, elixirsium acetate, voripasine; Microtubule modulators: such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fobutarelin, tesetaxel; Antimetabolites: for example, asparaginase 3, azacitidine, leucovorin, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; deoxyfluridine, elcitabine, raltitrexed, sapacitabine, tegafur 2, 3, trimetrexate; Anticancer antibiotics: such as bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozotocin, valrubicin, fenstatin, daunorubicin, plicamycin; aclarubicin, peclorubicin, pirarubicin; Hormones / antagonists such as abarelix, abiraterone, bicalutamide, buserelin, calosterone, chlorethoxyquin, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol acetate, mitotane, nefarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, cyclothiocarbamate, oltrona, enzalutamide1,3; Aromatase inhibitors: for example, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane; Small molecule kinase inhibitors: for example, crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linstatinib, linsitinib), masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigoseritinib, tipifamib, tivantinib, tivozanib, trametinib, trametinib, pimasertib, brivanib alanine, and cediranib.

[0224] In some embodiments, drugs administered in combination with the compounds described herein include any suitable drug effectively delivered by inhalation, such as analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; angina preparations, such as diltiazem; antiallergics, such as cromoglycate, ketotifen, or nedocromil; anti-infectives, such as cephalosporins, penicillins, streptomycins, sulfonamides, tetracyclines, or pentamidine; antihistamines, such as methapyrline; anti-inflammatory drugs, such as beclomethasone, flunisolide, budesonide, tipredan, triamcinolone acetonide, or fluticasone; antitussives, such as noscapine; bronchodilators, such as ephedrine, epinephrine, fenoterol, fluticasone, or fluticasone; Formoterol, isoproterenol, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, theaproterenol, rimiterol, salbutamol, salmeterol, terbutaline, isotharine, tulobuterol, metaproterenol, or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridyl)ethoxy]hexyl]-amino]methyl]benzyl alcohol; diuretics such as amiloride; anticholinergics such as ipratropium, atropine, or oxytropine; hormones such as cortisone, hydrocortisone, or prednisolone; xanthines such as aminophylline, cholinetheophylline, lysinetheophylline, or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. It will be clear to those skilled in the art that, where appropriate, the drug is used in the form of a salt (e.g., as an alkali metal or amine salt or as an acid addition salt) or as an ester (e.g., a lower alkyl ester) or as a solvate (e.g., a hydrate) to optimize the activity and / or stability of the drug.

[0225] The agents disclosed herein or other suitable agents are administered according to the condition being treated. Therefore, in some embodiments, one or more compounds of the present disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein and the second agent are administered simultaneously or separately. This combined administration can include administering two agents simultaneously in the same dosage form, administering simultaneously in separate dosage forms, and administering separately. In other words, the compounds described herein and any of the above-mentioned agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the above-mentioned agents can be administered simultaneously, with the two agents being present in separate preparations. In another alternative, the compounds of the present disclosure can be administered only after any of the agents described above, or vice versa. In some embodiments of the separate administration scheme, the compounds of the present disclosure and any of the above-mentioned agents are administered a few minutes apart, or a few hours apart, or a few days apart.

[0226] In some embodiments, the compound of structure (I) is administered as a monotherapy.

[0227] To identify signal transduction or mechanistic pathways and to detect interactions between various signal transduction pathways, various scientists have developed suitable models or model systems, such as cell culture models and transgenic animal models. To determine certain stages in the signal transduction cascade, interacting compounds can be used to modulate the signal. The compounds of the embodiments of the present disclosure can also be used as reagents for testing NEK7-dependent signal transduction pathways in animals and / or cell culture models or in clinical diseases mentioned in this application.

[0228] The methods of the embodiments of the embodiments of the present invention can be performed in vitro or in vivo. The sensitivity of specific cells to treatment with compounds of structure (I) can be specifically determined by in vitro testing (whether in the research process or in clinical applications). Typically, cell cultures are combined with compounds of various concentrations for a period of time sufficient for the active agent to inhibit NEK7 activity, typically from about 1 hour to 1 week. In vitro treatment can be performed using cultured cells from biopsy samples or cell lines.

[0229] In some embodiments, the compounds of structure (I) inhibit the IC of NEK7 50 The IC is determined by the concentration of compound required to inhibit 50% of NEK kinase activity. 50 The potency value is less than about 5 mM, preferably less than about 1 mM, and even more preferably less than about 0.100 mM, as described in further detail in the Examples.

[0230] The examples and formulations provided below further illustrate and exemplify the compounds of the present disclosure and methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and formulations. In the following examples, and throughout the specification and claims, unless otherwise indicated, molecules with a single stereocenter exist as a racemic mixture. Unless otherwise indicated, those molecules with two or more stereocenters exist as a racemic mixture of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0231] Example

[0232] The following examples are offered for illustrative purposes.

[0233] General Procedure

[0234] All proton NMR experiments were recorded at 400 MHz on a Bruker NEO spectrometer equipped with a BBFO probe. Deuterated solvents contained less than 0.05% v / v tetramethylsilane, which was used as a reference signal (set at 0.00 ppm). When the deuterated solvent did not contain tetramethylsilane, the spectra were analyzed according to published guidelines ( J. Org. Chem. 1997, 62(21), 7512-7515) using the residual undeuterated solvent peak as a reference signal. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are expressed in Hertz (Hz). The split patterns depict significant multimodality and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintet), or brs (broad singlet).

[0235] LC / MS analyses were performed on an Agilent Technologies UHPLC 1290 Infinity II with a G6125 MS detector.

[0236] Microwave reactions were performed using standard protocols by Anton Paar GmbH with a Monowave 300.

[0237] NEK7 enzyme assay

[0238] Casein substrate (a hydrolyzed and partially dephosphorylated mixture of α, β, and κ caseins from bovine milk, obtained from Sigma-Aldrich, catalog #C4765, diluted in 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 #N09-10 G, 0.1 μg / μL) were mixed in assay buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO). Compounds of interest (serial 3-fold dilutions in DMSO, from 10 μM to 0.5 nM) or vehicle (1% DMSO) were dispensed into the kinase reaction mixture by acoustic technology (Echo550; nanoliter range). After incubation at room temperature for 20 min, the cells were incubated by adding [ 33The kinase reaction was initiated with [P]-ATP (specific activity 10 μCi / μl), and the mixture was incubated at room temperature for 2 hours. The reaction was then stopped by spotting the reaction mixture onto phosphocellulose P81 paper. After washing, the radioactivity of the P81 paper was measured, and the kinase activity data were expressed as the percentage of kinase activity remaining in the test sample compared to the vehicle reaction. IC values ​​were obtained using Prism (GraphPad Software). 50 values ​​and curve fitting.

[0239] IL-1β release assay

[0240] Approximately 1.5 million THP-1 cells are seeded in each well of 6-well TC plates and hatched 24 hours in RPMI (10% FBS, 1% Penstrep) with 40 nM PMA. The culture medium is then removed and the cells were left to stand for 24 hours in RPMI (10% FBS, 1% Penstrep), after which the culture medium is removed and the cells are pretreated for 2 hours with the compound of interest (usually 3 times of continuous dilution in RPMI+5%FBS, a concentration range of 1 μM to 0.5 nM) of the various concentrations in RPMI (5% FBS). The culture medium is removed again and the cells are hatched for 2 hours in RMPI (5% FBS) with 250 ng / mL LPS and the compound of interest (concentration as above). The culture medium is removed for the last time and the cells are hatched 30 minutes in Opti-MEM with 20 μM nigericin and the compound of interest (concentration as above). The cell culture medium is then collected and the amount of the IL-1 β of cracking is measured using JESS instrument (ProteinSimple) and standard protocol. Cleaved Il-1β antibody was obtained from Cell Signaling (Catalog #83186S) and used at a 1:20 dilution in Antibody Diluent 2. Protein Simple 1x anti-rabbit HRP secondary antibody was used with Protein Simple luminol and peroxide for chemiluminescent detection. The primary antibody incubation time was increased from 30 to 60 minutes.

[0241] abbreviation: °C (degrees Celsius); 1 H NMR (proton nuclear magnetic resonance); CAN (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 chromatography mass spectrometry); MeOH (methanol); mg (milligram); min (minute); 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 (tert-butyldimethylsilyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography).

[0242] Preparation of synthetic intermediates

[0243] Intermediate A

[0244] 4-Chloro-5-iodo-7-nitropropane H -pyrrolo[2,3- d ]pyrimidine

[0245] At 0°C N -iodosuccinimide (1.465 g, 6.51 mmol) was added to 4-chloro-7 H -pyrrolo[2,3- d To the stirred solution of pyrimidine (1.000 g, 6.51 mmol) in DMF (10 mL) was added and the resulting mixture was stirred at 25 ° C for 12 hours. After the reaction was complete (as 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 × 25 mL), and dried to give the title compound (1.7 g, 93% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 12.96 (bs, 1H), 8.60 (s, 1H), 7.95 (d, J = 2.40 Hz, 1H); LCMS: 279.9 [M+H].

[0246] Intermediate B1

[0247] 4-Chloro-7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidine

[0248] Copper(II) acetate (0.650 g, 3.58 mmol), 2,2'-bipyridine (0.559 g, 3.58 mmol) and sodium bicarbonate (0.601 g, 7.16 mmol) were added to 4-chloro-5-iodo-7 H -pyrrolo[2,3- d ] pyrimidine (Al, 1.000 g, 3.58 mmol) and cyclopropylboronic acid (0.615 g, 7.16 mmol) in a solution of dichloroethane (10 mL), and the resulting mixture was stirred at 70 ° C under an oxygen atmosphere for 12 hours. After the reaction was completed (as shown in TLC), the reaction mixture was filtered through a pad of celite, then cleaned with DCM (2 × 20 mL). The filtrate combined was washed with water (20 mL) and brine (25 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to obtain crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to obtain the title compound (0.7 g, 61% yield) as a pale solid. 1 HNMR (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].

