Inhibitors of NEK7 kinase

Abstract

Compounds are provided that have activity as inhibitors of NEK7. The compounds have structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. Also provided are methods related to the preparation and use of such compounds, pharmaceutical compositions comprising such compounds, and methods of modulating the activity of the NLRP3 inflammasome.

Description

Background Technical Field

[0002] Embodiments of the present disclosure generally relate to compounds, methods for their preparation, and uses as therapeutic or prophylactic agents, for example, for treating inflammation.

[0003] Description of the Related Art

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

[0005] NEK7 is a member of the NIMA - related kinase (NEK) family, which acts as an NLRP3 - binding protein that regulates its oligomerization and activation. NEK7 is a serine / threonine kinase required for mitotic entry, cell cycle progression, cell division, and mitotic processes. It is expressed in a variety of tissues, such as the brain, heart, lung, liver, and spleen. Overexpression of NEK7 induces the production of abnormal cells, which are closely related to 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 of NLRP3 inflammasome activation that block the NLRP3 - NEK7 interaction may have therapeutic or prophylactic activity in several human diseases, such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the exact mechanism of NLRP3 - NEK7 has not been fully understood.

[0007] Therefore, there is a need to develop inhibitors that directly target NEK7 to affect the inflammatory responses regulated by the NLRP3 inflammasome in several pathological diseases, such as gout, atherosclerosis, type 2 diabetes, metabolic syndrome, macular degeneration, Alzheimer's disease, multiple sclerosis, and inflammatory bowel disease. Embodiments of the present disclosure 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 a compound of structure (I):

[0010]

[0011] its pharmaceutically acceptable salts, stereoisomers or prodrugs, wherein A, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are each as defined below.

[0012] In another aspect, there is also provided a pharmaceutical composition comprising the disclosed compound and its use method for treating inflammation. Detailed Description

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

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

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

[0016] Reference throughout the 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 invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, 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 pertains. As used in this specification and the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0018] "Amino" refers to the -NH2 group.

[0019] "Carboxy / carboxyl" refers to the CO2H group.

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

[0021] "Hydroxy / hydroxyl" refers to the -OH group.

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

[0023] "Oxo" refers to the ═O substituent.

[0024] "Thiol" refers to the -SH substituent.

[0025] "Thioxo" refers to the ═S substituent.

[0026] "Alkyl" refers to a saturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C 12 alkyl), from one to eight carbon atoms (C1-C8 alkyl), or from one to six carbon atoms (C1-C6 alkyl), or any value within these ranges (e.g., C4-C6 alkyl, etc.), and which is attached to the remainder 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 carbon atoms mentioned refers to the backbone carbon and the branched carbon, but does not include the carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, the alkyl group is optionally substituted.

[0027] "Alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C 12(alkenyl), having from 2 to 8 carbon atoms (C2-C8 alkenyl) or from 2 to 6 carbon atoms (C2-C6 alkenyl) or any value within these ranges, and is attached to the remainder of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. The number of carbon atoms mentioned refers to the backbone carbon and the branched-chain carbon, but does not include the carbon atoms belonging to any substituent. Unless specifically stated otherwise in this specification, the alkenyl group is optionally substituted.

[0028] The term "alkynyl" refers to an unsaturated straight-chain or branched-chain hydrocarbon group having 2 to 12 carbon atoms (C2-C 12 alkynyl), having 2 to 9 carbon atoms (C2-C9 alkynyl) or 2 to 6 carbon atoms (C2-C6 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, etc. The number of carbon atoms mentioned refers to the backbone carbon and the branched-chain carbon, but does not include the carbon atoms belonging to any substituent. Unless specifically stated otherwise in this specification, the alkynyl group is optionally substituted.

[0029] "Alkoxy" refers to a group of the formula -OR a wherein R a is an alkyl group as defined above, having from 1 to 12 carbon atoms (C1-C 12 alkoxy), having from 1 to 8 carbon atoms (C1-C8 alkoxy) or from 1 to 6 carbon atoms (C1-C6 alkoxy) or any value within these ranges. Unless specifically stated otherwise in the specification, the alkoxy group is optionally substituted.

[0030] "Amino" refers to a group of the formula -NR a R b wherein R a and R b are each independently H or a C1-C6 alkyl group as defined above. When both R a and R b are H, the "aminyl" group is the same as the "amino" group as defined above. Unless otherwise stated, the C1-C6 alkyl moiety of the amino group is optionally substituted.

[0031] "Aminoalkylcycloalkyl" refers to a group of the formula –R a R b NR c R d wherein R a is a cycloalkyl group as defined herein, R b is a C1-C6 alkyl group, R c is H or a C1-C6 alkyl group, and R dis a C1-C6 alkyl as defined above. Unless otherwise specified, the cycloalkyl and each C1-C6 alkyl moiety of the aminoalkylcycloalkyl group are optionally substituted.

[0032] "Aromatic ring" refers to a cyclic planar molecule or a part (i.e., a group) of a molecule having a ring with resonating bonds, which exhibits increased stability relative to other connecting arrangements of the same set of atoms. Generally, an aromatic ring contains a set of coplanar atoms bonded covalently and contains a number of π-electrons (e.g., alternating double and single bonds), where the π-electrons are even but not a multiple of 4 (i.e., 4n + 2 π-electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridyl, pyridazinyl, pyrimidinyl. Unless otherwise specifically stated in the specification, "aromatic ring" includes all groups that are optionally substituted.

[0033] "Aryl" refers to a carbocyclic system containing 6 to 18 carbon atoms (e.g., 6 to 10 carbon atoms (C6-C 10 aryl)) and at least one carbocyclic aromatic ring. For the purposes of the embodiments of the present invention, aryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, asym-indacene, sym-indacene, indan, indene, naphthalene, phenalene, phenanthrene, heptalene, pyrene, and benzo[ghi]perylene. Unless otherwise specifically stated in the specification, aryl groups are optionally substituted.

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

[0035] "Carbocyclic / carbocycle" is a ring system in which each of the ring atoms is carbon.

[0036] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic group consisting only of carbon and hydrogen atoms, which may include fused or bridged ring systems, having three to fifteen ring carbon atoms (C3-C 15 cycloalkyl), three to ten ring carbon atoms (C3-C 10a cycloalkyl group) or a cycloalkyl group having from three to eight ring carbon atoms (C3-C8 cycloalkyl group) or any value within these ranges, such as a cycloalkyl group having from three to four carbon atoms (C3-C4 cycloalkyl group), and which is saturated or partially unsaturated and is attached to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the cycloalkyl group is optionally substituted.

[0037] "Alkylcycloalkyl" means a group of the formula –R a R b wherein R a is a cycloalkyl group and R b is an alkyl group as defined above. Unless otherwise specifically stated in the specification, the alkylcycloalkyl group is optionally substituted.

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

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

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

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

[0042] "Haloalkylcycloalkyl" means a group of the formula –R a R b wherein R a is a cycloalkyl group and R b is a haloalkyl group as defined above. Unless otherwise specifically stated in the specification, the haloalkylcycloalkyl group is optionally substituted.

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

[0044] "Heterocyclic group" means a 3- to 18-membered, such as 3- to 10-membered or 3- to 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, the heterocyclic group is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spiro, and / or bridged ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclic group are optionally oxidized, and the nitrogen atoms are optionally quaternized. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithialanyl, decahydroisoquinolinyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrazine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidinonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithialanyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the heterocyclic group is optionally substituted.

[0045] "Haloheterocyclic alkyl" means a group of the formula -R a R b wherein R a is alkyl and R b is a haloheterocyclic group as defined herein. Unless otherwise specifically stated in the specification, the haloheterocyclic alkyl group is optionally substituted.

[0046] "Heterocyclic alkyl" means a group of the formula -R a R b wherein R a is alkyl and R b is a heterocyclic group as defined herein. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group is optionally substituted.

[0047] "Heteroaryl" means a 5- to 18-membered, such as a 5- to 6-membered ring system group, which contains one to thirteen ring carbon atoms, one to six ring heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. The heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxenyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl (i.e., thiacyclopentadienyl). Unless specifically stated otherwise in this specification, the heteroaryl group is 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 respectively refer to the following structures:

[0049]

[0050] Wherein the 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 covalently bonded to the remainder of the molecule through one of the carbon atoms in the ring of the 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.

[0051] As used herein, the term "substituted" means any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclic, heterocyclenyl, heterocyclicalkyl, 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, heterocyclic, heterocyclicalkyl, heteroaryl, heteroarylalkyl, and / or hydroxyalkyl substituents, which may also each be optionally substituted by one or more of the above substituents.

[0052] In some specific embodiments, the optional substituents are independently selected from halogen, hydroxy, cyano, amino, 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 3-8-membered heterocyclic.

[0053] The term "effective amount" or "therapeutically effective amount" means an amount of a compound described herein sufficient to achieve the intended application, which includes but is not limited to the treatment of diseases as defined below. The therapeutically effective amount can vary according to 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 the dose that induces a specific response in target cells, such as a reduction in platelet adhesion and / or cell migration. The specific dose will vary depending on the specific compound selected, the dosing regimen followed, whether administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is carried.

[0054] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result (including but not limited to a therapeutic and / or prophylactic effect) with respect to a disease, disorder, or medical condition. A therapeutic benefit means eradicating or ameliorating the underlying condition being treated. Additionally, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying condition, such that an improvement in the individual is observed, even though the individual may still be afflicted with the underlying condition. Prophylactic effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for prophylactic benefit, a composition is administered to an individual at risk of developing a specific disease, or an individual reporting one or more physiological symptoms of a disease, even though the disease may not yet have been diagnosed.

[0055] As used herein, the terms "co-administer", "administer in combination", and their grammatical equivalents encompass the administration of two or more agents to an animal, including a human, such that the two agents and / or their metabolites are present in the individual at the same time. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which both agents are present.

[0056] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0057] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness of the free base, are biologically tolerable or otherwise biologically suitable for administration to an individual. Generally, see S.M. 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 salts that are pharmacologically effective and suitable for 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, etc.; and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0058] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness of the free base, are biologically tolerable, or are otherwise biologically suitable for administration to an individual. Generally, see S.M. 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 salts that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable base addition salts are prepared by adding an inorganic base or an organic base to the 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, etc. 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 the following: 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 penicillin, ethylenediamine, glucosamine, N-methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0059] In some embodiments, the pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (e.g., methyl bromide).

[0060] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of the protein (e.g., NLRP3 inflammasome or NEK7) or by inhibiting the association of the NLRP3 inflammasome with NEK7. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Although the preferred antagonists herein interact (e.g., bind) particularly with the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also particularly included within this definition. The preferred biological activities inhibited by the antagonists are related to the development, growth, or spread of tumors.

[0061] As used herein, the term "agonist" refers to a compound having the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein or not. Thus, the term "agonist" is defined in the context of the biological action of a target polypeptide. Although the preferred agonists herein interact (e.g., bind) particularly with the target, compounds that initiate 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 within this definition.

[0062] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted into and within a cell to initiate an intracellular response.

[0063] The term "selectively inhibit" or "selectively inhibits" refers to the ability of a bioactive agent to preferentially reduce the target signal transduction activity compared to off-target signal transduction activity through direct or indirect interaction with the target.

[0064] "Individual" 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 individual is a mammal, and in some embodiments, the individual is a human.

[0065] "Mammal" includes humans and livestock animals as well as non-livestock animals, said livestock animals such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), said non-livestock animals such as wild animals, etc.

[0066] "Prodrug" is intended to mean a compound (e.g., a compound of structure (I)) that can be converted to a bioactive compound described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. In some aspects, a prodrug is inert when administered to a subject but is converted in vivo to an active compound, e.g., by hydrolysis. Prodrug compounds often afford advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, pp. 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Volume 14, as well as in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. The term "prodrug" also means to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian individual. Prodrugs of the active compounds described herein are generally prepared by modifying the functional groups present in the active compound in such a way that the modification is cleaved either in routine manipulation or in vivo to the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is linked to any group that cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively, when the prodrug of the active compound is administered to a mammalian individual. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the hydroxyl functional group in the active compound, or acetamide, formamide, and benzamide derivatives of the amine functional group, etc.

[0067] The term "in vivo" refers to events that occur within an individual.

[0068] The embodiments disclosed herein are also intended to cover all pharmaceutically acceptable compounds of structure (I).

[0069] Certain embodiments also contemplate in vivo metabolites of the disclosed compounds. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, principally due to enzymatic processes. Accordingly, embodiments include compounds produced by a method comprising administering to a mammal a compound of the present disclosure for a period of time sufficient to yield its metabolites. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal (e.g., a rat, mouse, guinea pig, monkey) or to a human such that sufficient metabolic time is allowed and isolating the conversion products from urine, blood, or other biological samples.

[0070] "Stable compound" and "stable structure" mean a compound that is sufficiently stable to be isolated to a useful degree of purity from a reaction mixture and formulated into an effective therapeutic agent.

[0071] Typically, crystallization yields solvates of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the present 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. Accordingly, the compounds of the present disclosure can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvated forms. The compounds of the present disclosure can be true solvates, while in other cases, the compounds of the present disclosure merely retain adventitious water or are mixtures of water with some adventitious solvent.

[0072] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and means that the description includes examples in which the event or circumstance occurs and examples in which it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted aryl groups and aryl groups having no substituents.

[0073] "Pharmaceutical composition" means a preparation of a compound of the present disclosure and a medium that is commonly acceptable in the art for delivering the compound of the present disclosure to a mammal (e.g., a human). Such media include all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0074] "Pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent.

[0075] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures, and the different three-dimensional structures are non-interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0076] The compounds of the present disclosure (i.e., the compounds of structure (I)) or their pharmaceutically acceptable salts may contain one or more geometrically asymmetric centers and may thus 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. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. 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 the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, this means that the compound includes E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0077] Embodiments of the present disclosure include all modes and conformationally restricted states of the rotamers of the compounds of the present invention. Atropisomers are also included, which are stereoisomers resulting from steric hindrance to rotation about a single bond, where the energy difference due to steric strain or other contributing factors is high enough to permit separation of individual conformational isomers. As an example, certain compounds of the present disclosure may exist as a mixture of atropisomers, or may be purified or enriched to exist as one atropisomer.