[0249] Intermediate B2

[0250] 4-Chloro-5-iodo-7-(oxetan-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidine

[0251] K2CO3 (0.40 g, 2.86 mmol) and 3-iodooxetane (0.32 g, 1.71 mmol) were added to 4-chloro-5-iodo-7 H -pyrrolo[2,3- d ] pyrimidine (A, 0.40 g, 1.43 mmol) in DMF (5 mL) solution, and the resulting mixture was stirred at 90 ° C in a sealed tube for 16 hours. After the reaction was complete (as indicated by TLC), the reaction mixture was poured into crushed ice (50 g) and stirred for 15 minutes. The resulting solid was filtered, washed with water (2 × 5 mL), and dried to obtain the title compound (0.2 g, 42% yield) as a pale solid. LCMS: 335.7 [M+H].

[0252] Intermediate B3

[0253] 1-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2-methylpropan-2-ol

[0254] NaH2PO4 (0.105 g, 0.877 mmol) was added to 4-chloro-5-iodo-7 H -pyrrolo[2,3- d ] pyrimidine (Al, 0.250 g, 0.895 mmol), 2,2-dimethyloxirane (0.157 ml, 1.762 mmol) and K2CO3 (0.121 g, 0.877 mmol) in a mixture of ACN (3mL) and water (10mL). The gained mixture was subjected to microwave irradiation for 1 hour at 150 ° C in a sealed tube. After the reaction was completed (as shown in TLC), the reaction mixture was concentrated under reduced pressure, and the gained crude material was passed through into flash chromatography (silica gel 230-400 mesh, eluted with 18% EtOAc in petroleum ether) to obtain the title compound (0.1 g, 17% yield) as a light brown solid. LCMS: 351.9 [M+H].

[0255] Intermediate B4

[0256] 4-Chloro-5-iodo-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidine

[0257] Triethylamine (0.905 g, 8.95 mmol) and copper (II) acetate (0.975 g, 5.37 mmol) were added to 4-chloro-5-iodo-7 H -pyrrolo[2,3- d] pyrimidine (A, 1.000 g, 3.58 mmol) and 3-pyridylboronic acid (0.880 g, 7.16mmol) in DCM (25 mL) solution, and the resulting mixture was stirred at 40 ° C under an oxygen atmosphere for 40 hours. After the completion of the reaction (as shown in LCMS), the reaction mixture was filtered through a pad of celite, then cleaned with DCM (2 × 50 mL). The filtrate merged was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude material. It was stirred at 25 ° C for 30 minutes with 30% diethyl ether in petroleum ether, filtered, and dried to obtain the title compound (0.4 g, 29% yield) as a brown solid. 1 H 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].

[0258] Intermediate B5

[0259] 4-Chloro-5-iodo-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine

[0260] By following a similar procedure as described for B4, 4-chloro-5-iodo-7 H -pyrrolo[2,3- d The title compound was initially obtained by mixing pyrimidine (A, 0.50 g, 1.789 mmol) and 4-pyridylboronic acid (0.44 g, 3.580 mmol) and obtained as a brown solid (0.21 g, 29% yield). LCMS: 356.9 [M+H].

[0261] Intermediate B6

[0262] 4-Chloro-5-iodo-7-(1-methylpiperidin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine

[0263] The title compound was prepared as reported in PCT Publication No. WO 2017 / 220477.

[0264] Intermediate B7

[0265] 7-(3-(Benzyloxy)cyclobutyl)-4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidine

[0266] Cs2CO3 (0.583 g, 1.789 mmol) and 3-(benzyloxy)cyclobutyl methanesulfonate (prepared as reported in PCT Publication No. WO 2019 / 092170, 0.459 g, 1.789 mmol) were added to 4-chloro-5-iodo-7 H -pyrrolo[2,3- d ] pyrimidine (A, 0.250 g, 0.895 mmol) in DMF (5 mL) solution, and the resulting mixture was stirred at 90 ° C for 12 hours. After the reaction was completed (as shown in TLC), the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated under reduced pressure to give crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound (0.14 g, 31% yield) as colorless jelly. LCMS: 440.0 [M+H].

[0267] Intermediate B8

[0268] 2-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)ethan-1-ol

[0269] K2CO3 (0.742 g, 5.37 mmol) and 2-bromoethane-1-ol (0.537 g, 4.29 mmol) were added to 4-chloro-5-iodo-7 H -pyrrolo[2,3- d ] pyrimidine (A, 1.000 g, 3.58 mmol) in DMF (6 mL) solution, and the resulting suspension was stirred at 80 ° C for 2 hours. After the reaction was completed (as shown in TLC), the reaction mixture was poured into crushed ice (25 g). The resulting solid was filtered, washed with water (20 mL), and dried to obtain the title compound (0.84 g, 64% yield) as a yellow solid. LCMS: 323.9 [M+H].

[0270] Intermediate B9

[0271] 4-Chloro-1-cyclopropyl-3-iodo-1 H -pyrrolo[3,2- c ]pyridine

[0272] Step 1: Synthesis of 4-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine

[0273] Triethylamine (0.332 g, 3.280 mmol), copper(II) acetate (0.298 g, 1.638 mmol) and molecular sieves (powdered, 0.050 g) were added to 4-chloro-1 H To the 4-nitro-pyrrolo-[3,2-c] pyridine (0.250 g, 1.638 mmol) and cyclopropylboronic acid (0.279 g, 3.280 mmol) in DMF (10 mL) solution, and the resulting suspension was stirred at 60 ° C for 12 hours in a sealed tube. After the completion of the reaction (as shown in TLC), the reaction mixture was filtered through a celite pad, which was then cleaned with EtOAc. The filtrate merged was concentrated under reduced pressure to give crude material, which was then purified by Isolera (silica gel 230-400 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound (0.19 g, 59% yield) as a yellow solid. 1 H 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].

[0274] Step 2: Synthesis of 4-chloro-1-cyclopropyl-3-iodo-1H-pyrrolo[3,2-c]pyridine

[0275] Will N -iodosuccinimide (0.350 g, 1.557 mmol) was added to 4-chloro-1-cyclopropyl-1 H-pyrrolo [3,2-c] pyridine (0.200 g, 1.038 mmol) in DMF (5 mL), and the resulting mixture was stirred at 80 ° C for 1 hour. After the reaction was completed (as shown in LCMS), the reaction mixture was poured into crushed ice (25 g) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title product (0.2 g), which was used without further purification. LCMS: 319.0 [M+H].

[0276] Intermediate C1

[0277] 7-Cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0278] 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 microwave irradiated at 150° C. for 1 hour. After completion of the reaction (as shown by TLC), the reaction mixture was concentrated under reduced pressure to give the title compound (0.75 g, 80% yield) as an off-white solid. 1 HNMR (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].

[0279] Intermediate C2

[0280] 5-iodo-7-(oxetane-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0281] The title compound was prepared from 4-chloro-5-iodo-7-(oxetan-3-yl)-7-nitropropane via a similar procedure as described for C1. H -pyrrolo[2,3- d] pyrimidine (B2, 0.5 g, 1.49 mmol) and aqueous ammonium hydroxide solution (25% in water, 2.5 mL) were prepared and obtained as a light brown solid (0.27 g, 58% yield). LCMS: 316.8 [M+H].

[0282] Intermediate C3

[0283] 1-(4-amino-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2-methylpropan-2-ol

[0284] Following a similar procedure as described for C1, 1-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2-methylpropan-2-ol (B3, 0.1 g, 0.284 mmol) and ammonium hydroxide (25% in water, 0.5 mL) to obtain the title compound as an off-white solid (0.08 g, 85% yield). 1 H NMR (400 MHz, DMSO- d 6) 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].

[0285] Intermediate C4

[0286] 5-iodo-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0287] Ammonium hydroxide (25% in water, 1 mL) was added to 4-chloro-5-iodo-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d To the pyrimidine (B4, 0.30 g, 0.841 mmol) in a solution of dioxane (10 mL), the resulting mixture was subjected to microwave irradiation at 150 ° C for 2 hours. After the reaction was complete (as shown in LCMS), the reaction mixture was concentrated under reduced pressure to give crude material, which was washed with methyl tert-butyl ether and dried to give the title compound (0.21 g, 63% yield) as a pale solid. LCMS: 337.8 [M+H].

[0288] Intermediate C5

[0289] 5-iodo-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0290] Following a similar procedure as described for C4, 4-chloro-5-iodo-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d Starting with pyrimidine (B5, 0.21 g, 0.589 mmol) and ammonium hydroxide (25% in water, 1 mL), the title compound was obtained and obtained as an off-white solid (0.16 g, 69% yield). LCMS: 337.9 [M+H].

[0291] Intermediate C6

[0292] 5-iodo-7-(1-methylpiperidin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0293] The title compound was prepared as reported in PCT Publication No. WO 2017 / 220477.

[0294] Intermediate C7

[0295] 7-(3-(Benzyloxy)cyclobutyl)-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0296] By following a procedure analogous to that described for C4, 7-(3-(benzyloxy)cyclobutyl)-4-chloro-5-iodo-7 H -pyrrolo[2,3- d The title compound was initially obtained by mixing pyrimidine (B7, 0.140 g, 0.318 mmol) and ammonium hydroxide (25% in water, 1.4 mL) and obtained as an off-white solid (0.06 g, 45% yield). LCMS: 421.1 [M+H].