[0078] In some embodiments, the compounds of structure (I) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of structure (I) are substantially one enantiomer or diastereomer.

[0079] "Tautomers" refer to the migration of a proton from one atom of a molecule to another atom of the same molecule. Embodiments thus include the tautomers of the disclosed compounds.

[0080] The chemical nomenclature and structural diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, which uses the ACD / Naming 9.07 software program and / or the ChemDraw Profesional 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, substituents are generally named before the group to which they are attached. For example, cyclopropyl ethyl contains an ethyl backbone with a cyclopropyl substituent. Unless otherwise described, all bonds are identified in the chemical structural diagrams herein, but it is assumed that all bonds on some carbon atoms are bonded to sufficient hydrogen atoms to complete the valency.

[0081] Compound

[0082] 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.

[0083] Embodiments of the present disclosure provide compounds having the following structure (I):

[0084]

[0085] or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:

[0086] A is a C6-C aryl, C3-C cycloalkyl, 3-10 membered heterocyclic group, or 5-6 membered monocyclic heteroaryl, each optionally substituted with one or more R 6 substituents; 10 Y is CHOH or NH; 10 R is H or C1-C6 alkyl;

[0087] R is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, or 5 or 6 membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group;

[0088] R 1 is H or C1-C6 alkyl;

[0089] R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, or 5 or 6 membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group;

[0090] R 3is H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocyclic group, or a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0091] R 4 is a heteroaryl group selected from: an oxazolyl group, an isoxazolyl group, a 1,2,3-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a 1,2,5-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3-thiadiazolyl group, a 1,2,4-thiadiazolyl group, a 1,2,5-thiadiazolyl group, and a 1,3,4-thiadiazolyl group, each optionally substituted with one or more substituents selected from: 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- to 8-membered heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclic group alkyl, 3- to 8-membered alkyl heterocyclic group cycloalkyl, 3- to 8-membered haloheterocyclic group alkyl, and C3-C8 halocycloalkyl, or a combination thereof;

[0092] R 5 is H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocyclic group, a C6-C 10 aryl group, or a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; and

[0093] R 6 is, independently at each occurrence, halogen, C1-C6 alkyl, cyano, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0094] In some embodiments of Structure (I):

[0095] A is a C6-C 6 aryl group, a C3-C 10 cycloalkyl group, a 3- to 10-membered heterocyclic group, or a 5- to 6-membered monocyclic heteroaryl group, each optionally substituted with one or more R 10 substituents;

[0096] Y is CHOH or NH;

[0097] R1 is H or a C1-C6 alkyl group;

[0098] R 2 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, or a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group;

[0099] R 3 is H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, or a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0100] R 4 is a heteroaryl group selected from: oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each optionally substituted with one or more substituents selected from: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl;

[0101] R 5 is H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a C6-C 10 aryl group, or a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; and

[0102] R 6 is independently at each occurrence halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0103] Some more specific embodiments provide compounds having the following structure (I):

[0104]

[0105] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:

[0106] A is each independently optionally substituted with one or more R 6 substituted C6-C 10 aryl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group or 5- or 6-membered monocyclic heteroaryl;

[0107] X is CH or N;

[0108] Y is CHOH or NH;

[0109] R 1 is H or C1-C6 alkyl;

[0110] R 2 is each independently optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl, said substituents being selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclic group;

[0111] R 3 is H, each independently optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl, said substituents being selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy;

[0112] R 4 is a heteroaryl 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 independently 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- to 8-membered heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclic group alkyl, 3- to 8-membered alkyl heterocyclic group cycloalkyl, 3- to 8-membered haloheterocyclic group alkyl and C3-C8 halocycloalkyl;

[0113] R 5is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, C6-C 10 aryl, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; and

[0114] R 6 is, independently at each occurrence, halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

[0115] In one embodiment, R 1 is H. In other embodiments, R 1 is C1-C6 alkyl, such as methyl.

[0116] In one embodiment, there is provided a compound of structure (I) wherein R 2 is branched C4-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclic group, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group.

[0117] In another embodiment, there is provided a compound of structure (I) wherein R 2 is branched C4-C6 alkyl, C3-C4 cycloalkyl, or C3-C8 heterocyclic group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group.

[0118] In a specific embodiment, R 2 is cyclopropyl or oxetanyl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group. In some embodiments, R 2 is cyclopropyl. In other embodiments, R 2 is oxetanyl. In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanyl.

[0119] In a specific embodiment, R 2is a cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl or oxetanyl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclic group. In some embodiments, R 2 is cyclopropyl. In other embodiments, R 2 is oxetanyl. In some embodiments, R 2 is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R 2 is N-methyl substituted pyrrolidinyl. In certain specific embodiments, R 2 is unsubstituted cyclobutyl.

[0120] In different embodiments, R 2 is a branched C4-C6 alkyl optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclic group. For example, in some embodiments, R 2 is 2-methylpropyl optionally substituted with hydroxy.

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

[0122]

[0123] In some specific embodiments, R 2 has one of the following structures:

[0124]

[0125] In other embodiments, R 3 is H. In other embodiments, R 3 is C1-C6 alkyl, such as methyl.

[0126] In any of the foregoing embodiments, R 4is an oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl or 1,3,4-oxadiazolyl, each optionally substituted with one or more substituents selected from: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered haloheterocyclic group alkyl and C3-C8 halocycloalkyl and combinations thereof. For example, in certain embodiments, R 4 is an isoxazolyl optionally substituted with one or more substituents selected from: 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 4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 halocycloalkyl.

[0127] In certain embodiments, R 4 is an 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: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered haloheterocyclic group alkyl and C3-C8 halocycloalkyl and combinations thereof.

[0128] In certain embodiments, R 4 is an isoxazolyl optionally substituted with one or more substituents selected from: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered haloheterocyclic group alkyl and C3-C8 halocycloalkyl and combinations thereof.

[0129] In certain embodiments, R4 is a triazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered haloheterocyclic group alkyl, and C3-C8 halocycloalkyl and combinations thereof.

[0130] In certain embodiments, R 4 is an isothiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered haloheterocyclic group alkyl, and C3-C8 halocycloalkyl and combinations thereof.

[0131] In certain embodiments, R 4 is a 1,2,4-thiadiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered haloheterocyclic group alkyl, and C3-C8 halocycloalkyl and combinations thereof.

[0132] In certain embodiments, R 4 is a 1,3,4-thiadiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered haloheterocyclic group alkyl, and C3-C8 halocycloalkyl and combinations thereof.

[0133] In certain embodiments, R 4is a 1,2,4-triazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered halopyrimidinyl alkyl and C3-C8 halocycloalkyl and combinations thereof.

[0134] In certain embodiments, R 4 is a 1,3,4-oxadiazolyl group optionally substituted with one or more substituents selected from: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, 3-8 membered heterocyclic group and C3-C8 halocycloalkyl or combinations thereof.

[0135] In certain embodiments, R 4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, amino, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 membered heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3-8 membered heterocyclic group alkyl, 3-8 membered alkyl heterocyclic group cycloalkyl, 3-8 membered halopyrimidinyl alkyl and C3-C8 halocycloalkyl and combinations thereof.

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

[0137]

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

[0139]

[0140] In other various embodiments, R 4 has one of the following structures:

[0141]

[0142]

[0143] In certain specific embodiments, R 2is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group; and

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

[0145]

[0146]

[0147] In certain specific embodiments, R 2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group; and

[0148] R 4 has one of the following structures:

[0149]

[0150]

[0151] In more specific embodiments, R 2 is C substituted with hydroxy or C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl. In some embodiments, R 2 has one of the following structures:

[0152]

[0153] In other embodiments, R 5 is H. In other embodiments, R 5 is C 1 -C 6 alkyl, such as methyl.

[0154] In certain embodiments, Y is C(H)(OH). In other embodiments, Y is NH.

[0155] In various embodiments, A is each optionally substituted with one or more R6 Substituted C6-C 10 aryl, C3-C 10 cycloalkyl, or 5- to 6-membered monocyclic heteroaryl. It is understood that A is a divalent group.

[0156] In certain embodiments, A is a divalent optionally substituted C 6-10 aryl. In certain embodiments, A is a divalent optionally substituted 3- to 8-membered saturated or partially unsaturated carbocycle. In certain embodiments, A is a divalent optionally substituted 3- to 10-membered heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, A is a divalent optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0157] In certain embodiments, A is a divalent group independently optionally substituted selected from phenyl, pyridyl, cyclohexyl, and cyclohexenyl. In other embodiments, A is phenyl. In various embodiments, A is a saturated or unsaturated cyclohexyl hydrocarbon group. In further embodiments, A is pyridyl.

[0158] In certain embodiments, A is an optionally substituted pyrimidinyl.

[0159] In any of the foregoing embodiments, A is unsubstituted. In various of the foregoing embodiments, A is substituted by one or more R 6 groups. For example, in some embodiments, R 6 is a halogen. In some embodiments, R 6 is chlorine or fluorine. In other embodiments, R 6 is fluorine.

[0160] In some embodiments, R 6 is a C1-C6 hydroxyalkyl. In some embodiments, the C1-C6 hydroxyalkyl is -CH2CH2OH. In other embodiments, R 6 is a cyano group. In some embodiments, R 6 is a C1-C6 alkoxy group. In more specific embodiments, the C1-C6 alkoxy group is methoxy.

[0161] In certain embodiments, A is a divalent group selected from: 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, azocinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, pseudindolyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridobenzimidazole, pyridothiazole, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiodiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thieno[2,3-b]thiazole, thieno[3,2-b]oxazole, thieno[2,3-c]imidazole, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl, each of which is optionally substituted.

[0162] In certain embodiments, A has one of the following structures:

[0163]

[0164] In some certain embodiments, A has one of the following structures:

[0165]

[0166] In some certain embodiments, A has one of the following structures:

[0167]

[0168] In certain embodiments, the compound has the following structure (IA):

[0169]

[0170] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:

[0171] R 2a is each independently a C1-C6 alkyl or C3-C8 cycloalkyl group optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclic group;

[0172] R 4a is an isoxazolyl group optionally substituted with one or more substituents selected from: C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.

[0173] In more specific embodiments, R 2a is a branched C1-C6 alkyl group substituted with hydroxy. In some embodiments, R 2a is a C3-C8 cycloalkyl group. In more specific embodiments, R 2a has one of the following structures:

[0174]

[0175] In certain embodiments, R 4a is an isoxazolyl group substituted with a C3-C8 haloalkyl cycloalkyl. In some embodiments, R 4a is a C3-C8 fluoroalkyl cycloalkyl. In more specific embodiments, R 4a is a fluoroalkyl cyclopropyl or fluoroalkyl cyclobutyl. In more specific embodiments, R 4a has one of the following structures:

[0176]

[0177] In some embodiments, X is CH. In some more specific embodiments, the compound has the following structure (IB):

[0178]

[0179] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:

[0180] A is each independently optionally substituted with one or more R6 Substituted C6-C 10 aryl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, or 5- or 6-membered monocyclic heteroaryl;

[0181] X is CH or N;

[0182] Y is CHOH or NH;

[0183] R 1 is H or C1-C6 alkyl;

[0184] R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclic group;

[0185] R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy;

[0186] R 4 is heteroaryl selected from: oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each optionally substituted with one or more substituents selected from: 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- to 8-membered heterocyclic group, C3-C8 haloalkyl cycloalkyl, C3-C8 aminoalkyl cycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclic group alkyl, 3- to 8-membered alkyl heterocyclic group cycloalkyl, 3- to 8-membered haloheterocyclic group alkyl, and C3-C8 halocycloalkyl;

[0187] R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C10 an aryl, or a 5- or 6-membered heteroaryl, the substituents being selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and

[0188] R 6 is independently, each time it appears, halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxyalkyl or C1-C6 haloalkyl.

[0189] In certain embodiments, the compounds of structure (I) are modulators of the NLRP3 inflammasome.

[0190] In a specific embodiment, the compounds of structure (I) are inhibitors of NEK7 in a patient or a biological sample.

[0191] In various different embodiments, the compounds have one of the structures set forth in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof. The compounds in Table 1 are prepared as described in the Examples or by methods known in the art and characterized by mass spectrometry and / or 1 1H NMR analysis.

[0192] Table 1. Representative Compounds of Structure (I)

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] It is understood that in the present description, combinations of substituents and / or variables of the formula are only permitted if such combinations result in stable compounds.

[0213] In additional embodiments, the various compounds of the present disclosure that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid by methods known to those skilled in the art. The salts of the compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0214] Methods for producing the compounds described herein are provided below. Generally, starting components can be obtained from sources such as SigmaAldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, (Wiley, December 2000)) or prepared as described herein.

[0215] The following general reaction scheme illustrates examples of the compounds of structure (I) of the present invention:

[0216]

[0217] or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein A, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are each as defined below.

[0218] General Reaction Scheme 1

[0219] The following general reaction scheme (where X1 and X 2 are each independently halogen, and X, R 1 , R 2 , R 3 and A have the meanings described herein) illustrate embodiments of a method for preparing amine intermediate D:

[0220]

[0221] As shown in General Reaction Scheme 1, pyrimidine / pyridine pyrrole (i.e., intermediate A) is alkylated with a cycloalkyl borate or a suitable electrophile in the presence of a base to obtain intermediate B. This precursor is treated with ammonium hydroxide to form a pyrrolo-pyrimidine / pyridine-4-amine derivative intermediate C. The resulting intermediate C can then be subjected to palladium-catalyzed arylation to form intermediate D.

[0222] General Reaction Scheme 2

[0223] The following general reaction scheme illustrates embodiments of a method for preparing carbamate intermediate E:

[0224]

[0225] As shown in General Reaction Scheme 2, intermediate E can be prepared by the reaction of phenyl chloroformate and the indicated heteroaryl amine (amine-substituted analog of R 4 ) in the presence of a base. General Reaction Scheme 2 describes the preparation of compounds in which R 5 is H; however, compounds in which R 5 is not H can be prepared by a similar method by dropping in R 5 after the preparation of intermediate E, or by using a suitably substituted heteroaryl amine. General Reaction Scheme 3

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

[0227]

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

[0229] General Reaction Scheme 4

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

[0231]

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

[0233] Any of the above reaction schemes can be modified at any step to add and / or modify substituents, which can be appropriately added or modified during any stage of the overall synthesis of the desired compound.

[0234] Those skilled in the art should also understand 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, mercapto, 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 mercapto include -C(O)-R" (where R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable protecting groups for carboxylic acid include alkyl esters, aryl esters, or arylalkyl esters. The protecting groups are optionally added or removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Edition, Wiley. As those skilled in the art will understand, the protecting group can also be a polymer resin, such as Wang resin, Rink resin, or 2-chlorotrityl-chloride resin.

[0235] 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, similarly, they can be administered to a mammal and then metabolized in vivo to form the compounds of the present disclosure that have pharmacological activity. Therefore, such derivatives can be described as "prodrugs". The prodrugs of the compounds of the present disclosure are included within the scope of the embodiments of the present disclosure.

[0236] Pharmaceutical Compositions

[0237] 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.

[0238] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0239] In certain embodiments, the compounds described herein are applied in a local rather than systemic manner, for example, by injecting the compound directly into an organ, usually in the form of a depot preparation or a sustained release preparation. In a specific embodiment, the long-acting preparation is applied 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 compound as described herein is provided in the form of a rapid release preparation, a prolonged release preparation, or an intermediate release preparation. In other embodiments, the compound as described herein is applied topically.

[0240] In a method of treatment according to an embodiment 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, such as 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 the drug, and the judgment of the treating physician.

[0241] The compounds according to the present disclosure are effective in 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 compound form used, the object to be treated, the body weight of the object to be treated, the preference and experience of the attending physician.

[0242] In some embodiments, the compounds of the present disclosure are administered in a single dose. Typically, such administration will be by injection, such as intravenous injection, in order to rapidly introduce the agent. However, other routes may be used as appropriate. A single dose of the compounds of the present disclosure can also be used to treat acute conditions.

[0243] In some embodiments, the compounds of the present disclosure are administered in multiple doses. In some embodiments, the daily dosing is about once, twice, three times, four times, five times, six times, or more than six times. In other embodiments, the dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compounds of the present disclosure and another agent (e.g., an anti-cancer agent) are co-administered about once a day to about six times a day. In another embodiment, the compounds of the present disclosure and the agent are administered for less than about 7 days. In another embodiment, the administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as necessary.

[0244] The administration of the compounds of the present disclosure can continue for as long as needed. In some embodiments, the compounds of the present disclosure are 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, the compounds of the present disclosure are 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, the compounds of the present disclosure are administered chronically on an ongoing basis, e.g., for treating chronic effects.

[0245] In some embodiments, the compounds of the present disclosure are administered in a separate dosage form. It is known in the art that due to inter-individual differences in compound pharmacokinetics, individualization of the dosing regimen is necessary for optimal treatment.

[0246] 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, which carriers comprise excipients and auxiliaries that facilitate processing the disclosed compounds into pharmaceutically acceptable preparations. Suitable formulations depend on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are suitable for formulating 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, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, (Lippincott Williams & Wilkins 1999).

[0247] The present disclosure provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0248] The present disclosure provides pharmaceutical compositions comprising one or more compounds selected from the compounds of formula (I) and pharmaceutically acceptable diluents, excipients, and carriers. In certain embodiments, the compounds are administered as a pharmaceutical composition, wherein one or more of the compounds selected from the compounds of formula (I) are admixed with other active ingredients, such as in combination therapy. All combinations of the active substances set forth in the combination therapy section below and all combinations of the active substances set forth throughout the present disclosure are encompassed herein. In specific embodiments, the pharmaceutical composition comprises one or more compounds of formula (I).

[0249] In one embodiment, the pharmaceutical composition of the compound of formula (I) is a modulator of the NLRP3 inflammasome.

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

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

[0252] In one embodiment, one or more compounds selected from the compounds of structure (I) are formulated as an aqueous solution. In a specific embodiment, by way of example only, the aqueous solution is selected from physiologically compatible buffers, such as Hank's solution, Ringer's solution, or saline buffer. In other embodiments, one or more compounds selected from the compounds of structure (I) are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation includes a penetrant suitable for the barrier to be penetrated. In other embodiments, where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions include physiologically compatible buffers and / or excipients.

[0253] 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, which include (by way of example only) tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0254] In certain embodiments, pharmaceutical formulations for oral use are obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the granule mixture, after addition of suitable auxiliaries if required, 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, methyl cellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose; 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 croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0255] In one embodiment, the dosage forms, such as dragee cores and tablets, are provided with one or more suitable coatings. In specific embodiments, concentrated sugar solutions are used to coat the dosage forms. The sugar solutions optionally contain additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbomer gels, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. For identification purposes, dyes and / or pigments are also optionally added to the coatings. Additionally, dyes and / or pigments are optionally used to characterize different combinations of the active compound dosage.

[0256] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In specific embodiments, the push-fit capsules contain the active ingredient admixed with one or more fillers. Fillers include (by way of example only) lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0257] In other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for rapid bolus or continuous infusion. In specific embodiments, the formulations for injection are provided in unit dosage forms (e.g., in ampoules) or in multi-dose containers. A preservative is optionally added to the injection formulation. In other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains formulating agents such as suspending agents, stabilizers and / or dispersing agents. In specific embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active compound in water-soluble form. In additional embodiments, a suspension of one or more compounds selected from the compounds of structure (I) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include (by way of example only) fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. In certain specific embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension contains a suitable stabilizer or a reagent that increases the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0258] 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 the active ingredient. The active ingredient is in the free acid or free base form or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also referred to as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomeric forms 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 comprises other drugs or medicaments, carriers, adjuvants such as preservatives, stabilizers, wetting agents or emulsifying agents, solubilizing agents, salts for adjusting osmotic pressure, buffers and / or other therapeutically valuable substances.

[0259] Methods for preparing compositions comprising 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 are 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 also optionally contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, and the like.

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

[0261] In certain embodiments, the aqueous suspension contains one or more polymers as suspending agents. Polymers include water-soluble polymers, such as cellulosic polymers, such as 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.

[0262] The pharmaceutical composition may also optionally include a solubilizing agent to aid in the solubility of one or more compounds selected from the compounds of structure (I). The term "solubilizing agent" generally includes agents that result in the formation of micellar solutions or true solutions of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, may be used as solubilizing agents, as may ophthalmologically acceptable ethylene glycol, polyethylene glycol, such as polyethylene glycol 400 and glycol ethers.

[0263] In addition, the pharmaceutical composition optionally includes one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and trishydroxymethylaminomethane; 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.

[0264] Optionally, the composition further comprises one or more salts in an amount such that the osmotic pressure of the composition reaches 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.

[0265] 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.

[0266] 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 alkyl phenyl ethers such as octoxynol 10 and octoxynol 40.

[0267] The composition may contain one or more antioxidants to enhance chemical stability when needed. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0268] In certain embodiments, the aqueous suspension composition is enclosed in a single-dose non-reclosable container. Alternatively, a multi-dose reclosable container is used, in which case a preservative is typically included in the composition.

[0269] 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 additional embodiments, sustained release systems are used, such as semipermeable matrices of solid hydrophobic polymers containing a therapeutic agent, to deliver the compounds described herein. A variety of sustained release materials are useful herein. In some embodiments, the sustained release capsule releases the compound for several weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional protein stabilization strategies are employed.

[0270] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to: (a) from about 0.5% to about 2% w / v glycerol, (b) from about 0.1% to about 1% w / v methionine, (c) from about 0.1% to about 2% w / v monothioglycerol, (d) from about 1 mM to about 10 mM EDTA, (e) from about 0.01% to about 2% w / v ascorbic acid, (f) from 0.003% to about 0.02% w / v polysorbate 80, (g) from 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0271] 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 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%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0272] 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 from 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.

[0273] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is 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, 0.0003 g, 0.0002 g, or 0.0001 g.

[0274] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical 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.

[0275] Packaging materials for packaging the pharmaceutical compositions described herein include those found, for example, in 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, flasks, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment. For example, the container includes one or more of the compounds described herein, optionally in the form of a composition or in combination with another medicament disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). Such a kit optionally contains a compound with an identifying description or label or instructions related to its use in the methods described herein.

[0276] For example, the kit generally 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) that are desirable 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, packages, containers, 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 generally also be included. The label is optionally located on or associated with the container. For example, the label is located on the container when the letters, numbers, or other characters forming the label are attached, molded, or etched onto the container itself, and the label is associated with the container when the label is present in a container or carrier that also holds the container, such as a package insert. In addition, the label is used to indicate that the contents are for a specific therapeutic application. Further, the label indicates the instructions for use of the contents, e.g., in the methods described herein. In certain embodiments, the pharmaceutical composition is present in a packaging or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The packaging, for example, contains a metal or plastic foil, such as a blister pack. Alternatively, the packaging or dispenser device is accompanied by instructions for administration. Alternatively, the packaging or dispenser is also accompanied by a notice required by a government agency that regulates the manufacture, use, or sale of the drug, which notice reflects the form of the drug approved by the agency for human or veterinary administration. Such a notice, for example, is the label of a prescription drug approved by the U.S. Food and Drug Administration, or an approved product insert. In some embodiments, a composition containing the compounds provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and labeled for the treatment of a designated condition.

[0277] Method

[0278] Embodiments of the present disclosure can be used as modulators of the NLRP3 inflammasome by inhibiting NEK7 in a host species. Accordingly, the compounds of structure (I) can also be used to treat conditions mediated by effector signaling molecules such as IL-β and IL-18.

[0279] The host or patient can belong to any mammalian species, such as a primate species, particularly human; rodents, including mice, rats, and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental studies and provide models for treating human diseases.

[0280] In one embodiment, the present disclosure can be used as an inhibitor of the NLRP3 inflammasome activation mechanism. Accordingly, the compounds of structure (I) can also be used to treat conditions caused by activation in a host species.

[0281] In another embodiment, the compounds of structure (I) can be used as inhibitors of the NLRP3 (protein)-NEK7 (protein) interaction. Accordingly, the compounds can also be used to treat conditions caused by the association of NLRP3-NEK7 in a host species.

[0282] In certain embodiments, the compounds of structure (I) can be used to treat human conditions mediated by effectors selected from IL-β, IL-18, and caspase-1.

[0283] Embodiments of the present disclosure also relate to the use of a compound according to structure (I) and / or a physiologically acceptable salt thereof for prophylactic or therapeutic treatment and / or monitoring of diseases caused by, mediated by, and / or regulated by NLRP3 inflammasome activity. Furthermore, embodiments of the present invention relate to the use of a compound according to structure (I) and / or a physiologically acceptable salt thereof for the preparation of a medicament for prophylactic or therapeutic treatment and / or monitoring of diseases caused by, mediated by, and / or regulated by NLRP3 inflammasome activity. In certain embodiments, the present invention provides the use of a compound according to structure I or a physiologically acceptable salt thereof for the preparation of a medicament for prophylactic or therapeutic treatment of NLRP3-mediated disorders.

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

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

[0286] In certain other embodiments, the compounds of structure (I) are used in methods for treating a disorder or disease selected from autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, transplantation, sperm motility, erythrocyte deficiency, transplant rejection, lung injury, respiratory diseases, ischemic conditions, and cancer. In some more specific embodiments, the compounds of structure (I) are used in methods for treating myelodysplastic syndrome (MDS).

[0287] In some embodiments, NEK7-related disorders treatable with the compounds of structure (I) are 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 syndrome, cryopyrin-associated periodic syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer.

[0288] Also included herein are methods of treatment wherein 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, the combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, calcium fenoprofen, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

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

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

[0291] The anti-inflammatory agent can also be a corticosteroid. For example, the corticosteroid can be cortisone, dexamethasone, methylprednisolone, prednisone, prednisolone sodium phosphate or prednisone.

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

[0293] The present disclosure also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor such as methotrexate or a dihydroorotate dehydrogenase inhibitor such as leflunomide.

[0294] The therapeutic agent can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by the biotransformation of products of the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory agents, analgesic antipyretics, agents that inhibit prostaglandin and thromboxane synthesis, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, endocrine secretions, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived endocrine secretions, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and leukotriene inhibitors.

[0295] Other embodiments of the present disclosure relate to combinations in which at least one anti-inflammatory compound is a monoclonal antibody (e.g., eculizumab or pecilizumab), a TNF antagonist (e.g., etanercept or infliximab, which are anti-TNFα monoclonal antibodies).

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

[0297] Other embodiments of the present disclosure also relate to combinations in which at least one active agent is an immunosuppressive compound, such as an immunosuppressive compound selected from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0298] The compounds of structure (I) disclosed herein can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any agent administered to a patient suffering from cancer for the treatment of cancer.