[0297] Intermediate C8

[0298] 5-iodo-7-(2-methoxyethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0299] The title compound was prepared as reported in PCT Publication No. WO 2014 / 184069A1.

[0300] Intermediate C9

[0301] 2-(4-amino-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)ethan-1-ol

[0302] By following a similar procedure as described for C4, 2-(4-chloro-5-iodo-7 H -pyrrolo[2,3- d

[0366] pyrimidin-7-yl)ethane-1-ol (B8, 0.84 g, 2.61 mmol) and ammonium hydroxide (25% in water, 8 mL) were used to initially obtain the title compound, which was obtained as an off-white solid (0.94 g, 69% yield). LCMS: 305.0 [M+H].

[0303] Intermediate C10

[0304] 7-cyclobutyl-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0305] The title compound was prepared as reported in PCT Publication No. WO 2016 / 075224.

[0306] Intermediate C11

[0307] 5-iodo-7-(1-methylpyrrolidin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0308] The title compound was prepared as reported in PCT Publication No. WO 2016 / 075224.

[0309] Intermediate D1

[0310] 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0311] 7-cyclopropyl-5-iodo-7 H-pyrrolo[2,3- d A mixture of pyrimidin-4-amine (C1, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol) and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 minutes. Pd(PPh3)4 was then added. To 4-nitro-2-nitro-2-oxo-4-nitro-1-oxo-2-nitro-2-oxo-4-nitro-2-oxo-2-nitro-3-nitro-2-oxo ... 1 H 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].

[0312] Intermediate D2

[0313] 5-(4-aminophenyl)-7-(oxetan-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0314] Step 1: 5-(4-nitrophenyl)-7-(oxetan-3-yl) -7 H - Pyrrolo [2,3- d ] Pyrimidine-4-amine synthesis

[0315] The title compound was prepared from 4-chloro-5-iodo-7-(oxetan-3-yl)-7-nitropropane via a similar procedure as described for D1. H -pyrrolo[2,3- d] pyrimidine (C2, 0.252 g, 0.797 mmol) and (4-nitrophenyl) boronic acid (0.200 g, 1.198 mmol) were prepared starting from the reaction mixture and obtained as a light brown solid (0.143 g, 58% yield). LCMS: 312.1 [M+H].

[0316] Step 2: 5-(4-aminophenyl)-7-(oxetan-3-yl) -7 H - Pyrrolo [2,3- d ] Pyrimidine-4-amine synthesis

[0317] Iron powder (0.251 g, 4.5 mmol) and ammonium chloride (0.240 g, 4.5 mmol) were added to 5-(4-nitrophenyl)-7-(oxetan-3-yl)-7 H -pyrrolo[2,3- d To the 4- amine (0.14 g, 0.45 mmol) in ethanol (5 mL) and water (2 mL) was added pyrimidine-4-amine (0.14 g, 0.45 mmol), and the resulting mixture was stirred at 80 ° C for 3 hours. After the reaction was complete (as shown in TLC), the mixture was filtered through a celite pad, then cleaned with EtOAc (2 x 5 mL). The filtrate merged was concentrated under reduced pressure to obtain residue, which was dissolved in EtOAc (25 mL), washed with salt solution (5 mL), through Na2SO4 dried, filtered, and concentrated under reduced pressure to obtain the title compound (0.12 g, quantitative yield) as a brown solid, which was used without further purification. LCMS: 281.9 [M+H].

[0318] Intermediate D3

[0319] 1-(4-amino-5-(4-amino-3-fluorophenyl)-7-nitropropene H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2-methylpropan-2-ol

[0320] By a method similar to that described for D1, 1-(4-amino-5-iodo-7 H -pyrrolo[2,3- dTo the mixture of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylamine (0.086 g, 0.361 mmol) and 2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.05 g, 0.361 mmol) was added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylamine (0.05 g, 0.361 mmol) to prepare the title compound and obtain it as a light yellow gum (0.05 g, 53% yield). LCMS: 316.1 [M+H].

[0321] Intermediate D4

[0322] 5-(4-aminophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0323] Step 1: 7-cyclopropyl-5-(4-nitrophenyl) -7 H - Pyrrolo [2,3- d ] Synthesis of pyrimidine-4-amine

[0324] By following a similar procedure as described for D1, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was initially obtained by mixing pyrimidin-4-amine (C1, 0.18 g, 0.60 mmol) and (4-nitrophenyl)boronic acid (0.12 g, 0.72 mmol) and was obtained as a light brown solid (0.10 g, 56% yield). 1 H 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].

[0325] Step 2: 5-(4-aminophenyl)-7-cyclopropyl -7 H - Pyrrolo [2,3- d ] Synthesis of pyrimidine-4-amine

[0326] Following a similar procedure as described for step 2 of D2, 7-cyclopropyl-5-(4-nitrophenyl)-7 H -pyrrolo[2,3- dThe title compound was obtained starting from 4-[(2-[(2-[(2-[(2-[(2-pyrimidin-4-amine (0.10 g, 0.33 mmol) and Fe / NH4Cl) was obtained and obtained as a brown gum (0.08 g, 90% yield)] which was used without further purification. 1 H 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].

[0327] Intermediate D5

[0328] 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0329] By following a similar procedure as described for D1, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d To the reaction mixture of 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) was added to give the title compound, which was obtained as a pale yellow gum (0.15 g, 76% yield). LCMS: 284.1 [M+H].

[0330] Intermediate D6

[0331] 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0332] Step 1: 7-cyclopropyl-5-(6-nitropyridin-3-yl) -7 H - Pyrrolo [2,3- d ] Synthesis of pyrimidine-4-amine

[0333] By following a similar procedure as described for D1, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- dThe title compound was obtained starting with pyrimidin-4-amine (C1, 0.28 g, 0.94 mmol) and 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.28 g, 1.13 mmol) and was obtained as a light brown solid (0.16 g, 57% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 8.73 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 8.8Hz, 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].

[0334] Step 2: 5-(6-aminopyridin-3-yl)-7-cyclopropyl -7 H - Pyrrolo [2,3- d ] Synthesis of pyrimidine-4-amine

[0335] By following a similar procedure as described for step 2 of D2, the 7-cyclopropyl-5-(6-nitropyridin-3-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (0.16 g, 0.54 mmol) and Fe / NH4Cl and obtained as a light brown solid (0.1 g, 70% yield) which was used without further purification. LCMS: 267.0 [M+H].

[0336] Intermediate D7

[0337] 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0338] Step 1: (4-(4-amino-7-cyclopropyl) -7 H - Pyrrolo [2,3- d ] Pyrimidin-5-yl)cyclohex-3-en-1-yl)amino Synthesis of tert-Butyl Formate

[0339] K2CO3 (0.318 g, 2.299 mmol) was added to 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d ] pyrimidine-4-amine (Cl, 0.230 g, 0.766 mmol) and (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohex-3-ene-1-yl) tert-butyl carbamate (0.372 g, 1.150 mmol) in dioxane (1 mL) and water (0.3 mL).Solution N2 was purged 10 minutes, then Pd(PPh3)4 (0.044 g, 0.038 mmol), and gained mixture was subjected to microwave irradiation for 1 hour at 100 ° C.After the reaction was completed (as shown in TLC), the mixture was filtered through a celite pad, then cleaned with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC (eluting with a gradient of ammonium acetate in water and ACN based on mass) to give the title product (0.18 g, 62% yield) as a pale yellow gum. LCMS: 370.2 [M+H].

[0340] Step 2: 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl -7 H - Pyrrolo [2,3- d ] Synthesis of pyrimidine-4-amine become

[0341] TFA (0.012 g, 0.108 mmol) was added to (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d To the methyl group was added 4-[[(4-[ ...

[0342] Intermediate D8

[0343] 5-(4-amino-3-fluorophenyl)-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0344] 5-iodo-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d ] 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 K cO a mixture of (0.131 g, 0.949 mmol) in dioxane (5 mL), water (2 mL) and ethanol (3 mL) was purged with N for 10 minutes. PdCl (dppf) (0.017 g, 0.024 mmol) was added and the resulting mixture was subjected to microwave irradiation at 100 ° C for 1 hour. After the reaction was complete (as shown in LCMS), the reaction mixture was filtered through a celite pad, then washed with EtOAc (5 mL). The filtrate merged is concentrated under reduced pressure to obtain residue, which is dissolved in EtOAc (50 mL), washed with water (5 mL) and salt solution (5 mL), over NaSODry, filtered and concentrated under reduced pressure. The resulting crude material is purified by GRACE (silica gel 230-400 mesh, eluted with 4% MeOH in DCM) to obtain the title compound (0.2 g, 70% yield) as a brown solid. LCMS: 321.0 [M+H].

[0345] Intermediate D9

[0346] 5-(4-amino-3-fluorophenyl)-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0347] Following a similar procedure as described for D8, 5-iodo-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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) and obtained as a light yellow gum (0.08 g, 51% yield). LCMS: 321.0 [M+H].

[0348] Intermediate D10

[0349] 5-(4-amino-3-fluorophenyl)-7-(1-methylpiperidin-4-yl)-7 H-pyrrolo[2,3- d ]pyrimidin-4-amine

[0350] By following a similar procedure as described for D8, 5-iodo-7-(1-methylpiperidin-4-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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) and obtained as a brown gum (0.15 g, 80% yield). LCMS: 341.1 [M+H].

[0351] Intermediate D11

[0352] 5-(4-amino-3-methylphenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0353] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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) and obtained as a brown gum (0.13 g, 56% yield). LCMS: 280.1 [M+H].