[0299] In some embodiments, the anti-cancer agent belongs to the following categories:

[0300] Alkylating agents: such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate, lomustine, melphalan, dibromomannitol, dibromodulcitol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, dichloromethyldiethylamine, carboquone; apaziquone, fotemustine, glutophosphamide, ifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834;

[0301] Platinum compounds: such as carboplatin, cisplatin, iproplatin, nedaplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

[0302] DNA modifying agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; aclarubicin, brostallicin, pixantrone, ranimustine 1,3;

[0303] Topoisomerase inhibitors: such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elacridar, volasertib;

[0304] Microtubule regulators: such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; forbifermin, tesetaxel;

[0305] Antimetabolites: such as asparaginase 3, azacitidine, calcium folinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elsamitrucin, raltitrexed, sapacitabine, tegafur 2,3, trimetrexate;

[0306] Anticancer antibiotics: such as bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zeniplatin, zorubicin, daunomycin, plicamycin; aclarubicin, peplomycin, pirarubicin;

[0307] Hormones / antagonists such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, flucortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol acetate, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, cyproterone, oteronel, enzalutamide 1,3;

[0308] Aromatase inhibitors: such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

[0309] Small molecule kinase inhibitors: such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifamib, tivantinib, tivozanib, trametinib, trametinib, pimasertib, blinatumomab alaninate, cediranib.

[0310] In some embodiments, the drugs co-administered with the compounds described herein include any suitable drug that can be effectively delivered by inhalation, such as analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl or morphine; angina pectoris preparations, such as diltiazem; anti-allergy drugs, such as cromoglycate, ketotifen or nedocromil; anti-infective drugs, such as cephalosporins, penicillins, streptomycins, sulfonamides, tetracyclines or pentamidine; antihistamines, such as methapyrilene; anti-inflammatory drugs, such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, such as noscapine; bronchodilators, such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, orciprenaline, phenylephrine, phenylpropanolamine, pirbuterol, procaterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline 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 oxitropium; hormones, such as cortisone, hydrocortisone or prednisolone; xanthines, such as aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, such as insulin or glucagon. It will be apparent to those skilled in the art that, where appropriate, the drugs are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and / or stability of the drugs.

[0311] The pharmaceutical agents or other suitable agents disclosed herein are administered according to the condition being treated. Thus, 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 are administered simultaneously or separately from the second agent. Such co-administration can include administering the two agents simultaneously in the same dosage form, simultaneously in separate dosage forms and separately. In other words, the compounds described herein and any of the above 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 agents can be administered simultaneously, where the two agents are present in separate formulations. 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 agents described above are administered at intervals of a few minutes, or a few hours, or a few days.

[0312] In some embodiments, the compounds of structure (I) are administered as a single therapy.

[0313] For the identification of signal transduction or mechanism pathways and for the detection of interactions between various signal transduction pathways, various scientists have developed suitable models or model systems, such as cell culture models and models of transgenic animals. To determine certain stages in a signal transduction cascade, interacting compounds can be utilized 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 animal and / or cell culture models or in the clinical diseases mentioned in the present application.

[0314] The methods of the embodiments of the present invention can be carried out in vitro or in vivo. The sensitivity of a particular cell to treatment with a compound of structure (I) can be specifically determined by in vitro testing (either during research or in clinical applications). Generally, a cell culture is combined with various concentrations of the compound for a period of time sufficient for the active agent to inhibit NEK7 activity, typically from about 1 hour to 1 week. Cultured cells from biopsy samples or cell lines can be used for in vitro treatment.

[0315] In some embodiments, the IC of the compound of structure (I) inhibits NEK7 50 It is determined by the concentration of the compound required to inhibit 50% of the NEK kinase activity. The compound of structure (I) shows an IC 50 potency value of less than about 5 mM, preferably less than about 1 mM, and even more preferably less than about 0.100 mM, as described in further detail in the examples.

[0316] The following examples and preparations further illustrate and exemplify the compounds of the present disclosure and the methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, unless otherwise indicated, molecules having a single stereocenter are present as a racemic mixture. Those molecules having two or more stereocenters are present as a racemic mixture of diastereoisomers, unless otherwise indicated. Single enantiomers / diastereoisomers can be obtained by methods known to those skilled in the art.

[0317] Examples

[0318] The following examples are provided for illustrative purposes.

[0319] General Procedures

[0320] All proton NMR experiments were recorded at 400 MHz on a Bruker NEO spectrometer equipped with a BBFO probe. The deuterated solvent contained less than 0.05% v / v tetramethylsilane, which was used as the reference signal (set at 0.00 ppm). When the deuterated solvent did not contain tetramethylsilane, the residual undeuterated solvent peak was used as the reference signal according to the published guidelines (J. Org. Chem. 1997, 62(21), 7512 - 7515). Chemical shifts were expressed in parts per million (ppm, δ units). Coupling constants were in hertz (Hz). Splitting patterns depicted distinct multiplet nature and were designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintet), or brs (broad singlet).

[0321] LC / MS analysis was performed on an Agilent Technologies UHPLC 1290 Infinity II with a G6125 MS detector.

[0322] Microwave reactions were carried out using a Monowave 300 by Anton Paar GmbH according to standard protocols.

[0323] NEK7 enzyme assay

[0324] Casein substrate (from bovine milk, a mixture of hydrolyzed and partially dephosphorylated α, β, and κ caseins, obtained from Sigma - Aldrich, catalog number #C4765, diluted to a final concentration of 1 mg / mL in distilled water) and full - length recombinant human NEK7 (expressed by baculovirus in Sf9 insect cells using an N - terminal GST tag, obtained from SignalChem, catalog number #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 (serially 3 - fold diluted 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 minutes, by adding 33P]-ATP (specific activity 10 μCi / μl) initiated the kinase reaction, and the mixture was incubated at room temperature for 2 hours. Then, the reaction was 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 was expressed as the percentage of remaining kinase activity in the test sample compared to the vehicle reaction. IC 50 values and curve fitting were obtained using Prism (GraphPad Software).

[0325] IL-1β Release Assay

[0326] Approximately 1.5 million THP-1 cells were seeded into each well of a 6-well TC plate and incubated with 40 nM PMA in RPMI (10% FBS, 1% Penstrep) for 24 hours. Then the medium was removed and the cells were rested in RPMI (10% FBS, 1% Penstrep) for 24 hours, after which the medium was removed and the cells were pretreated with various concentrations of the compound of interest in RPMI (5% FBS) (usually serially 3-fold diluted in RPMI + 5% FBS, concentration range from 1 μM to 0.5 nM) for 2 hours. The medium was removed again, and the cells were incubated with 250 ng / mL LPS and the compound of interest (concentration as above) in RPMI (5% FBS) for 2 hours. For the last time, the medium was removed, and the cells were incubated with 20 μM nigericin and the compound of interest (concentration as above) in Opti-MEM for 30 minutes. Then the cell medium was collected and the amount of cleaved IL-1β was determined using a JESS instrument (ProteinSimple) and standard protocols. The cleaved Il-1β antibody was obtained from Cell Signaling (Catalog number #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 chemiluminescence detection. The primary antibody incubation time was increased from 30 minutes to 60 minutes.

[0327] Abbreviations:

[0328] °C (degrees Celsius); 11H NMR (Proton Nuclear Magnetic Resonance); CAN (Acetonitrile); Boc (tert-Butyloxycarbonyl); DCM (Dichloromethane); DIPEA (N,N-Diisopropylethylamine); DMAP (4-Dimethylaminopyridine); DMF (N,N-Dimethylformamide); DMSO-d6 (Deuterated Dimethyl Sulfoxide); eq (Equivalent); EtOAc (Ethyl Acetate); g (Gram); h (Hour); HPLC (High Performance Liquid Chromatography); LCMS (Liquid Chromatography Mass Spectrometry); MeOH (Methanol); mg (Milligram); min (Minute); mL (Milliliter); mmol (Millimole); n-BuOH (1-Butanol); Pd(PPh3)4 (Palladium-Tetrakis(triphenylphosphine)); PdCl2(dppf) ([1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)); TBAF (Tetra-n-butylammonium Fluoride); TBDMS (tert-Butyldimethylsilyl); TFA (Trifluoroacetic Acid); THF (Tetrahydrofuran); TLC (Thin Layer Chromatography).

[0329] Preparation of Synthetic Intermediates

[0330] Intermediate A

[0331] 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0332]

[0333] At 0 °C, N-iodosuccinimide (1.465 g, 6.51 mmol) was added to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 6.51 mmol) in DMF (10 mL) and the resulting mixture was stirred at 25 °C for 12 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice-cold water (100 mL) and stirred at 25 °C for 15 min. The resulting solid was filtered, washed with water (2 × 25 mL), and dried to give the title compound as an off-white solid (1.7 g, 93% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 12.96 (bs, 1H), 8.60 (s, 1H), 7.95 (d, J = 2.40 Hz, 1H); LCMS: 279.9 [M+H].

[0334] Intermediate B1

[0335] 4-Chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0336]

[0337] Copper(II) acetate (0.650 g, 3.58 mmol), 2,2'-bipyridine (0.559 g, 3.58 mmol), and sodium bicarbonate (0.601 g, 7.16 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A1, 1.000 g, 3.58 mmol) and cyclopropylboronic acid (0.615 g, 7.16 mmol) in dichloroethane (10 mL), and the resulting mixture was stirred at 70 °C under an oxygen atmosphere for 12 h. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite and then washed with DCM (2 × 20 mL). The combined filtrates were washed with water (20 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude material, which was purified by flash chromatography (silica gel 230 - 400 mesh, eluting with 15% EtOAc in petroleum ether) to afford the title compound as an off-white solid (0.7 g, 61% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.67 (s, 1H), 7.96 (s, 1H), 3.63 - 3.69 (m, 1H), 1.06 - 1.10 (m, 4H). LCMS: 319.9 [M+H].

[0338] Intermediate B2

[0339] 4-Chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0340]

[0341] K2CO3 (0.40 g, 2.86 mmol) and 3-iodooxetane (0.32 g, 1.71 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 0.40 g, 1.43 mmol) in DMF (5 mL), and the resulting mixture was stirred in a sealed tube at 90 °C for 16 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into crushed ice (50 g) and stirred for 15 min. The resulting solid was filtered, washed with water (2 × 5 mL), and dried to afford the title compound as an off-white solid (0.2 g, 42% yield). LCMS: 335.7 [M+H].

[0342] Intermediate B3

[0343] 1-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

[0344]

[0345] NaH2PO4 (0.105 g, 0.877 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A1, 0.250 g, 0.895 mmol), 2,2-dimethyloxirane (0.157 mL, 1.762 mmol), and K2CO3 (0.121 g, 0.877 mmol) in ACN (3 mL) and water (1 mL). The resulting mixture was irradiated with microwave at 150 °C for 1 h in a sealed tube. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure, and the resulting crude material was purified by flash chromatography (silica gel 230 - 400 mesh, eluted with 18% EtOAc in petroleum ether) to give the title compound as a light brown solid (0.1 g, 17% yield). LCMS: 351.9 [M+H].

[0346] Intermediate B4

[0347] 4-chloro-5-iodo-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0348]

[0349] Triethylamine (0.905 g, 8.95 mmol) and copper(II) acetate (0.975 g, 5.37 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 1.000 g, 3.58 mmol) and 3-pyridylboronic acid (0.880 g, 7.16 mmol) in DCM (25 mL), and the resulting mixture was stirred at 40 °C under an oxygen atmosphere for 40 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was filtered through a pad of celite, and then washed with DCM (2 × 50 mL). The combined filtrates were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude material. It was stirred with 30% diethyl ether in petroleum ether at 25 °C for 30 min, filtered, and dried to give the title compound as a brown solid (0.4 g, 29% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 9.05 (bs, 1H), 8.73 (s, 1H), 8.67 (bs, 1H), 8.48 (s, 1H), 8.26 - 8.28 (m, 1H), 7.64 - 7.67 (m, 1H). LCMS: 356.8 [M+H].

[0350] Intermediate B5

[0351] 4-Chloro-5-iodo-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0352]

[0353] The title compound was obtained by following a similar procedure as described for B4, starting from 4-chloro-5-iodo-7H-pyrrolo[2,3-d]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].

[0354] Intermediate B6

[0355] 4-Chloro-5-iodo-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0356]

[0357] The title compound was prepared as reported in PCT Publication No. WO 2017 / 220477.

[0358] Intermediate B7

[0359] 7-(3-(Benzyloxy)cyclobutyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0360]

[0361] 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 a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 0.250 g, 0.895 mmol) in DMF (5 mL), and the resulting mixture was stirred at 90 °C for 12 h. After completion of the reaction (as shown by 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 over Na2SO4, filtered, and concentrated under reduced pressure to give a crude material, which was purified by flash chromatography (silica gel 230 - 400 mesh, eluting with 30% EtOAc in petroleum ether) to give the title compound as a colorless gum (0.14 g, 31% yield). LCMS: 440.0 [M+H].

[0362] Intermediate B8

[0363] 2-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol

[0364]

[0365] Potassium carbonate (0.742 g, 5.37 mmol) and 2-bromoethan-1-ol (0.537 g, 4.29 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A, 1.000 g, 3.58 mmol) in DMF (6 mL), and the resulting suspension was stirred at 80 °C for 2 h. After completion of the reaction (as shown by TLC), the reaction mixture was poured into crushed ice (25 g). The resulting solid was filtered, washed with water (20 mL), and dried to give the title compound as a yellow solid (0.84 g, 64% yield). LCMS: 323.9 [M+H].

[0366] Intermediate B9

[0367] 4-Chloro-1-cyclopropyl-3-iodo-1H-pyrrolo[3,2-c]pyridine

[0368] Step 1: Synthesis of 4-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine

[0369]

[0370] 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 a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (0.250 g, 1.638 mmol) and cyclopropylboronic acid (0.279 g, 3.280 mmol) in DMF (10 mL), and the resulting suspension was stirred in a sealed tube at 60 °C for 12 h. After completion of the reaction (as shown by TLC), the reaction mixture was filtered through a pad of Celite and then washed with EtOAc. The combined filtrates were concentrated under reduced pressure to give a crude material, which was purified by Isolera (silica gel 230 - 400 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound as a yellow solid (0.19 g, 59% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.04 (d, J = 5.6 Hz, 1H), 7.56 - 7.60 (m, 2H), 6.52 - 6.53 (m, 1H), 3.55 - 3.58 (m, 1H), 1.00 - 1.13 (m, 4H). LCMS: 193.1 [M+H].