[0354] Intermediate D12

[0355] 5-(4-amino-3-fluorophenyl)-7-(3-(benzyloxy)cyclobutyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0356] By following a similar procedure as described for D8, 7-(3-(benzyloxy)cyclobutyl)-5-iodo-7 H -pyrrolo[2,3- dThe title compound was obtained starting with 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) and obtained as a brown solid (0.03 g, 53% yield). LCMS: 404.2 [M+H].

[0357] Intermediate D13

[0358] Step 1: 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -7 H - Pyrrole and [2,3- d ] Synthesis of pyrimidine-4-amine

[0359] Potassium acetate (0.245 g, 2.499 mmol) was added to 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d ] pyrimidine-4-amine (Cl, 0.250 g, 0.833 mmol) and bis(pinacolato) diboron (0.317 g, 1.250 mmol) in DMSO (5mL) solution, and the resulting mixture was purged with N2 for 10 minutes. Then PdCl2(dppf) (0.030 g, 0.042 mmol) was added, and the reaction mixture was stirred at 85 ° C for 2 hours. After the reaction was complete, the reaction mixture was filtered through a celite pad, which was then washed with DCM (2 × 20 mL). The combined filtrate was concentrated under reduced pressure to give the title compound as a black residue, which was used without further purification. LCMS: 300.9 [M+H].

[0360] Step 2: 5-(5-amino-4-methylpyridin-2-yl)-7-cyclopropyl -7 H - Pyrrolo [2,3- d ] Pyrimidine-4-amine synthesis

[0361] By following a similar procedure as described for D8, the product was synthesized from 6-bromo-4-methylpyridin-3-amine (0.142 g, 0.759 mmol) and 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-ylpyridin-3-amine (0.142 g, 0.759 mmol). H -pyrrolo[2,3- dThe title compound was obtained starting with pyrimidin-4-amine (0.251 g, 0.835 mmol) and was obtained as a brown gum (0.05 g, 13% yield). LCMS: 281.0 [M+H].

[0362] Intermediate D14

[0363] 5-(5-aminopyridin-2-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0364] By following a similar procedure as described for D8, the product was synthesized from 6-bromo-4-methylpyridin-3-amine (0.130 g, 0.751 mmol) and 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-ylpyridin-3-amine (0.130 g, 0.751 mmol). H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (step 1 of intermediate D13, 0.248 g, 0.827 mmol) and was obtained as a brown gum (0.03 g, 4.5% yield). LCMS: 267.0 [M+H].

[0365] Intermediate D15

[0366] 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0367] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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) and obtained as a light yellow solid (0.10 g, 19% yield). LCMS: 302.1 [M+H].

[0368] Intermediate D16

[0369] 5-(4-amino-2,5-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0370] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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 publication No. WO 2017 / 172093, 0.106 g, 4.17 mmol) and obtained as a light yellow solid (0.05 g, 40% yield). LCMS: 302.1 [M+H].

[0371] Intermediate D17

[0372] 5-(4-amino-2,6-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0373] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (C1, 0.055 g, 0.183 mmol) and 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (prepared as reported in PCT Publication No. WO 2017 / 172093, 0.056 g, 0.220 mmol) and obtained as a light brown gum (0.046 g) which was used without further purification. LCMS: 301.9 [M+H].

[0374] Intermediate D18

[0375] 1-(4-amino-5-(6-aminopyridin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2-methylpropan-2-ol

[0376] By following a similar procedure as described for D8, the product was prepared from 1-(4-amino-5-iodo-7 H -pyrrolo[2,3- dTo the reaction mixture was added 4-[ ...

[0377] Intermediate D19

[0378] 5-(2-aminopyrimidin-5-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0379] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (C1, 0.25 g, 0.833 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.184 g, 0.833 mmol) and obtained as a colorless gum (0.08 g, 34% yield). LCMS: 268.2 [M+H].

[0380] Intermediate D20

[0381] (2-amino-5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanol

[0382] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (C1, 0.200 g, 0.666 mmol) and (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanol (prepared as reported in PCT Publication No. WO 2011 / 130628, 0.184 g, 0.733 mmol) and obtained as a light yellow gum (0.025 g, 13% yield). LCMS: 296.0 [M+H].

[0383] Intermediate D21

[0384] 2-amino-5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzonitrile

[0385] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.203 g, 0.833 mmol) and obtained as a yellow gum (0.13 g, 34% yield). LCMS: 291.2 [M+H].

[0386] Intermediate D22

[0387] 5-(4-amino-3-fluorophenyl)-7-(2-methoxyethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0388] By following a similar procedure as described for D8, 5-iodo-7-(2-methoxyethyl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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) and obtained as a light brown solid (0.12 g, 42% yield). LCMS: 302.2 [M+H].

[0389] Intermediate D23

[0390] 2-(4-amino-5-(4-amino-3-fluorophenyl)-7-nitropropene H -pyrrolo[2,3- d ]pyrimidin-7-yl)ethan-1-ol

[0391] By following a similar procedure as described for D8, 2-(4-amino-5-iodo-7 H -pyrrolo[2,3- dThe title compound was obtained starting with 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.39 g, 1.644 mmol) and obtained as a brown solid (0.3 g, 63% yield). LCMS: 288.1 [M+H].

[0392] Intermediate D24

[0393] 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0394] By following a similar procedure as described for D8, 7-cyclobutyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (C10, 0.410 g, 1.305 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.309 g, 1.305 mmol) and was obtained as a brown solid (0.18 g, 37% yield). 1 H 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].

[0395] Intermediate D25

[0396] 5-(4-amino-3-chlorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0397] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- dThe title compound was obtained starting with 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) and obtained as a yellow solid (0.03 g, 12% yield). LCMS: 300.1 [M+H].

[0398] Intermediate D26

[0399] 5-(4-amino-3-methoxyphenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0400] By following a similar procedure as described for D8, 7-cyclopropyl-5-iodo-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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) and obtained as a light yellow gum (0.04 g, 16% yield). LCMS: 296.1 [M+H].

[0401] Intermediate D27

[0402] 5-(4-amino-3-fluorophenyl)-7-(1-methylpyrrolidin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

[0403] By following a similar procedure as described for D8, 5-iodo-7-(1-methylpyrrolidin-3-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with 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) and obtained as a brown solid (0.084 g, 27% yield). LCMS: 327.2 [M+H].

[0404] Intermediates E1-E25

[0405] General procedure for the synthesis of carbamate intermediate E: At 0 ℃, pyridine (1.2 equivalents) and phenylchloroformate (1.5 equivalents) are added into the solution of amine (1.0 equivalent) in THF (10 volumes).The reaction mixture is made to be warming up to 25 ℃ and stirred 12 hours.After reaction is accomplished (as shown in TLC), mixture is diluted with EtOAc (10 mL) and washed with salt solution (5mL).With organic layer through Na sO dry, filter, and under reduced pressure concentrate, obtain roughage, by it by flash chromatography (silica gel 230-400 order, with 10% to 20%EtOAc in oil) purifying, obtain required carbamate.

[0406] The following carbamates were prepared using the general procedure described above:

[0407] All amines used in the synthesis of carbamate intermediate E are commercially available except the following: like Synthesis 2013, 45, 171–173 reported the synthesis of 3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-amine (precursor of E6) and 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (precursor of E7).

[0408] 3-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-5-amine (precursor of E8) and 3-(2-fluoroprop-2-yl)isoxazol-5-amine (precursor of E9) were synthesized from 3,3,3-trifluoro-2,2-dimethylpropanoic acid methyl ester and 2-fluoro-2-methylpropanoic acid methyl ester, respectively, and then Synthesis Proceedings reported in 2013, 45, 171–173.

[0409] The synthesis of 3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-amine (precursor of E16) was reported in PCT Publication No. WO 2010 / 036630.

[0410] like J. Med. Chem. 2012, 55(3), 1082-1105 reported the synthesis of 2-(5-aminoisoxazol-3-yl)-2-methylpropionitrile (precursor of E22) and 3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-amine (precursor of E24).

[0411] The synthesis of 3-(((tert-butyldiphenylsilyl)oxy)methyl)isoxazol-5-amine (precursor of E23) was reported in PCT Publication No. WO 2013 / 104561.

[0412] 5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-amine (precursor of E25) was synthesized as disclosed in PCT No. WO 2011 / 022473.

[0413] Synthesis of 3-(3-methyloxetane-3-yl)isoxazol-5-amine (precursor of E14):

[0414] NH2OH H2SO4 (0.520 g, 3.16 mmol) was added to a solution of 3-(3-methyloxetane-3-yl)-3-oxopropionitrile (prepared as reported in PCT 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 an aqueous NaOH solution (1 M), and the reaction mixture was stirred at 80 ° C for 15 hours. After the reaction was completed (as shown by TLC), the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in EtOAc (25 mL), washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (silica gel 230-400 mesh, eluting with 30% EtOAc in petroleum ether) to give the title product (0.09 g, 20% yield) as a light brown solid. 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].

[0415] Synthesis of 3-(1-methylcyclobutyl)isoxazol-5-amine (precursor of E21):

[0416] NH2OH·H2SO4 (0.699 g, 4.25 mmol) was added to a solution of 3-(1-methylcyclobutyl)-3-oxopropionitrile (prepared as reported in PCT 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 an aqueous NaOH solution (1 M), and the reaction mixture was stirred at 80 ° C for 15 hours. After the reaction was complete (as shown by TLC), the reaction mixture was concentrated under reduced pressure to give a residue, which was placed in DCM (25 mL), washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (silica gel 230-400 mesh, eluting with 40% EtOAc in petroleum ether) to give the title product as an off-white solid (0.110 g, 19% yield). 1 H NMR (400 MHz, CDCl3) δ = 5.04 (s, 1H), 2.43-2.49 (m, 2H), 1.96-2.02 (m, 4H), 1.50 (s, 3H). LCMS:153.2 [M+H].

[0417] Preparation of Examples

[0418] General Urea Formation Procedure for Synthesis of Examples 1 to 62

[0419] 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 completion of the reaction (as shown by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by reverse phase preparative HPLC to give the desired product.

[0420] 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 completion of the reaction (as shown by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by reverse phase preparative HPLC to give the desired product.

[0421] The following compounds were prepared using the general method described above.

[0422] Example 1

[0423] 1-(4-(4-amino-7-(oxetan-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0424] According to the general procedure for urea formation (Method A), 5-(4-aminophenyl)-7-(oxetan-3-yl)-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.16 g, 0.30 mmol) and was obtained as an off-white solid (0.026 g, 9% yield). 1 H 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].

[0425] Example 2

[0426] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0427] According to the general procedure for urea formation (Method A), 5-(4-aminophenyl)-7-(oxetan-3-yl)-7 H -pyrrolo[2,3- dThe title compound was prepared starting from pyrimidin-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.16 g, 0.30 mmol) and was obtained as an off-white solid (0.026 g, 9% yield). 1 H 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].

[0428] Example 3

[0429] 1-(5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0430] According to the general procedure for urea formation (Method A), 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D6, 0.100 g, 0.376 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.098 g, 0.386 mmol) and was 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].

[0431] Example 4

[0432] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea

[0433] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (5-(tert-butyl)isoxazol-3-yl)carbamate (E2, 0.091 g, 0.35 mmol) and was obtained as an off-white solid (0.021 mg, 13% yield). 1 H 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].

[0434] Example 5

[0435] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0436] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.088 g, 0.282 mmol) and was obtained as a white solid (0.031 mg, 22% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 10.59 (bs, 1H), 8.84 (bs, 1H), 8.11-8.17 (m, 2H), 7.26-7.37 (m, 3H), 6.20 (s, 1H), 6.16 (bs, 2H), 3.55-3.61 (m, 1H), 1.45-1.49 (m, 2H), 1.38-1.43 (m, 2H), 1.03-1.08 (m, 4H). LCMS: 502.1 [M+H].

[0437] Example 6

[0438] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0439] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.060 g, 0.180 mmol) and phenyl (5-cyclopropylisoxazol-3-yl)carbamate (E5, 0.044 g, 0.282 mmol) and was 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].

[0440] Example 7

[0441] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-methylisoxazol-5-yl)urea

[0442] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H-pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (3-methylisoxazol-5-yl)carbamate (E3, 0.077 g, 0.35 mmol) and was obtained as an off-white solid (0.024 mg, 17% yield). 1 H 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].

[0443] Example 8

[0444] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea

[0445] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.127 g, 0.44 mmol) and phenyl (5-methylisoxazol-3-yl)carbamate (E4, 0.097 g, 0.44 mmol) and was obtained as a white solid (0.033 mg, 18% yield). 1 H 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].

[0446] Example 9

[0447] 1-(4-(4-amino-7-cyclopropyl-7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

[0448] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.076 g, 0.26 mmol) and phenyl (3-(2-fluoropropan-2-yl)isoxazol-5-yl)carbamate (E9, 0.070 g, 0.26 mmol) and was obtained as a white solid (0.018 g, 14% yield). 1 H 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].

[0449] Example 10

[0450] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0451] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.10 g, 0.35 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.11 g, 0.35 mmol) and was obtained as an off-white solid (0.010 g, 6% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 9.99 (bs, 1H), 8.86 (bs, 1H), 8.14-8.18 (m, 2H), 7.24-7.36 (m, 3H), 6.90 (s, 1H), 6.15 (bs, 2H), 3.56-3.61 (m, 1H), 1.48-1.57 (m, 4H), 1.02-1.07 (m, 4H). LCMS: 502.2 [M+H].

[0452] Example 11

[0453] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-3-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0454] According to the general procedure for urea formation (Method A), 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D5, 0.070 g, 0.24 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.082 g, 0.24 mmol) and was obtained as an off-white solid (0.011 g, 9% yield). 1 H NMR (400 MHz, DMSO- d 6) 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].

[0455] Example 12

[0456] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea

[0457] According to the general procedure for urea formation (Method A), 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)carbamate (E8, 0.055 g, 0.176 mmol) and was obtained as an off-white solid (9.9 mg, 11% yield). 1 H 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].

[0458] Example 13

[0459] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0460] According to the general procedure for urea formation (Method A), 5-(4-aminophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D4, 0.080 g, 0.30 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.078 g, 0.30 mmol) and was obtained as an off-white solid (0.036 g, 28% yield). 1 H 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].

[0461] Example 14

[0462] 1-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0463] According to the general procedure for urea formation (Method A), 1-(4-amino-5-(4-amino-3-fluorophenyl)-7 H -pyrrolo[2,3- d The title compound was prepared starting from (4-(4-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.085 g, 0.273 mmol) and obtained as a light brown solid (0.011 g, 8% yield). 1 H NMR (400 MHz, DMSO- 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].

[0464] Example 15

[0465] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)cyclohex-3-en-1-yl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0466] According to the general procedure for urea formation (Method A), 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was prepared starting from pyrimidin-4-amine (D7, 0.120 g, 0.446 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.116 g, 0.446 mmol) and was obtained as an off-white solid (0.013 g, 7% yield). 1 H 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].

[0467] Example 16

[0468] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)cyclohexyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0469] Platinum oxide (0.016 g, 0.069 mmol) was added to 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d To the 4-thiazolyl-2-ol (4-(4-(4-pyrimidine-5-yl)cyclohexamethylene-3-ene-1-yl)-3-(3-(tert-butyl)isoxazole-5-yl)urea (embodiment 15, 0.100 g, 0.230 mmol) in a solution of EtOAc (5 mL), and by gained suspension at room temperature under H2atmosphere, stirred 12 hours. After the completion of the reaction (as shown in LCMS), reaction mixture was filtered through a diatomaceous earth pad, then cleaned with EtOAc (2x5 mL). The filtrate merged was concentrated under reduced pressure to obtain crude material, which was passed through into preparative HPLC (based on mass, with the gradient elution of ammonium acetate in water and ACN) to obtain the title product (2.0 mg, 2% yield) as pale solid. 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].

[0470] Example 17

[0471] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclopropyl)isoxazol-5-yl)urea

[0472] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1-methylcyclopropyl)isoxazol-5-yl)carbamate (E10, 0.046 g, 0.176 mmol) and was obtained as an off-white solid (0.013 g, 16% yield). 1 H 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].

[0473] Example 18

[0474] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(tert-butyl)thiazol-2-yl)urea

[0475] According to the general procedure for urea formation (Method A), (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with phenyl (4-(tert-butyl)thiazol-2-amine) (0.015 g, 0.099 mmol) and 4-(tert-butyl)thiazol-2-amine (0.015 g, 0.099 mmol) and was obtained as an off-white solid (7.0 mg, 15% yield). 1 H 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].

[0476] Example 19

[0477] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)urea

[0478] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (5-(tert-butyl)-1,3,4-thiadiazol-2-yl)carbamate (E12, 0.049 g, 0.176 mmol) and was obtained as an off-white solid (2.0 mg, 2% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.19-8.23 (m, 2H), 7.30-7.35 (m, 2H), 7.23 (s, 1H), 3.50-3.54 (m, 1H), 1.49 (s, 9H), 1.08-1.17 (m, 4H). LCMS: 466.9 [M+H].

[0479] Example 20

[0480] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isothiazol-5-yl)urea

[0481] According to the general procedure for urea formation (Method A), (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with phenyl (4-(tert-butyl)thiazol-2-amine) (0.015 g, 0.099 mmol) and 4-(tert-butyl)thiazol-2-amine (0.015 g, 0.099 mmol) and was obtained as an off-white solid (2.0 mg, 4% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.21 (s, 1H), 8.11-8.17 (m, 1H), 7.30-7.34 (m, 2H), 7.23 (s, 1H), 6.78 (s, 1H), 3.50-3.54 (m, 1H), 1.35 (s, 9H), 1.08-1.30 (m, 4H). LCMS: 466.0 [M+H].

[0482] Example 21

[0483] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)urea

[0484] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(tert-butyl)-1,2,4-thiadiazol-5-yl)carbamate (E13, 0.049 g, 0.176 mmol) and was obtained as an off-white solid (8.0 mg, 10% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 11.54 (bs, 1H), 9.00 (bs, 1H), 8.09-8.18 (m, 2H), 7.28-7.39 (m, 3H), 6.19 (bs, 2H), 3.57-3.61 (m, 1H), 1.34 (s, 9H), 1.03-1.05 (m,4H). LCMS: 467.0 [M+H].

[0485] Example 22

[0486] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(1-(tert-butyl)-1 H -1,2,4-triazol-3-yl)urea

[0487] According to the general procedure for urea formation (Method A), (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)carbamic acid phenyl ester (E11, 0.040 g, 0.099 mmol) and 1-(tert-butyl)-1 H The title compound was obtained starting with -1,2,4-triazol-3-amine (0.014 g, 0.099 mmol) and was obtained as an off-white solid (3.0 mg, 6% yield). 1 H 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].