[0371] Step 2: Synthesis of 4-chloro-1-cyclopropyl-3-iodo-1H-pyrrolo[3,2-c]pyridine

[0372]

[0373] Add N-iodosuccinimide (0.350 g, 1.557 mmol) to a solution of 4-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine (0.200 g, 1.038 mmol) in DMF (5 mL), and stir the resulting mixture at 80 °C for 1 h. After completion of the reaction (as shown by LCMS), pour the reaction mixture into crushed ice (25 g) and extract with EtOAc (2 × 25 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter, and concentrate under reduced pressure to give the title product (0.2 g), which is used without further purification. LCMS: 319.0 [M+H].

[0374] Intermediate C1

[0375] 7-Cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0376]

[0377] Irradiate a mixture of 4-chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (B1, 1.00 g, 2.191 mmol) and ammonium hydroxide (25% in water, 5 mL) in a microwave at 150 °C for 1 h. After completion of the reaction (as shown by TLC), concentrate the reaction mixture under reduced pressure to give the title compound as an off-white solid (0.75 g, 80% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.12 (s, 1H), 7.39 (s, 1H), 6.57 (bs, 2H), 3.48 - 3.54 (m, 1H), 0.97 - 1.01 (m, 4H). LCMS: 301.0 [M+H].

[0378] Intermediate C2

[0379] 5-Iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0380]

[0381] The title compound was prepared via a similar procedure as described for C1, starting from 4-chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (B2, 0.5 g, 1.49 mmol) and aqueous ammonium hydroxide (25% in water, 2.5 mL), and obtained as a light brown solid (0.27 g, 58% yield). LCMS: 316.8 [M+H].

[0382] Intermediate C3

[0383] 1-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

[0384]

[0385] According to a similar procedure as described for C1, starting from 1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (B3, 0.1 g, 0.284 mmol) and ammonium hydroxide (25% in water, 0.5 mL), the title compound was obtained as an off-white solid (0.08 g, 85% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.12 (s, 1H), 7.38 (s, 1H), 4.81 (s, 1H), 4.04 (s, 2H), 1.03 (s, 6H). LCMS: 333.0 [M+H].

[0386] Intermediate C4

[0387] 5-Iodo-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0388]

[0389] Ammonium hydroxide (25% in water, 1 mL) was added to a solution of 4-chloro-5-iodo-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (B4, 0.30 g, 0.841 mmol) in dioxane (10 mL), and the resulting mixture was irradiated with microwave at 150 °C for 2 h. After completion of the reaction (as shown by LCMS), the reaction mixture was concentrated under reduced pressure to give a crude material, which was washed with methyl tert-butyl ether and dried to give the title compound as an off-white solid (0.21 g, 63% yield). LCMS: 337.8 [M+H].

[0390] Intermediate C5

[0391] 5-Iodo-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0392]

[0393] Following a similar procedure as described for C4, starting from 4-chloro-5-iodo-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (B5, 0.21 g, 0.589 mmol) and ammonium hydroxide (25% in water, 1 mL), the title compound was obtained as an off-white solid (0.16 g, 69% yield). LCMS: 337.9 [M+H].

[0394] Intermediate C6

[0395] 5-Iodo-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0396]

[0397] The title compound was prepared as reported in PCT Publication No. WO 2017 / 220477.

[0398] Intermediate C7

[0399] 7-(3-(Benzyloxy)cyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0400]

[0401] The title compound was obtained as an off-white solid (0.06 g, 45% yield) by following a similar procedure as described for C4, starting from 7-(3-(benzyloxy)cyclobutyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (B7, 0.140 g, 0.318 mmol) and ammonium hydroxide (25% in water, 1.4 mL). LCMS: 421.1 [M+H].

[0402] Intermediate C8

[0403] 5-Iodo-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0404]

[0405] The title compound was prepared as reported in PCT Publication No. WO 2014 / 184069 A1.

[0406] Intermediate C9

[0407] 2-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol

[0408]

[0409] The title compound was obtained by following a similar procedure as described for C4, starting from 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (B8, 0.84 g, 2.61 mmol) and ammonium hydroxide (25% in water, 8 mL), and was obtained as an off-white solid (0.94 g, 69% yield). LCMS: 305.0 [M+H].

[0410] Intermediate C10

[0411] 7-Cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0412]

[0413] The title compound was prepared as reported in PCT Publication No. WO 2016 / 075224.

[0414] Intermediate C11

[0415] 5-Iodo-7-(1-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0416]

[0417] The title compound was prepared as reported in PCT Publication No. WO 2016 / 075224.

[0418] Intermediate D1

[0419] 5-(4-Amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0420]

[0421] 7-Cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in a mixture of 1,4-dioxane (1 mL) and water (0.3 mL) were purged with N2 for 10 minutes. Then Pd(PPh3)4 (0.062 g, 0.053 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 hours. After completion of the reaction (as indicated by TLC), the mixture was filtered through a Celite pad and then washed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230 - 400 mesh, eluting with 3% MeOH in DCM) to give the title compound as a yellow solid (0.110 g, 73% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.13 (s, 1H), 7.05 - 7.09 (m, 1H), 6.95 - 6.98 (m, 1H), 6.82 - 6.86 (m, 1H), 6.10 (bs, 2H), 5.22 (bs, 2H), 3.52 - 3.58 (m, 1H), 1.00 - 1.04 (m, 4H). LCMS: 284.1 [M+H].

[0422] Intermediate D2

[0423] 5-(4-Aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0424] Step 1: Synthesis of 5-(4-nitrophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0425]

[0426] The title compound was prepared via a similar procedure as described for D1, starting from 4-chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (C2, 0.252 g, 0.797 mmol) and (4-nitrophenyl)boronic acid (0.200 g, 1.198 mmol), and obtained as a light brown solid (0.143 g, 58% yield). LCMS: 312.1 [M+H].

[0427] Step 2: Synthesis of 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0428]

[0429] Iron powder (0.251 g, 4.5 mmol) and ammonium chloride (0.240 g, 4.5 mmol) were added to a solution of 5-(4-nitrophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.14 g, 0.45 mmol) in ethanol (5 mL) and water (2 mL), and the resulting mixture was stirred at 80 °C for 3 h. After completion of the reaction (as indicated by TLC), the mixture was filtered through a pad of celite and then washed with EtOAc (2 x 5 mL). The combined filtrates were concentrated under reduced pressure to give a residue, which was dissolved in EtOAc (25 mL), washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a brown solid (0.12 g, quantitative yield), which was used without further purification. LCMS: 281.9 [M+H].

[0430] Intermediate D3

[0431] 1-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

[0432]

[0433] The title compound was prepared by a similar method as described for D1, starting from 1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (C3, 0.100 g, 0.301 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.086 g, 0.361 mmol), and was obtained as a pale yellow gum (0.05 g, 53% yield). LCMS: 316.1 [M+H].

[0434] Intermediate D4

[0435] 5-(4-aminophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0436] Step 1: Synthesis of 7-cyclopropyl-5-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0437]

[0438] The title compound was obtained starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.18 g, 0.60 mmol) and (4-nitrophenyl)boronic acid (0.12 g, 0.72 mmol) by following a similar procedure as described for D1, and was obtained as a light brown solid (0.10 g, 56% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.28 - 8.32 (m, 2H), 8.21 (s, 1H), 7.77 (s, 1H), 7.70 - 7.73 (m, 2H), 7.55 (s, 1H), 5.69 (bs, 2H), 3.61 - 3.64 (m, 1H), 1.04 - 1.09 (m, 4H). LCMS: 296.1 [M+H].

[0439] Step 2: Synthesis of 5-(4-aminophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0440]

[0441] The title compound was obtained starting from 7-cyclopropyl-5-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.10 g, 0.33 mmol) and Fe / NH4Cl following a similar method as described for Step 2 of D2, and was obtained as a brown gum (0.08 g, 90% yield), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.04 - 7.11 (m, 2H), 7.04 (s, 1H), 6.63 - 6.67 (m, 2H), 6.05 (bs, 2H), 5.27 (bs, 2H), 3.51 - 3.57 (m, 1H), 0.99 - 1.04 (m, 4H). LCMS: 266.0 [M+H].

[0442] Intermediate D5

[0443] 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0444]

[0445] The title compound was obtained by following a similar procedure as described for D1, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.21 g, 0.69 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.20 g, 0.83 mmol), and was obtained as a pale yellow gum (0.15 g, 76% yield). LCMS: 284.1 [M+H].

[0446] Intermediate D6

[0447] 5-(6-Aminopyridin-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0448] Step 1: Synthesis of 7-cyclopropyl-5-(6-nitropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0449]

[0450] The title compound was obtained by following a similar procedure as described for D1, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.28 g, 0.94 mmol) and 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.28 g, 1.13 mmol), and was obtained as a light brown solid (0.16 g, 57% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.73 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.23 (s, 1H), 8.17 - 8.20 (m, 1H), 7.67 (s, 1H), 6.49 (bs, 2H), 3.61 - 3.67 (m, 1H), 1.06 - 1.09 (m, 4H). LCMS: 297.1 [M+H].

[0451] Step 2: Synthesis of 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0452]

[0453] The title compound was obtained by following a similar procedure as described in Step 2 for D2, starting from 7-cyclopropyl-5-(6-nitropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.16 g, 0.54 mmol) and Fe / NH4Cl, and was obtained as a light brown solid (0.1 g, 70% yield), which was used without further purification. LCMS: 267.0 [M+H].

[0454] Intermediate D7

[0455] 5-(4-Aminocyclohex-1-en-1-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0456] Step 1: Synthesis of tert-butyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohex-3-en-1-yl)carbamate

[0457]

[0458] K2CO3 (0.318 g, 2.299 mmol) was added to a solution of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Cl, 0.230 g, 0.766 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (0.372 g, 1.150 mmol) in dioxane (1 mL) and water (0.3 mL). The solution was purged with N2 for 10 minutes, then Pd(PPh3)4 (0.044 g, 0.038 mmol) was added, and the resulting mixture was irradiated in a microwave at 100 °C for 1 hour. After completion of the reaction (as shown by TLC), the mixture was filtered through a pad of diatomaceous earth and then washed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to give a crude material, which was purified by preparative HPLC (gradient elution with ammonium acetate in water and ACN based on mass) to give the title product as a pale yellow gum (0.18 g, 62% yield). LCMS: 370.2 [M+H].

[0459] Step 2: Synthesis of 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0460]

[0461] At 0 °C, TFA (0.012 g, 0.108 mmol) was added to a solution of tert-butyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohex-3-en-1-yl)carbamate (0.040 g, 0.108 mmol) in DCM (2 mL), and the resulting solution was stirred at room temperature for 12 h. After completion of the reaction (as shown by TLC), the reaction mixture was concentrated under reduced pressure to give the title product as a brown gum (0.029 g), which was used without further purification. LCMS: 270.1 [M+H].

[0462] Intermediate D8

[0463] 5-(4-Amino-3-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0464]

[0465] 5-Iodo-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C4, 0.160 g, 0.475 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.169 g, 0.712 mmol) and K2CO3 (0.131 g, 0.949 mmol) in a mixture of dioxane (5 mL), water (2 mL) and ethanol (3 mL) were purged with N2 for 10 min. PdCl2(dppf) (0.017 g, 0.024 mmol) was added, and the resulting mixture was irradiated by microwave at 100 °C for 1 h. After completion of the reaction (as shown by LCMS), the reaction mixture was filtered through a pad of celite and then washed with EtOAc (5 mL). The combined filtrates were concentrated under reduced pressure to give a residue, which was dissolved in EtOAc (50 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by GRACE (silica gel 230 - 400 mesh, eluting with 4% MeOH in DCM) to give the title compound as a brown solid (0.2 g, 70% yield). LCMS: 321.0 [M+H].

[0466] Intermediate D9

[0467] 5-(4-Amino-3-fluorophenyl)-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0468]

[0469] Following a similar procedure as described for D8, starting from 5-iodo-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C5, 0.160 g, 0.475 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.169 g, 0.712 mmol), the title compound was obtained and isolated as a pale yellow gum (0.08 g, 51% yield). LCMS: 321.0 [M+H].

[0470] Intermediate D10

[0471] 5-(4-Amino-3-fluorophenyl)-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0472]

[0473] By following a similar procedure as described for D8, starting from 5-iodo-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C6, 0.180 g, 0.504 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.131 g, 0.554 mmol), the title compound was obtained and isolated as a brown gum (0.15 g, 80% yield). LCMS: 341.1 [M+H].

[0474] Intermediate D11

[0475] 5-(4-Amino-3-methylphenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0476]

[0477] By following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.214 g, 0.916 mmol), the title compound was obtained and isolated as a brown gum (0.13 g, 56% yield). LCMS: 280.1 [M+H].

[0478] Intermediate D12

[0479] 5-(4-Amino-3-fluorophenyl)-7-(3-(benzyloxy)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0480]

[0481] The title compound was obtained by following a similar procedure as described for D8, starting from 7-(3-(benzyloxy)cyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C7, 0.060 g, 0.143 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.037 g, 0.157 mmol), and was obtained as a brown solid (0.03 g, 53% yield). LCMS: 404.2 [M+H].

[0482] Intermediate D13

[0483] Step 1: Synthesis of 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0484]

[0485] Potassium acetate (0.245 g, 2.499 mmol) was added to a solution of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and bis(pinacolato)diboron (0.317 g, 1.250 mmol) in DMSO (5 mL), and the resulting mixture was purged with 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 completion of the reaction, the reaction mixture was filtered through a pad of Celite and then washed with DCM (2 × 20 mL). The combined filtrates were concentrated under reduced pressure to give the title compound as a black residue, which was used without further purification. LCMS: 300.9 [M+H].

[0486] Step 2: Synthesis of 5-(5-amino-4-methylpyridin-2-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0487]

[0488] The title compound was obtained by following a similar procedure as described for D8, starting from 6-bromo-4-methylpyridin-3-amine (0.142 g, 0.759 mmol) and 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.251 g, 0.835 mmol), and was obtained as a brown gum (0.05 g, 13% yield). LCMS: 281.0 [M+H].