[0488] Example 23

[0489] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)urea

[0490] According to the general procedure for urea formation (Method A), (4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with phenyl (5-(4-[(2-(4-pyrimidin-5-yl)-2-fluorophenyl)carbamate) (E11, 0.040 g, 0.099 mmol) and 5-(tert-butyl)-1,3,4-oxadiazol-2-amine (0.014 g, 0.099 mmol) and was obtained as an off-white solid (2.0 mg, 4% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.35 (s, 1H), 8.26-8.30 (m, 1H), 7.48 (s, 1H), 7.31-7.40 (m, 2H), 3.69-3.71 (m, 1H), 1.45 (s, 9H), 1.17-1.22 (m, 4H). LCMS:451.0 [M+H].

[0491] Example 24

[0492] 1-(4-(4-amino-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0493] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-(pyridin-3-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D8, 0.100 g, 0.312 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.107 g, 0.343 mmol) and was obtained as a white solid (0.023 g, 14% yield). 1 H 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].

[0494] Example 25

[0495] 1-(4-(4-amino-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0496] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-(pyridin-4-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D9, 0.080 g, 0.250 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.086 g, 0.275 mmol) and was obtained as an off-white solid (0.046 g, 33% yield). 1 H 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].

[0497] Example 26

[0498] 1-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0499] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-(1-methylpiperidin-4-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D10, 0.020 g, 0.059 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.018 g, 0.059 mmol) and was obtained as a white solid (2.4 mg, 7% yield). 1 H 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].

[0500] Example 27

[0501] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(3-methyloxetan-3-yl)isoxazol-5-yl)urea

[0502] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting from pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(3-methyloxetan-3-yl)isoxazol-5-yl)carbamate (E14, 0.048 g, 0.176 mmol) and was obtained as a white solid (3.4 mg, 4% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 10.56 (s, 1H), 8.94 (bs, 1H), 8.42 (s, 1H), 8.19 (t, J = 8.4 Hz, 1H), 7.57 (bs, 3H), 7.38 (d, J = 10.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.22 (s, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.52 (d, J = 5.6 Hz, 2H), 3.68-3.69 (m, 1H), 1.63 (s, 3H), 1.09-1.10 (m, 4H). LCMS: 464.1 [M+H].

[0503] Example 28

[0504] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea

[0505] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(trifluoromethyl)isoxazol-5-yl)carbamate (E15, 0.048 g, 0.176 mmol) and was obtained as a white solid (2.9 mg, 4% yield). 1 H 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].

[0506] Example 29

[0507] 1-(4-(4-amino-7-cyclopropyl-7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)urea

[0508] Step 1: 1-(4-(4-amino-7-cyclopropyl) -7 H - Pyrrolo [2,3- d ] Pyrimidin-5-yl)-2-fluorophenyl)-3- Synthesis of (3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-yl)urea

[0509] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.131 g, 0.461 mmol) and phenyl (3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-yl)carbamate (E16, 0.180 g, 0.461 mmol) and obtained as an off-white solid (0.013 g, 5% yield). LCMS: 580.0 [M+H].

[0510] Step 2: 1-(4-(4-amino-7-cyclopropyl) -7 H - Pyrrolo [2,3- d ] Pyrimidin-5-yl)-2-fluorophenyl)-3- Synthesis of (3-(1-hydroxy-2-methylpropane-2-yl)isoxazol-5-yl)urea

[0511] TBAF (1 M in THF, 0.067 ml) was added to 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d To the HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC to give the title compound (TFA salt, 2.2 mg, 21% yield) of 4-((tert-butyldimethylsilyl)oxy)-2-methylprop-2-yl)isoxazol-5-yl)urea (0.013 g, 0.022 mmol) in THF (2 ml). The resulting solution was stirred at 25° C. for 4 hours. After the reaction was complete (as shown by TLC), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give the title compound (TFA salt, 2.2 mg, 21% yield) as a white solid. 1 HNMR (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].

[0512] Example 30

[0513] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0514] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.055 g, 0.194 mmol) and phenyl (3-(sec-butyl)isoxazol-5-yl)carbamate (E17, 0.051 g, 0.194 mmol) and was obtained as a white solid (0.012 g, 14% yield). 1 H 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].

[0515] Example 31

[0516] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(pentan-3-yl)isoxazol-5-yl)urea

[0517] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(pentan-3-yl)isoxazol-5-yl)carbamate (E18, 0.048 g, 0.176 mmol) and was obtained as a white solid (0.016 g, 19% yield). 1 H 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].

[0518] Example 32

[0519] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea

[0520] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.056 g, 0.198 mmol) and phenyl (3-isopropylisoxazol-5-yl)carbamate (E19, 0.049 g, 0.198 mmol) and was obtained as an off-white solid (0.018 g, 21% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 10.34 (bs, 1H), 8.81 (bs, 1H), 8.12-8.16 (m, 2H), 7.25-7.36 (m, 3H), 6.15 (bs, 2H), 6.04 (s, 1H), 3.55-3.59 (m, 1H), 2.89-2.96 (m, 1H), 1.21-1.25 (m, 6H), 1.07-1.09 (m, 4H). LCMS: 436.0 [M+H].

[0521] Example 33

[0522] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-ethylisoxazol-5-yl)urea

[0523] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.061 g, 0.215 mmol) and phenyl (3-ethylisoxazol-5-yl)carbamate (E20, 0.050 g, 0.215 mmol) and was obtained as an off-white solid (0.020 g, 22% yield). 1 H NMR (400 MHz, DMSO- d 6) 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].

[0524] Example 34

[0525] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclobutyl)isoxazol-5-yl)urea

[0526] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.075 g, 0.265 mmol) and phenyl (3-(1-methylcyclobutyl)isoxazol-5-yl)carbamate (E21, 0.072 g, 0.265 mmol) and was obtained as a white solid (6.8 mg, 5% yield). 1 H 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].

[0527] Example 35

[0528] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)urea

[0529] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting from pyrimidin-4-amine (D1, 0.070 g, 0.247 mmol) and phenyl (3-(2-cyanopropan-2-yl)isoxazol-5-yl)carbamate (E22, 0.067 g, 0.247 mmol) and was obtained as a white solid (4.1 mg, 3% yield). 1H 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].

[0530] Example 36

[0531] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(hydroxymethyl)isoxazol-5-yl)urea

[0532] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (D1, 0.250 g, 0.882 mmol) and phenyl (3-(((tert-butyldimethylsilyl)oxy)methyl)isoxazol-5-yl)carbamate (E23, 0.308 g, 0.882 mmol) were used to obtain the title compound and was obtained as an off-white solid (0.029 g, 8% yield). 1 H 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 [M H].

[0533] Note: Cleavage of the TBDMS group was observed during purification when eluting with a gradient of 10 mM ammonium acetate in water and ACN.

[0534] Example 37

[0535] 1-(5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0536] According to the general procedure for urea formation (Method A), 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D6, 0.300 g, 1.127 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.352 g, 1.127 mmol) and was obtained as an off-white solid (0.018 g, 3% yield). 1 H NMR (400 MHz, DMSO- d 6) 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].

[0537] Example 38

[0538] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methylphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0539] According to the general procedure for urea formation (Method A), 5-(4-amino-3-methylphenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D11, 0.270 g, 0.967 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.302 g, 0.967 mmol) and was obtained as an off-white solid (0.080 g, 16% yield). 1 H 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].

[0540] Example 39

[0541] 1-(4-(4-amino-7-(3-hydroxycyclobutyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0542] Step 1: 1-(4-(4-amino-7-(3-(benzyloxy)cyclobutyl) -7 H - Pyrrolo [2,3- d ] Pyrimidin-5-yl)-2- (fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isothiazolyl)propane Nausea Synthesis of 5-oxazol-5-yl urea

[0543] According to the general procedure for urea formation (Method B), 5-(4-amino-3-fluorophenyl)-7-(3-(benzyloxy)cyclobutyl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D12, 0.033 g, 0.082 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.028 g, 0.090 mmol) and obtained as a pale gum (0.038 g, 29% yield). LCMS: 622.3 [M+H].

[0544] Step 2: 1-(4-(4-amino-7-(3-hydroxycyclobutyl) -7 H - Pyrrolo [2,3- d ] Pyrimidin-5-yl)-2-fluorobenzene Synthesis of 3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0545] Boron trichloride (1 M in DCM, 0.901 mL, 0.901 mmol) was added dropwise to 1-(4-(4-amino-7-(3-(benzyloxy)cyclobutyl)-7 H -pyrrolo[2,3- d To the solution of 4-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.070 g, 0.113 mmol) in DCM (5 mL) was added 4-(3-[[(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl]-pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.070 g, 0.113 mmol) in DCM (5 mL), and the resulting mixture was stirred at 0 ° C for 3 hours. After the reaction was complete (as shown by TLC and LCMS), the reaction mixture was cooled to -70 ° C, neutralized with NH4OH (25% in water), and extracted with DCM (2 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude material, which was purified by preparative HPLC (eluted with a gradient of 1% TFA in water and ACN) to give the title product (0.012 g, 20% yield) as a white solid. 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].

[0546] Example 40

[0547] 1-(6-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-4-methylpyridin-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0548] According to the general procedure for urea formation (Method A), 5-(5-amino-4-methylpyridin-2-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D13, 0.050 g, 0.102 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.032 g, 0.102 mmol) and was obtained as an off-white solid (8 mg, 16% yield).1 H 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].

[0549] Example 41

[0550] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,6-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0551] According to the general procedure for urea formation (Method B), 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D15, 0.080 g, 0.266 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.083 g, 0.266 mmol) and was obtained as an off-white solid (8 mg, 5.6% yield). 1 H NMR (400 MHz, DMSO- d 6) 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].

[0552] Example 42

[0553] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d]pyrimidin-5-yl)-2,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0554] According to the general procedure for urea formation (Method B), 5-(4-amino-2,5-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D16, 0.100 g, 0.332 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.104 g, 0.332 mmol) and was obtained as an off-white solid (8 mg, 5% yield). 1 H 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].

[0555] Example 43

[0556] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0557] According to the general procedure for urea formation (Method B), 5-(4-amino-2,6-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D17, 0.0724 g, 0.240 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.075 g, 0.240 mmol) and was obtained as an off-white solid (3 mg, 2% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 8.14 (s, 1H), 7.39-7.42 (m, 2H), 7.24 (s, 1H), 6.15 (s, 1H), 6.02 (bs, 2H), 3.58-3.59 (m, 1H), 1.36-1.44 (m, 4H), 1.03-1.05 (m, 4H). LCMS: 520.2 [M+H].

[0558] Example 44

[0559] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0560] Step 1: 1-(5-Bromo-3-fluoropyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea Synthesis

[0561] The title compound was obtained following the general procedure for urea formation (Method B) starting from 5-bromo-3-fluoropyridin-2-amine (0.040 g, 0.209 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.065 g, 0.209 mmol) and obtained as a light yellow solid (0.020 g, 23% yield). LCMS: 410.9 [M+H].

[0562] Step 2: 1-(4-(4-amino-7-cyclopropyl) -7 H - Pyrrolo[2,3-d]pyrimidin-5-yl)-3,5-difluorophenyl)- Synthesis of 3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0563] Following a similar procedure for intermediate D8, the product was prepared from 1-(5-bromo-3-fluoropyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.020 g, 0.049 mmol) and (tert-butoxycarbonyl)(7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-yl)-1-[4-(2-methyl-3-thiazolyl)-1-yl] ... H -pyrrolo[2,3- d The title compound was obtained starting with tert-butyl 4-[(4-[(4-pyrimidin-4-yl)methyl]-pyrimidin-4-yl)carbamate (prepared as reported in PCT Publication No. WO 2018 / 015879, 0.024 g, 0.049 mmol) and was obtained as an off-white solid (2 mg, 7% yield). 1H NMR (400 MHz, CD3OD) δ = 8.32-8.33 (m, 2H), 7.81-7.84 (m, 1H), 7.50 (s, 1H), 6.42 (s, 1H), 3.60-3.68 (m, 1H), 1.41-1.50 (m, 4H), 1.13-1.23 (m, 4H). LCMS: 503.1 [M+H]. Note: Cleavage of the Boc group was observed during the reaction.

[0564] Example 45

[0565] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-yl)urea

[0566] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-yl)carbamate (E24, 0.092 g, 0.282 mmol) and was obtained as an off-white solid (0.035 g, 22% yield). 1 H 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].

[0567] Example 46

[0568] 1-(5-(4-amino-7-(2-hydroxy-2-methylpropyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0569] According to the general procedure for urea formation (Method B), 1-(4-amino-5-(6-aminopyridin-3-yl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with (4-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.105 g, 0.335 mmol) and (7-(trifluoromethyl)cyclopropyl)isoxazol-7-yl)-2-methylpropan-2-ol (D18, 0.100 g, 0.335 mmol) and was obtained as an off-white solid (0.010 g, 6% yield). 1 H 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].

[0570] Example 47

[0571] 1-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0572] According to the general procedure for urea formation (Method B), 1-(4-amino-5-(4-amino-3-fluorophenyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2-methylpropan-2-ol (D3, 0.120 g, 0.381 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.119 g, 0.381 mmol) were used to obtain the title compound and was obtained as an off-white solid (0.028 g, 13% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 10.04 (bs, 1H), 8.94 (bs, 1H), 8.41 (s, 1H), 8.23-8.27 (m, 1H), 7.55 (s, 1H), 7.36-7.40 (m, 1H), 7.27-7.30 (m, 1H), 6.91 (s, 1H), 4.18 (s, 2H), 1.51-1.58 (m, 4H), 1.07-1.11 (m, 6H). LCMS: 534.2 [M+H].

[0573] Example 48

[0574] 1-(5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyrimidin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0575] According to the general procedure for urea formation (Method B), 5-(2-aminopyrimidin-5-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting from pyrimidin-4-amine (D19, 0.080 g, 0.299 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.093 g, 0.299 mmol) and was obtained as an off-white solid (4 mg, 3% yield). 1 H 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].

[0576] Example 49

[0577] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-(hydroxymethyl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0578] 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 starting with (4-(4-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)methanol (D20, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.021 g, 0.068 mmol) and was obtained as an off-white solid (3 mg, 8% yield). 1 H 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].

[0579] Example 50

[0580] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-cyanophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0581] According to the general procedure for urea formation (Method B), 2-amino-5-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with (4-(4-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)benzonitrile (D21, 0.130 g, 0.287 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.089 g, 0.287 mmol) and was obtained as an off-white solid (5 mg, 3% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 8.62 (s, 1H), 7.43-7.52 (m, 3H), 6.86 (s, 1H), 6.05 (s, 1H), 3.67-3.70 (m, 1H), 1.38-1.46 (m, 4H), 1.08-1.10 (m, 4H). LCMS: 509.2 [M+H].

[0582] Example 51

[0583] 1-(4-(4-amino-7-(2-methoxyethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0584] According to the general procedure for urea formation (Method B), 5-(4-amino-3-fluorophenyl)-7-(2-methoxyethyl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D22, 0.075 g, 0.249 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.078 g, 0.249 mmol) and was obtained as an off-white solid (0.037 g, 28% yield). 1 H 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].

[0585] Example 52

[0586] 1-(4-(4-amino-7-(2-hydroxyethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0587] According to the general procedure for urea formation (Method B), 2-(4-amino-5-(4-amino-3-fluorophenyl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with (4-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.087 g, 0.278 mmol) and was obtained as an off-white solid (0.011 g, 7% yield). 1 H 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].

[0588] Example 53

[0589] 1-(4-(4-amino-7-cyclobutyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0590] According to the general procedure for urea formation (Method B), 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D24, 0.150 g, 0.504 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.158 g, 0.504 mmol) and was obtained as an off-white solid (0.111 g, 38% yield). 1 H NMR (400 MHz, DMSO- d6) δ = 10.67 (bs, 1H), 8.96 (bs, 1H), 8.38 (s, 1H), 8.18-8.22 (m, 1H), 7.93 (s, 1H), 7.43 (bs, 2H), 7.41 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.21 (s, 1H), 5.23-5.27 (m, 1H), 2.51-2.68 (m, 4H), 1.84-1.89 (m, 2H), 1.38-1.49 (m, 4H). LCMS: 516.1 [M+H].

[0591] Example 54

[0592] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-chlorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0593] According to the general procedure for urea formation (Method B), 5-(4-amino-3-chlorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D25, 0.050 g, 0.167 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.052 g, 0.167 mmol) and was obtained as an off-white solid (6 mg, 7% yield). 1 H 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].

[0594] Example 55

[0595] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3-d ]pyrimidin-5-yl)-2-methoxyphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0596] According to the general procedure for urea formation (Method B), 5-(4-amino-3-methoxyphenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D26, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.021 g, 0.068 mmol) and was obtained as an off-white solid (7 mg, 19% yield). 1 H 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].

[0597] Example 56

[0598] 1-(4-(4-amino-7-(1-methylpyrrolidin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0599] According to the general procedure for urea formation (Method B), 5-(4-amino-3-fluorophenyl)-7-(1-methylpyrrolidin-3-yl)-7 H -pyrrolo[2,3- dThe title compound was obtained starting from pyrimidin-4-amine (D27, 0.040 g, 0.123 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.036 g, 0.115 mmol) and was obtained as a white solid (0.015 mg, 24% yield). 1 H 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].

[0600] Example 57

[0601] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-yl)urea

[0602] According to the general procedure for urea formation (Method A), 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D1, 0.160 g, 0.565 mmol) and phenyl (5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-yl)carbamate (E25, 0.184 g, 0.565 mmol) and was obtained as a white solid (0.081 mg, 28% yield). 1 H 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].

[0603] Example 58

[0604] 1-(4-(4-amino-7-cyclobutyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0605] According to the general procedure for urea formation (Method B), 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D24, 0.204 g, 0.686 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.214 g, 0.686 mmol) and was obtained as an off-white solid (0.096 g, 27% yield). 1 H 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].

[0606] Example 59

[0607] 1-(6-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyridin-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0608] According to the general procedure for urea formation (Method B), 5-(5-aminopyridin-2-yl)-7-cyclopropyl-7 H -pyrrolo[2,3- dThe title compound was obtained starting with pyrimidin-4-amine (D14, 0.030 g, 0.045 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.014 g, 0.045 mmol) and was obtained as an off-white solid (5 mg, 23% yield). 1 H NMR (400 MHz, DMSO- d 6) 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].

[0609] Example 60

[0610] 1-(4-(4-amino-7-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,6-difluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0611] According to the general procedure for urea formation (Method A), 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7 H -pyrrolo[2,3- d The title compound was obtained starting with pyrimidin-4-amine (D15, 0.150 g, 0.498 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.155 g, 0.498 mmol) and was obtained as an off-white solid (0.015 g, 6% yield). 1 H 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].

[0612] Example 61

[0613] 1-(4-(4-amino-7-(2-hydroxyethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0614] According to the general procedure for urea formation (Method B), 2-(4-amino-5-(4-amino-3-fluorophenyl)-7 H -pyrrolo[2,3- d The title compound was obtained starting with (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.109 g, 0.348 mmol) and was obtained as a white solid (0.035 mg, 20% yield). 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].