[0489] Intermediate D14

[0490] 5-(5-Aminopyridin-2-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0491]

[0492] The title compound was obtained by following a similar procedure as described for D8, starting from 6-bromo-4-methylpyridin-3-amine (0.130 g, 0.751 mmol) and 7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (step 1 of intermediate D13, 0.248 g, 0.827 mmol), and was obtained as a brown gum (0.03 g, 4.5% yield). LCMS: 267.0 [M+H].

[0493] Intermediate D15

[0494] 5-(4-Amino-3,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0495]

[0496] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.500 g, 0.751 mmol) and 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.425 g, 1.666 mmol), and was obtained as a light yellow solid (0.10 g, 19% yield). LCMS: 302.1 [M+H].

[0497] Intermediate D16

[0498] 5-(4-Amino-2,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0499]

[0500] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.125 g, 0.417 mmol) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (prepared as reported in PCT Publication No. WO 2017 / 172093, 0.106 g, 4.17 mmol), and was obtained as a light yellow solid (0.05 g, 40% yield). LCMS: 302.1 [M+H].

[0501] Intermediate D17

[0502] 5-(4-Amino-2,6-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0503]

[0504] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.055 g, 0.183 mmol) and 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (prepared as reported in PCT Publication No. WO 2017 / 172093, 0.056 g, 0.220 mmol), and was obtained as a light brown gum (0.046 g), which was used without further purification. LCMS: 301.9 [M+H].

[0505] Intermediate D18

[0506] 1-(4-Amino-5-(6-aminopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

[0507]

[0508] The title compound was obtained by following a similar procedure as described for D8, starting from 1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (C3, 0.280 g, 0.733 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.161 g, 0.733 mmol), and was obtained as a yellow gum (0.12 g, 50% yield). LCMS: 299.1 [M+H].

[0509] Intermediate D19

[0510] 5-(2-Aminopyrimidin-5-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0511]

[0512] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.25 g, 0.833 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.184 g, 0.833 mmol), and was obtained as a colorless gum (0.08 g, 34% yield). LCMS: 268.2 [M+H].

[0513] Intermediate D20

[0514] (2-Amino-5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanol

[0515]

[0516] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.200 g, 0.666 mmol) and (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanol (prepared as reported in PCT Publication No. WO 2011 / 130628, 0.184 g, 0.733 mmol), and was obtained as a light yellow gum (0.025 g, 13% yield). LCMS: 296.0 [M+H].

[0517] Intermediate D21

[0518] 2-Amino-5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile

[0519]

[0520] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.203 g, 0.833 mmol), and obtained as a yellow gum (0.13 g, 34% yield). LCMS: 291.2 [M+H].

[0521] Intermediate D22

[0522] 5-(4-Amino-3-fluorophenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0523]

[0524] The title compound was obtained by following a similar procedure as described for D8, starting from 5-iodo-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C8, 0.200 g, 0.629 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.149 g, 0.629 mmol), and obtained as a light brown solid (0.12 g, 42% yield). LCMS: 302.2 [M+H].

[0525] Intermediate D23

[0526] 2-(4-Amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol

[0527]

[0528] The title compound was obtained by following a similar procedure as described for D8, starting from 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (C9, 0.50 g, 1.644 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.39 g, 1.644 mmol), and obtained as a brown solid (0.3 g, 63% yield). LCMS: 288.1 [M+H].

[0529] Intermediate D24

[0530] 5-(4-Amino-3-fluorophenyl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0531]

[0532] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C10, 0.410 g, 1.305 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.309 g, 1.305 mmol), and was obtained as a brown solid (0.18 g, 37% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.51 (s, 1H), 7.09 - 7.13 (m, 1H), 6.98 - 7.01 (m, 1H), 6.84 - 6.88 (m, 1H), 6.21 (bs, 2H), 5.14 - 5.26 (m, 3H), 2.67 - 2.68 (m, 2H), 2.38 - 2.39 (m, 2H), 1.85 - 1.86 (m, 2H). LCMS: 298.0 [M+H].

[0533] Intermediate D25

[0534] 5-(4-Amino-3-chlorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0535]

[0536] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.211 g, 0.833 mmol), and was obtained as a yellow solid (0.03 g, 12% yield). LCMS: 300.1 [M+H].

[0537] Intermediate D26

[0538] 5-(4-Amino-3-methoxyphenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0539]

[0540] The title compound was obtained by following a similar procedure as described for D8, starting from 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.250 g, 0.833 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.208 g, 0.833 mmol), and was obtained as a pale yellow gum (0.04 g, 16% yield). LCMS: 296.1 [M+H].

[0541] Intermediate D27

[0542] 5-(4-Amino-3-fluorophenyl)-7-(1-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0543]

[0544] The title compound was obtained by following a similar procedure as described for D8, starting from 5-iodo-7-(1-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C11, 0.155 g, 0.452 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.107 g, 0.452 mmol), and was obtained as a brown solid (0.084 g, 27% yield). LCMS: 327.2 [M+H].

[0545] Intermediate E1-E25

[0546] General procedure for the synthesis of carbamate intermediate E:

[0547] Pyridine (1.2 equiv) and phenyl chloroformate (1.5 equiv) were added to a solution of the amine (1.0 equiv) in THF (10 volumes) at 0 °C. The reaction mixture was allowed to warm to 25 °C and stirred for 12 h. After completion of the reaction (as shown by TLC), the mixture was diluted with EtOAc (10 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, 10% to 20% EtOAc in petroleum ether) to give the desired carbamate.

[0548] The following carbamates were prepared using the above general procedure:

[0549]

[0550]

[0551]

[0552]

[0553] All amines used for the synthesis of the carbamate intermediate E are commercially available, except for the following:

[0554] As reported in Synthesis 2013, 45, 171–173, the synthesis of 3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-amine (precursor of E6) and 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (precursor of E7).

[0555] The synthesis of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (precursor of E8) and 3-(2-fluoropropan-2-yl)isoxazol-5-amine (precursor of E9) from methyl 3,3,3-trifluoro-2,2-dimethylpropionate and methyl 2-fluoro-2-methylpropionate respectively, followed by the procedure reported in Synthesis 2013, 45, 171–173.

[0556] As reported in PCT Publication No. WO 2010 / 036630, the synthesis of 3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-amine (precursor of E16).

[0557] As reported in J.Med.Chem.2012, 55(3), 1082-1105, the synthesis of 2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile (precursor of E22) and 3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-amine (precursor of E24).

[0558] As reported in PCT Publication No. WO 2013 / 104561, the synthesis of 3-(((tert-butyldiphenylsilyl)oxy)methyl)isoxazol-5-amine (precursor of E23).

[0559] As reported in PCT Publication No. WO 2011 / 022473, the synthesis of 5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-amine (precursor of E25).

[0560] Synthesis of 3-(3-methyloxetan-3-yl)isoxazol-5-amine (precursor of E14):

[0561]

[0562] NH2OH·H2SO4 (0.520 g, 3.16 mmol) was added to a solution of 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile (prepared as reported in PCT Publication No. WO 2019 / 192962, 0.400 g, 2.87 mmol) and sodium hydroxide (0.126 g, 3.16 mmol) in EtOH (10 mL) and water (10 mL). The pH of the resulting mixture was adjusted to 7.5 using aqueous NaOH (1 M), and the reaction mixture was stirred at 80 °C for 15 h. After completion of the reaction (as indicated 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 as a light brown solid (0.09 g, 20% yield). 1 1H 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].

[0563] Synthesis of 3-(1-methylcyclobutyl)isoxazol-5-amine (precursor of E21):

[0564]

[0565] NH2OH·H2SO4 (0.699 g, 4.25 mmol) was added to a solution of 3-(1-methylcyclobutyl)-3-oxopropanenitrile (prepared as reported in PCT Publication No. WO 2017 / 060874, 0.500 g, 3.86 mmol) and sodium hydroxide (0.170 g, 4.25 mmol) in EtOH (10 mL) and water (10 mL). The pH of the resulting mixture was adjusted to 7.5 using aqueous NaOH (1 M), and the reaction mixture was stirred at 80 °C for 15 h. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue, which was taken up in DCM (25 mL), washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (silica gel 230 - 400 mesh, eluting with 40% EtOAc in petroleum ether) to give the title product as an off-white solid (0.110 g, 19% yield). 11H 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].

[0566] Preparation of Examples

[0567] General Urea Formation Procedure for Synthesizing Examples 1 to 62

[0568] Method A - Triethylamine (2.0 equiv) was added to a mixture of amine intermediate D (1.0 equiv) and carbamate intermediate E (1.0 equiv) in THF (10 volumes), and the resulting mixture was stirred in a sealed tube at 60 °C for 12 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give a crude material, which was purified by reverse-phase preparative HPLC to give the desired product.

[0569] Method B - DMAP (0.05 equiv) and DIPEA (1.5 equiv) were added to a solution of amine intermediate D (1.0 equiv) and carbamate intermediate E (1.0 equiv) in THF (10 volumes), and the resulting mixture was stirred in a sealed tube at 60 °C for 12 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give a crude material, which was purified by reverse-phase preparative HPLC to give the desired product.

[0570] The following compounds were prepared using the general method described above.

[0571] Example 1

[0572] 1-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0573]

[0574] The title compound was prepared according to the general procedure for urea formation (Method A) starting from 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.16 g, 0.30 mmol), and obtained as an off-white solid (0.026 g, 9% yield). 11H NMR (400 MHz, DMSO-d6) δ = 10.48 (broad singlet, 1H), 9.34 (broad singlet, 1H), 8.15 (singlet, 1H), 7.70 (singlet, 1H), 7.61 (doublet, J = 8.8 Hz, 2H), 7.45 (doublet, J = 8.8 Hz, 2H), 6.08 (broad singlet, 2H), 6.07 (singlet, 1H), 5.86 - 5.90 (multiplet, 1H), 4.97 - 5.05 (multiplet, 4H), 1.27 (singlet, 9H). LCMS: 448.2 [M+H].

[0575] Example 2

[0576] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0577]

[0578] According to the general procedure for urea formation (Method A), starting from 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D2, 0.178 g, 0.63 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.16 g, 0.30 mmol), the title compound was prepared and obtained as an off-white solid (0.026 g, 9% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.48 (broad singlet, 1H), 9.34 (broad singlet, 1H), 8.15 (singlet, 1H), 7.70 (singlet, 1H), 7.61 (doublet, J = 8.8 Hz, 2H), 7.45 (doublet, J = 8.8 Hz, 2H), 6.08 (broad singlet, 2H), 6.07 (singlet, 1H), 5.86 - 5.90 (multiplet, 1H), 4.97 - 5.05 (multiplet, 4H), 1.27 (singlet, 9H). LCMS: 448.2 [M+H].

[0579] Example 3

[0580] 1-(5-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0581]

[0582] According to the general procedure for urea formation (Method A), the title compound was prepared starting from 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D6, 0.100 g, 0.376 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.098 g, 0.386 mmol), and obtained as an off-white solid (9.6 mg, 6% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.46 - 8.47 (m, 1H), 8.22 (s, 1H), 7.89 - 7.92 (m, 2H), 7.35 - 7.38 (m, 1H), 7.28 (s, 1H), 6.23 (s, 1H), 3.50 - 3.57 (m, 1H), 1.27 (s, 9H), 1.07 - 1.16 (m, 4H); LCMS: 433.2 [M+H].

[0583] Example 4

[0584] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea

[0585]

[0586] According to the general procedure for urea formation (Method A), the title compound was prepared starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (5-(tert-butyl)isoxazol-3-yl)carbamate (E2, 0.091 g, 0.35 mmol), and obtained as an off-white solid (0.021 mg, 13% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.86 (bs, 1H), 8.87 (bs, 1H), 8.17 - 8.21 (m, 2H), 7.24 - 7.35 (m, 3H), 6.51 (s, 1H), 6.17 (bs, 2H), 3.56 - 3.60 (m, 1H), 1.31 (s, 9H), 1.02 - 1.07 (m, 4H). LCMS: 450.2 [M+H].

[0587] Example 5

[0588] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0589]

[0590] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.088 g, 0.282 mmol), the title compound was prepared and 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].

[0591] Example 6

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

[0593]

[0594] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.060 g, 0.180 mmol) and phenyl (5-cyclopropylisoxazol-3-yl)carbamate (E5, 0.044 g, 0.282 mmol), the title compound was prepared and obtained as an off-white solid (8.4 mg, 9% yield). 1 H NMR (400 MHz, CD3OD) δ = 8.20 - 8.22 (m, 2H), 7.28 - 7.33 (m, 2H), 7.22 (s, 1H), 6.35 (s, 1H), 3.49 - 3.55 (m, 1H), 2.08 - 2.12 (m, 1H), 1.08 - 1.16 (m, 6H), 0.97 - 0.99 (m, 2H). LCMS: 434.2 [M+H].

[0595] Example 7

[0596] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-methylisoxazol-5-yl)urea

[0597]

[0598] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.100 g, 0.35 mmol) and phenyl (3-methylisoxazol-5-yl)carbamate (E3, 0.077 g, 0.35 mmol), the title compound was prepared and obtained as an off-white solid (0.024 mg, 17% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.35 (bs, 1H), 8.84 (bs, 1H), 8.10 - 8.18 (m, 2H), 7.25 - 7.36 (m, 3H), 6.13 (bs, 2H), 5.99 (s, 1H), 3.55 - 3.61 (m, 1H), 2.18 (s, 3H), 1.00 - 1.08 (m, 4H). LCMS: 408.1 [M+H].