[0615] Example 62

[0616] 1-(4-(4-amino-1-cyclopropyl-1 H -pyrrolo[3,2- c ]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0617] Step 1: Preparation of 1-cyclopropyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrrolo[3,2-c]pyridin-4-amine synthesis

[0618] 4-Chloro-1-cyclopropyl-3-iodo-1 H -pyrrolo[3,2-c]pyridine (B9, 0.300 g, 0.942 mmol) and (2,5-dimethoxyphenyl)methanamine (0.429 mL, 2.83 mmol) were added to the n-The mixture in BuOH (10 mL) was stirred at 110 ° C for 12 hours. After the reaction was completed (as shown in LCMS), the reaction mixture was concentrated under reduced pressure to obtain crude material, which was passed through Isolera (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) and purified. The title product (0.10 g, 19% yield) in a yellow jelly is obtained. LCMS: 450.0 [M+H].

[0619] Step 2: 3-(4-amino-3-fluorophenyl)-1-cyclopropyl-N-(2,4-dimethoxybenzyl)-1H-pyrrolo[3, Synthesis of 2-c]pyridin-4-amine

[0620] Following a similar procedure as described for intermediate D8, 1-cyclopropyl- N -(2,4-dimethoxybenzyl)-3-iodo-1 H To the reaction mixture of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (0.100 g, 0.423 mmol) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (0.100 g, 0.423 mmol) was added to give the title compound, which was obtained as a brown gum (0.080 g, 41% yield). LCMS: 433.2 [M+H].

[0621] Step 3: 1-(4-(1-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)-1H-pyrrolo[3,2-c]pyridine- Synthesis of 3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0622] According to the general procedure for urea formation (Method B), 3-(4-amino-3-fluorophenyl)-1-cyclopropyl- N -(2,4-dimethoxybenzyl)-1 H The title compound was obtained starting with 4-pyrrolo[3,2-c]pyridin-4-amine (0.080 g, 0.185 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.058 g, 0.185 mmol) and obtained as an off-white solid (0.027 g, 17% yield). LCMS: 651.3 [M+H].

[0623] Step 4: 1-(4-(4-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3- Synthesis of (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0624] Triethylsilane (4.8 mg, 0.041 mmol) and TFA (4.7 mg, 0.041 mmol) were added to 1-(4-(1-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)-1-yl)-1-ol at 0°C. H To the solution of 4-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.027 g, 0.041 mmol) in DCM (2 mL) was added 4-(4-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.027 g, 0.041 mmol) in DCM (2 mL), and the resulting mixture was stirred at 25 ° C for 12 hours. After completion of the reaction (as shown by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC (eluting with a gradient of 0.1% TFA in water) to give the title product (5 mg, 24% yield) as an off-white solid. 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].

[0625] Biological Example 1

[0626] Biochemical assays of compounds

[0627] Representative compounds were tested for their inhibitory activity on NEK7 and IL-1β release according to the above procedure. The results are given in the table below.

[0628] Table 2 . Activity of representative compounds

[0629] For the NEK7 IC in Table 2 50 active: IC 50 Greater than 1500 nM IC 50 501 – 1500 nM IC 50 301 – 500 nM IC 50 151 – 300 nM IC 50 Less than 150 nM For the IL-1β IC in Table 2 50 active: + IC 50 Greater than 1000 nM ++ IC 50 301 – 500 nM +++ IC 50 151 – 300 nM ++++ IC 50 Less than 150 nM - indicates that the value was not measured The various embodiments described above can be combined to provide other embodiments. All U.S. patents, U.S. patent application publications, U.S. patent publications, foreign patents, foreign patent applications, and non-patent publications referenced in this specification and / or listed in the application data sheet include, but are not limited to, U.S. Provisional Patent Application No. 63 / 022,159 filed on May 8, 2020 and U.S. Provisional Patent Application No. 63 / 170,761 filed on April 5, 2021, which are incorporated herein by reference in their entirety. If necessary, aspects of the embodiments can be modified to adopt the concepts of various patents, applications, and disclosures to provide other embodiments.

[0630] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments along with the full scope of equivalents provided by such claims. Therefore, the claims are not limited by this disclosure.

Claims

1. A compound having the following structure (I): (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is each optionally replaced by one or more R 6 Substituted C6-C 10 Aryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group or 5-6 membered monocyclic heteroaryl; X is CH or N; Y is CHOH or NH; R 1 is H or C1-C6 alkyl; R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; R 3 is H, a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R 4 is a heteroaryl group selected from the group consisting of 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 optionally substituted with one or more substituents selected from the group consisting of: halogen aliphatic, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, or 5- or 6-membered heteroaryl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R 6 is independently at each occurrence halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxyalkyl or C1-C6 haloalkyl.

2. The compound of claim 1, wherein R 1 It’s H.

3. The compound of claim 1 or 2, wherein R 2 It is a branched C4-C6 alkyl group, a C3-C4 cycloalkyl group, a C3-C8 heterocyclyl group, or a 5- or 6-membered heteroaryl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl.

4. The compound according to any one of claims 1 to 3, wherein R 2 It is a branched C4-C6 alkyl, C3-C4 cycloalkyl or C3-C8 heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl.

5. The compound of any one of claims 1 to 4, wherein R 2 is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl or oxetanyl, each optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl.

6. The compound of claim 5, wherein R 2 is unsubstituted.

7. The compound of any one of claims 1 to 4, wherein R 2 It is a branched C4-C6 alkyl group optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl.

8. The compound of claim 7, wherein R 2 is 2-methylpropyl optionally substituted by hydroxy.

9. The compound of any one of claims 1 to 8, wherein R 2 Has one of the following structures: ; ; ; ; ; ; ; ; or .

10. The compound of any one of claims 1 to 9, wherein R 3 It’s H.

11. The compound of any one of claims 1 to 10, wherein R 4 is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1,3,4-oxadiazolyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

12. The compound of claim 11, wherein R 4 is isoxazolyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

13. The compound of claim 11, wherein R 4 is a thiazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

14. The compound of claim 11, wherein R 4 is an isothiazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

15. The compound of claim 11, wherein R 4 It is a 1,2,4-thiadiazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

16. The compound of claim 11, wherein R 4 It is a 1,3,4-thiadiazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

17. The compound of claim 11, wherein R 4 It is a 1,2,4-triazolyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

18. The compound of claim 11, wherein R 4 It is 1,3,4-oxadiazolyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl and C3-C8 halocycloalkyl, and combinations thereof.

19. The compound of any one of claims 1 to 18, wherein R 4 Substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminoalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 membered heterocyclylalkyl, 3-8 membered alkylheterocyclylcycloalkyl, 3-8 membered haloheterocyclylalkyl or C3-C8 halocycloalkyl or a combination thereof.

20. The compound of any one of claims 1 to 19, wherein R 4 Has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

21. The compound of any one of claims 1 to 20, wherein R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl; and R 4 Has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

22. The compound of claim 21, wherein R 2 It is a C1-C6 alkyl group substituted by a hydroxy group or a C1-C6 alkoxy group.

23. The compound of claim 21 or 22, wherein R 2 Has one of the following structures: or .

24. The compound of any one of claims 1 to 23, wherein R 5 It’s H.

25. The compound of any one of claims 1 to 24, wherein Y is NH.

26. The compound of any one of claims 1 to 24, wherein Y is CHOH.

27. The compound of any one of claims 1 to 26, wherein A is optionally substituted with one or more R 6 Substituted C6-C 10 Aryl, C3-C 10 cycloalkyl or 5-6 membered monocyclic heteroaryl.

28. The compound of claim 27, wherein A is phenyl.

29. The compound of claim 27, wherein A is a saturated or unsaturated cyclohexyl group.

30. The compound of claim 27, wherein A is pyridinyl.

31. The compound of claim 27, wherein A is pyrimidinyl.

32. The compound of any one of claims 1 to 31, wherein A is unsubstituted.

33. The compound of any one of claims 1 to 31, wherein A is replaced by one or more R 6 replace.

34. The compound of claim 33, wherein R 6 It's a halogen.

35. The compound of claim 34, wherein the halogen is chlorine or fluorine.

36. The compound of claim 33, wherein R 6 It is a C1-C6 hydroxyalkyl group.

37. The compound of claim 36, wherein C1-C6 hydroxyalkyl is -CH2CH2OH.

38. The compound of claim 33, wherein R 6 It's cyano.

39. The compound of claim 33, wherein R 6 It is a C1-C6 alkoxy group.

40. The compound of claim 39, wherein the C1-C6 alkoxy group is a methoxy group.

41. A compound as described in any one of claims 1 to 40, wherein A has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

42. The compound of any one of claims 1 to 41, wherein the compound has the following structure (IA): (IA) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: R 2a is a C1-C6 alkyl or C3-C8 cycloalkyl group, each optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R 4a isoxazolyl optionally substituted by one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.

43. The compound of claim 42, wherein R 2a Has one of the following structures: or .

44. The compound of claim 42 or 43, wherein R 4a Has one of the following structures: or .

45. The compound of any one of claims 1 to 41, wherein X is CH.

46. ​​The compound of claim 1, wherein the compound has one of the structures listed in Table 1, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

47. The compound of any one of claims 1 to 46, wherein the compound is a modulator of the NLRP3 inflammasome.

48. The compound of any one of claims 1 to 47, wherein the compound is an inhibitor of NEK7.

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48 and a pharmaceutically acceptable carrier, diluent or excipient.

50. A method of treating a NLRP3-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 48 or a pharmaceutical composition of claim 49.

51. The method of claim 50, wherein the disorder is selected from the group consisting of autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases, and ischemic conditions.

52. The method of claim 50 or 51, wherein the condition is selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver disease, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, and Mueller-Weiss syndrome.

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