[0599] Example 8

[0600] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea

[0601]

[0602] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.127 g, 0.44 mmol) and phenyl (5-methylisoxazol-3-yl)carbamate (E4, 0.097 g, 0.44 mmol), the title compound was prepared and obtained as a white solid (0.033 mg, 18% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 9.88 (bs, 1H), 8.96 (bs, 1H), 8.15 - 8.19 (m, 2H), 7.24 - 7.35 (m, 3H), 6.54 (s, 1H), 6.15 (bs, 2H), 3.55 - 3.61 (m, 1H), 2.38 (s, 3H), 1.00 - 1.07 (m, 4H). LCMS: 408.2 [M+H].

[0603] Example 9

[0604] 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

[0605]

[0606] According to the general procedure for urea formation (Method A), the title compound was prepared starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.076 g, 0.26 mmol) and phenyl (3-(2-fluoropropan-2-yl)isoxazol-5-yl)carbamate (E9, 0.070 g, 0.26 mmol), and obtained as a white solid (0.018 g, 14% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.99 (bs, 1H), 8.17 (s, 1H), 8.09 - 8.14 (m, 1H), 7.25 - 7.36 (m, 3H), 6.18 (s, 1H), 6.09 (bs, 2H), 3.57 - 3.61 (m, 1H), 1.71 (s, 3H), 1.66 (s, 3H), 1.02 - 1.05 (m, 4H). LCMS: 454.2 [M+H].

[0607] Example 10

[0608] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0609]

[0610] According to the general procedure for urea formation (Method A), the title compound was prepared starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.10 g, 0.35 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.11 g, 0.35 mmol), and obtained as an off-white solid (0.010 g, 6% yield). 11H 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].

[0611] Example 11

[0612] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0613]

[0614] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D5, 0.070 g, 0.24 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.082 g, 0.24 mmol), the title compound was prepared and obtained as an off-white solid (0.011 g, 9% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.56 (bs, 1H), 9.29 (bs, 1H), 8.16 (s, 1H), 7.58 - 7.62 (m, 1H), 7.27 - 7.36 (m, 2H), 7.22 (s, 1H), 6.20 (s, 1H), 6.00 (bs, 2H), 3.55 - 3.60 (m, 1H), 1.38 - 1.48 (m, 4H), 1.02 - 1.06 (m, 4H). LCMS: 502.2 [M+H].

[0615] Example 12

[0616] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea

[0617]

[0618] According to the general procedure for urea formation (Method A), the title compound was prepared starting from 5-(4-amino-2-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)carbamate (E8, 0.055 g, 0.176 mmol), and obtained as an off-white solid (9.9 mg, 11% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.59 (bs, 1H), 8.83 (bs, 1H), 8.18 (s, 1H), 8.12 - 8.17 (m, 1H), 7.25 - 7.36 (m, 3H), 6.22 (s, 1H), 6.17 (bs, 2H), 3.55 - 3.61 (m, 1H), 1.52 (s, 6H), 1.02 - 1.07 (m, 4H). LCMS: 504.2 [M+H].

[0619] Example 13

[0620] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0621]

[0622] According to the general procedure for urea formation (Method A), the title compound was prepared starting from 5-(4-aminophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D4, 0.080 g, 0.30 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.078 g, 0.30 mmol), and obtained as an off-white solid (0.036 g, 28% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.13 (bs, 1H), 8.93 (bs, 1H), 8.16 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.22 (s, 1H), 6.08 (s, 1H), 6.00 (bs, 2H), 3.56 - 3.59 (m, 1H), 1.27 (s, 9H), 1.05 - 1.07 (m, 4H). LCMS: 430.2 [M-H].

[0623] Example 14

[0624] 1-(4-(4-Amino-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0625]

[0626] According to the general procedure for urea formation (Method A), starting from 1-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (D3, 0.086 g, 0.273 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.085 g, 0.273 mmol), the title compound was prepared and obtained as a light brown solid (0.011 g, 8% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.92 (bs, 1H), 9.06 (bs, 1H), 8.11 - 8.15 (m, 2H), 7.26 - 7.35 (m, 3H), 6.18 (s, 1H), 6.14 (bs, 2H), 4.86 (bs, 1H), 4.11 (bs, 2H), 1.37 - 1.46 (m, 4H), 1.06 - 1.08 (m, 6H). LCMS: 534.1 [M+H].

[0627] Example 15

[0628] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohex-3-en-1-yl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0629]

[0630] According to the general procedure for urea formation (Method A), starting from 5-(4-aminocyclohex-1-en-1-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D7, 0.120 g, 0.446 mmol) and phenyl (3-(tert-butyl)isoxazol-5-yl)carbamate (E1, 0.116 g, 0.446 mmol), the title compound was prepared and obtained as an off-white solid (0.013 g, 7% yield). 1HNMR(400MHz, DMSO-d6) δ = 9.83(bs, 1H), 8.39(bs, 1H), 7.47(s, 1H), 6.54(d, J = 7.6Hz, 1H), 5.93(s, 1H), 5.67(bs, 1H), 3.88 - 3.90(m, 2H), 3.61 - 3.67(m, 2H), 2.08 - 2.14(m, 1H), 1.92 - 1.95(m, 1H), 1.69 - 1.73(m, 1H), 1.24(s, 9H), 1.05 - 1.08(m, 4H). LCMS: 436.2[M + H].

[0631] Example 16

[0632] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohexyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0633]

[0634] Platinum(IV) oxide (0.016 g, 0.069 mmol) was added to a solution of 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohex-3-en-1-yl)-3-(3-(tert-butyl)isoxazol-5-yl)urea (Example 15, 0.100 g, 0.230 mmol) in EtOAc (5 mL), and the resulting suspension was stirred at room temperature under a H2 atmosphere for 12 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was filtered through a Celite pad and then washed with EtOAc (2 x 5 mL). The combined filtrates were concentrated under reduced pressure to give a crude material, which was purified by preparative HPLC (gradient elution with ammonium acetate in water and ACN based on mass) to give the title product as an off-white solid (2.0 mg, 2% yield). 1 H NMR(400MHz, 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[M - H].

[0635] Example 17

[0636] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclopropyl)isoxazol-5-yl)urea

[0637]

[0638] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(1-methylcyclopropyl)isoxazol-5-yl)carbamate (E10, 0.046 g, 0.176 mmol), the title compound was obtained and obtained as an off-white solid (0.013 g, 16% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.40 (bs, 1H), 8.84 (bs, 1H), 8.11 - 8.17 (m, 2H), 7.24 - 7.36 (m, 3H), 6.16 (bs, 2H), 5.84 (s, 1H), 3.55 - 3.61 (m, 1H), 1.38 (s, 3H), 1.02 - 1.07 (m, 4H), 0.94 - 0.96 (m, 2H), 0.83 - 0.84 (m, 2H). LCMS: 448.2 [M+H].

[0639] Example 18

[0640] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(tert-butyl)thiazol-2-yl)urea

[0641]

[0642] According to the general procedure for urea formation (Method A), starting from phenyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 4-(tert-butyl)thiazol-2-amine (0.015 g, 0.099 mmol), the title compound was obtained and obtained as an off-white solid (7.0 mg, 15% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.99 (bs, 1H), 9.29 (bs, 1H), 8.46 (s, 1H), 8.26 - 8.30 (m, 1H), 7.67 (s, 1H), 7.38 - 7.41 (m, 1H), 7.27 - 7.30 (m, 1H), 6.70 (s, 1H), 3.71 (bs, 1H), 1.27 (s, 9H), 1.10 - 1.10 (m, 4H). LCMS: 466.0 [M+H].

[0643] Example 19

[0644] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)urea

[0645]

[0646] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (5-(tert-butyl)-1,3,4-thiadiazol-2-yl)carbamate (E12, 0.049 g, 0.176 mmol), the title compound was obtained and 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].

[0647] Example 20

[0648] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isothiazol-5-yl)urea

[0649]

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

[0651] Example 21

[0652] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)urea

[0653]

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

[0655] Example 22

[0656] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(1-(tert-butyl)-1H-1,2,4-triazol-3-yl)urea

[0657]

[0658] According to the general procedure for urea formation (Method A), starting from phenyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 1-(tert-butyl)-1H-1,2,4-triazol-3-amine (0.014 g, 0.099 mmol), the title compound was obtained and obtained as an off-white solid (3.0 mg, 6% yield). 11H NMR (400 MHz, DMSO-d6) δ = 10.70 (broad singlet, 1H), 10.16 (broad singlet, 1H), 8.54 (singlet, 1H), 8.31 - 8.35 (multiplet, 1H), 8.16 (singlet, 1H), 7.25 - 7.37 (multiplet, 3H), 6.17 (broad singlet, 2H), 3.56 - 3.59 (multiplet, 1H), 1.57 (singlet, 9H), 1.02 - 1.05 (multiplet, 4H). LCMS: 450.0 [M+H].

[0659] Example 23

[0660] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)urea

[0661]

[0662] According to the general procedure for urea formation (Method A), starting from phenyl (4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamate (E11, 0.040 g, 0.099 mmol) and 5-(tert-butyl)-1,3,4-oxadiazol-2-amine (0.014 g, 0.099 mmol), the title compound was obtained and obtained as an off-white solid (2.0 mg, 4% yield). 1 1H NMR (400 MHz, CD3OD) δ = 8.35 (singlet, 1H), 8.26 - 8.30 (multiplet, 1H), 7.48 (singlet, 1H), 7.31 - 7.40 (multiplet, 2H), 3.69 - 3.71 (multiplet, 1H), 1.45 (singlet, 9H), 1.17 - 1.22 (multiplet, 4H). LCMS: 451.0 [M+H].

[0663] Example 24

[0664] 1-(4-(4-Amino-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0665]

[0666] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D8, 0.100 g, 0.312 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.107 g, 0.343 mmol), the title compound was obtained and obtained as a white solid (0.023 g, 14% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.69 (bs, 1H), 9.13 (bs, 1H), 8.97 (bs, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.31 - 8.36 (m, 2H), 8.20 - 8.24 (m, 1H), 7.95 (s, 1H), 7.62 - 7.65 (m, 1H), 7.38 - 7.50 (m, 2H), 6.76 (bs, 2H), 6.21 (s, 1H), 1.39 - 1.47 (m, 4H). LCMS: 538.8 [M+H].

[0667] Example 25

[0668] 1-(4-(4-Amino-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0669]

[0670] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D9, 0.080 g, 0.250 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.086 g, 0.275 mmol), the title compound was obtained and obtained as an off-white solid (0.046 g, 33% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.68 (bs, 1H), 9.00 (bs, 1H), 8.89 (d, J = 6.4 Hz, 2H), 8.58 (d, J = 6.4 Hz, 2H), 8.43 (s, 1H), 8.21 - 8.27 (m, 2H), 7.49 - 7.52 (m, 1H), 7.39 - 7.42 (m, 1H), 6.90 (bs, 2H), 6.22 (s, 1H), 1.39 - 1.49 (m, 4H). LCMS: 538.9 [M+H].

[0671] Example 26

[0672] 1-(4-(4-Amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0673]

[0674] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D10, 0.020 g, 0.059 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.018 g, 0.059 mmol), the title compound was obtained and isolated as a white solid (2.4 mg, 7% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.68 (bs, 1H), 8.96 (bs, 1H), 8.32 (s, 1H), 8.16 - 8.20 (m, 1H), 7.55 (s, 1H), 7.38 - 7.41 (m, 1H), 7.29 - 7.31 (m, 1H), 6.98 (bs, 2H), 6.21 (s, 1H), 4.85 - 4.91 (m, 1H), 3.59 - 3.62 (m, 4H), 2.85 (s, 3H), 2.21 - 2.34 (m, 4H), 1.38 - 1.49 (m, 4H). LCMS: 559.2 [M+H].

[0675] Example 27

[0676] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(3-methyloxetan-3-yl)isoxazol-5-yl)urea

[0677]

[0678] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(3-methyloxetan-3-yl)isoxazol-5-yl)carbamate (E14, 0.048 g, 0.176 mmol), the title compound was obtained and isolated as a white solid (3.4 mg, 4% yield). 11H 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].

[0679] Example 28

[0680] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea

[0681]

[0682] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(trifluoromethyl)isoxazol-5-yl)carbamate (E15, 0.048 g, 0.176 mmol), the title compound was obtained and obtained as a white solid (2.9 mg, 4% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 11.03 (bs, 1H), 8.97 (bs, 1H), 8.19 (s, 1H), 8.10 (t, J = 8.4 Hz, 1H), 7.27 - 7.38 (m, 3H), 6.54 (s, 1H), 6.30 (bs, 2H), 3.56 - 3.60 (m, 1H), 1.03 - 1.05 (m, 4H). LCMS: 461.9 [M+H].

[0683] Example 29

[0684] 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

[0685] Step 1: Synthesis of 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-yl)urea

[0686]

[0687] According to the general procedure for urea formation (Method A), starting from 5-(4-Amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.131 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), the title compound was obtained and obtained as an off-white solid (0.013 g, 5% yield). LCMS: 580.0 [M+H].

[0688] Step 2: Synthesis of 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)urea

[0689]

[0690] TBAF (1 M in THF, 0.067 ml) was added to a solution of 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)isoxazol-5-yl)urea (0.013 g, 0.022 mmol) in THF (2 ml) at 0 °C, and the resulting solution was stirred at 25 °C for 4 hours. After completion of the reaction (as 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 as a white solid (TFA salt, 2.2 mg, 21% yield). 1 1H NMR (400 MHz, CD3OD) δ = 8.36 (s, 1H), 8.23 (t, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.30 - 7.38 (m, 2H), 6.20 (s, 1H), 3.69 - 3.72 (m, 1H), 3.61 (s, 2H), 1.32 (s, 6H), 1.18 - 1.24 (m, 4H). LCMS: 466.2 [M+H].

[0691] Example 30

[0692] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazol-5-yl)urea

[0693]

[0694] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.055 g, 0.194 mmol) and phenyl (3-(sec-butyl)isoxazol-5-yl)carbamate (E17, 0.051 g, 0.194 mmol), the title compound was obtained and obtained as a white solid (0.012 g, 14% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.39 (bs, 1H), 8.84 (bs, 1H), 8.12 - 8.14 (m, 2H), 7.25 - 7.36 (m, 3H), 6.16 (bs, 2H), 6.02 (s, 1H), 3.56 - 3.59 (m, 1H), 2.68 - 2.73 (m, 1H), 1.56 - 1.60 (m, 2H), 1.18 - 1.20 (m, 3H), 1.01 - 1.10 (m, 4H), 0.81 - 0.89 (m, 3H). LCMS: 450.0 [M+H].

[0695] Example 31

[0696] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(pentan-3-yl)isoxazol-5-yl)urea

[0697]

[0698] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.050 g, 0.176 mmol) and phenyl (3-(pentan-3-yl)isoxazol-5-yl)carbamate (E18, 0.048 g, 0.176 mmol), the title compound was obtained and obtained as a white solid (0.016 g, 19% yield). 11H NMR (400 MHz, DMSO-d6) δ = 10.65 (bs, 1H), 9.06 (bs, 1H), 8.37 (s, 1H), 8.18 (t, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.35 - 7.38 (m, 1H), 7.26 - 7.28 (m, 3H), 5.98 (s, 1H), 3.65 - 3.68 (m, 1H), 1.49 - 1.68 (m, 4H), 1.07 - 1.09 (m, 4H), 0.79 - 0.82 (m, 6H). LCMS: 464.0 [M+H].

[0699] Example 32

[0700] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea

[0701]

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

[0703] Example 33

[0704] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-ethylisoxazol-5-yl)urea

[0705]

[0706] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.061 g, 0.215 mmol) and phenyl (3-ethylisoxazol-5-yl)carbamate (E20, 0.050 g, 0.215 mmol), the title compound was obtained and obtained as an off-white solid (0.020 g, 22% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.31 (bs, 1H), 8.81 (bs, 1H), 8.12 - 8.17 (m, 2H), 7.25 - 7.36 (m, 3H), 6.15 (bs, 2H), 6.03 (s, 1H), 3.55 - 3.60 (m, 1H), 2.54 - 2.60 (m, 2H), 1.05 - 1.21 (m, 3H), 1.03 - 1.04 (m, 4H). LCMS: 422.0 [M+H].

[0707] Example 34

[0708] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclobutyl)isoxazol-5-yl)urea

[0709]

[0710] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.075 g, 0.265 mmol) and phenyl (3-(1-methylcyclobutyl)isoxazol-5-yl)carbamate (E21, 0.072 g, 0.265 mmol), the title compound was obtained and obtained as a white solid (6.8 mg, 5% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.42 (bs, 1H), 8.90 (bs, 1H), 8.42 (s, 1H), 8.18 - 8.22 (m, 1H), 7.58 (s, 1H), 7.37 - 7.40 (m, 1H), 7.27 - 7.29 (m, 1H), 6.06 (s, 1H), 3.67 - 3.71 (m, 1H), 2.34 - 2.38 (m, 2H), 1.85 - 2.08 (m, 4H), 1.42 (s, 3H), 1.07 - 1.11 (m, 4H). LCMS: 462.2 [M+H].

[0711] Example 35

[0712] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)urea

[0713]

[0714] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.070 g, 0.247 mmol) and phenyl (3-(2-cyanopropan-2-yl)isoxazol-5-yl)carbamate (E22, 0.067 g, 0.247 mmol), the title compound was obtained and obtained as a white solid (4.1 mg, 3% yield). 1 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].

[0715] Example 36

[0716] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(hydroxymethyl)isoxazol-5-yl)urea

[0717]

[0718] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.250 g, 0.882 mmol) and phenyl (3-(((tert-butyldimethylsilyl)oxy)methyl)isoxazol-5-yl)carbamate (E23, 0.308 g, 0.882 mmol), the title compound was obtained and obtained as an off-white solid (0.029 g, 8% yield). 11H NMR (400 MHz, DMSO-d6) δ = 10.43 (bs, 1H), 8.92 (bs, 1H), 8.40 (s, 1H), 8.18 - 8.22 (m, 1H), 7.56 (s, 1H), 7.37 - 7.40 (m, 1H), 7.27 - 7.29 (m, 1H), 6.12 (s, 1H), 4.43 (s, 2H), 3.66 - 3.71 (m, 1H), 1.08 - 1.11 (m, 4H). LCMS: 422.0 [M-H].

[0719] Note: Cleavage of the TBDMS group was observed during purification when gradient elution with 10 mM ammonium acetate in water and ACN was used.

[0720] Example 37

[0721] 1-(5-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0722]

[0723] According to the general procedure for urea formation (Method A), starting from 5-(6-aminopyridin-3-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D6, 0.300 g, 1.127 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.352 g, 1.127 mmol), the title compound was obtained and obtained as an off-white solid (0.018 g, 3% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 11.77 (bs, 1H), 9.85 (bs, 1H), 8.39 - 8.40 (m, 1H), 8.18 (s, 1H), 7.86 - 7.88 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 6.26 (s, 1H), 6.23 (bs, 2H), 3.58 - 3.61 (m, 1H), 1.40 - 1.49 (m, 4H), 1.03 - 1.06 (m, 4H). LCMS: 485.0 [M+H].

[0724] Example 38

[0725] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0726]

[0727] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-methylphenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D11, 0.270 g, 0.967 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.302 g, 0.967 mmol), the title compound was obtained and obtained as an off-white solid (0.080 g, 16% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.63 (bs, 1H), 8.29 (bs, 1H), 8.16 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.22 - 7.32 (m, 3H), 6.17 (s, 1H), 6.08 (bs, 2H), 3.55 - 3.60 (m, 1H), 2.29 (s, 3H), 1.37 - 1.48 (m, 4H), 1.00 - 1.05 (m, 4H). LCMS: 498.1 [M+H].

[0728] Example 39

[0729] 1-(4-(4-Amino-7-(3-hydroxycyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

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

[0731]

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

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

[0734]

[0735] At -60 °C, boron trichloride (1 M in DCM, 0.901 mL, 0.901 mmol) was added dropwise to a solution of 1-(4-(4-amino-7-(3-(benzyloxy)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.070 g, 0.113 mmol) in DCM (5 mL), and the resulting mixture was stirred at 0 °C for 3 h. After completion of the reaction (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 a crude material, which was purified by preparative HPLC (gradient elution with 1% TFA in water and ACN) to give the title product as a white solid (0.012 g, 20% yield). 1 1H NMR (400 MHz, CD3OD) δ = 8.33 (s, 1H), 8.22 - 8.26 (m, 1H), 7.77 (s, 1H), 7.34 - 7.42 (m, 2H), 6.33 (s, 1H), 5.58 - 5.62 (m, 1H), 4.64 - 4.66 (m, 1H), 2.85 - 2.92 (m, 2H), 2.58 - 2.64 (m, 2H), 1.39 - 1.49 (m, 4H). LCMS: 531.8 [M+H].

[0736] Example 40

[0737] 1-(6-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-methylpyridin-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0738]

[0739] According to the general procedure for urea formation (Method A), starting from 5-(5-amino-4-methylpyridin-2-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D13, 0.050 g, 0.102 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.032 g, 0.102 mmol), the title compound was obtained and obtained as an off-white solid (8 mg, 16% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.81 (bs, 1H), 8.76 (s, 1H), 8.51 (bs, 1H), 8.08 (s, 1H), 7.93 - 7.94 (m, 2H), 7.12 (bs, 2H), 6.17 (s, 1H), 3.53 - 3.56 (m, 1H), 2.30 (s, 3H), 1.37 - 1.46 (m, 4H), 1.05 - 1.08 (m, 4H). LCMS: 499.2 [M+H].

[0740] Example 41

[0741] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,6-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0742]

[0743] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D15, 0.080 g, 0.266 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.083 g, 0.266 mmol), the title compound was obtained and obtained as an off-white solid (8 mg, 5.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.78 (bs, 1H), 8.71 (bs, 1H), 8.42 (bs, 1H), 7.67 (s, 1H), 7.56 (bs, 2H), 7.23 - 7.29 (m, 2H), 6.14 (s, 1H), 3.67 - 3.76 (m, 1H), 1.37 - 1.47 (m, 4H), 1.09 - 1.12 (m, 4H). LCMS: 519.7 [M+H].

[0744] Example 42

[0745] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0746]

[0747] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-2,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D16, 0.100 g, 0.332 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.104 g, 0.332 mmol), the title compound was obtained and obtained as an off-white solid (8 mg, 5% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.63 (bs, 1H), 9.01 (bs, 1H), 8.16 (s, 1H), 8.04 - 8.09 (m, 1H), 7.28 - 7.34 (m, 2H), 6.21 (s, 1H), 6.16 (bs, 2H), 3.55 - 3.61 (m, 1H), 1.36 - 1.49 (m, 4H), 1.00 - 1.04 (m, 4H). LCMS: 520.1 [M+H].

[0748] Example 43

[0749] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0750]

[0751] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-2,6-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D17, 0.0724 g, 0.240 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.075 g, 0.240 mmol), the title compound was obtained and obtained as an off-white solid (3 mg, 2% yield). 11H 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].

[0752] Example 44

[0753] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

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

[0755]

[0756] According to 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), the title compound was obtained and isolated as a light yellow solid (0.020 g, 23% yield). LCMS: 410.9 [M+H].

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

[0758]

[0759] According to a similar procedure for intermediate D8, starting from 1-(5-bromo-3-fluoropyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.020 g, 0.049 mmol) and tert-butyl ((tert-butoxycarbonyl)(7-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (prepared as reported in PCT Publication No. WO2018 / 015879, 0.024 g, 0.049 mmol), the title compound was obtained and isolated as an off-white solid (2 mg, 7% yield). 11H 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.

[0760] Example 45

[0761] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-yl)urea

[0762]

[0763] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-yl)carbamate (E24, 0.092 g, 0.282 mmol), the title compound was obtained and obtained as an off-white solid (0.035 g, 22% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.66 (bs, 1H), 8.90 (bs, 1H), 8.21 (s, 1H), 8.12 - 8.16 (m, 1H), 7.26 - 7.36 (m, 3H), 6.41 (bs, 2H), 6.14 (s, 1H), 3.54 - 3.56 (m, 1H), 2.57 - 2.68 (m, 4H), 2.03 - 2.05 (m, 2H), 1.04 - 1.06 (m, 4H). LCMS: 515.9 [M+H].

[0764] Example 46

[0765] 1-(5-(4-Amino-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0766]

[0767] According to the general procedure for urea formation (Method B), starting from 1-(4-amino-5-(6-aminopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (D18, 0.100 g, 0.335 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.105 g, 0.335 mmol), the title compound was obtained and obtained as an off-white solid (0.010 g, 6% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 11.74 (bs, 1H), 9.91 (bs, 1H), 8.41 - 8.43 (m, 2H), 7.89 - 7.92 (m, 1H), 7.80 (bs, 2H), 7.68 - 7.71 (m, 1H), 7.59 (s, 1H), 6.26 (s, 1H), 4.20 (s, 2H), 1.38 - 1.50 (m, 4H), 1.11 - 1.12 (m, 6H). LCMS: 516.9 [M+H].

[0768] Example 47

[0769] 1-(4-(4-Amino-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0770]

[0771] According to the general procedure for urea formation (Method B), starting from 1-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol (D3, 0.120 g, 0.381 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.119 g, 0.381 mmol), the title compound was obtained and 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].

[0772] Example 48

[0773] 1-(5-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0774]

[0775] According to the general procedure for urea formation (Method B), starting from 5-(2-aminopyrimidin-5-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D19, 0.080 g, 0.299 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.093 g, 0.299 mmol), the title compound was obtained and obtained as an off-white solid (4 mg, 3% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.76 (bs, 1H), 9.04 (bs, 1H), 8.65 (bs, 1H), 8.34 (bs, 2H), 7.61 (s, 1H), 6.66 (bs, 2H), 6.10 (s, 1H), 3.66 - 3.71 (m, 1H), 1.37 - 1.45 (m, 4H), 1.11 - 1.11 (m, 4H). LCMS: 485.9 [M+H].

[0776] Example 49

[0777] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-(hydroxymethyl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0778]

[0779] According to the general procedure for urea formation (Method A), starting from (2-amino-5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanol (D20, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.021 g, 0.068 mmol), the title compound was obtained and obtained as an off-white solid (3 mg, 8% yield). 11H NMR (400 MHz, DMSO-d6) δ = 10.96 (bs, 1H), 8.56 (bs, 1H), 8.17 (s, 1H), 7.91 - 7.93 (m, 1H), 7.34 - 7.42 (m, 2H), 7.21 (s, 1H), 6.04 - 6.17 (m, 3H), 5.49 (bs, 1H), 4.57 (bs, 2H), 3.56 - 3.61 (m, 1H), 1.37 - 1.47 (m, 4H), 1.00 - 1.06 (m, 4H). LCMS: 514.1 [M+H].

[0780] Example 50

[0781] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-cyanophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0782]

[0783] According to the general procedure for urea formation (Method B), starting from 2-amino-5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (D21, 0.130 g, 0.287 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.089 g, 0.287 mmol), the title compound was obtained and isolated as an off-white solid (5 mg, 3% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.62 (s, 1H), 7.43 - 7.52 (m, 3H), 6.86 (s, 1H), 6.05 (s, 1H), 3.67 - 3.70 (m, 1H), 1.38 - 1.46 (m, 4H), 1.08 - 1.10 (m, 4H). LCMS: 509.2 [M+H].

[0784] Example 51

[0785] 1-(4-(4-Amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0786]

[0787] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-3-fluorophenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D22, 0.075 g, 0.249 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.078 g, 0.249 mmol), the title compound was obtained and obtained as an off-white solid (0.037 g, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.63 (bs, 1H), 8.88 (bs, 1H), 8.13 - 8.18 (m, 2H), 7.42 (s, 1H), 7.26 - 7.36 (m, 2H), 6.35 (bs, 2H), 6.20 (s, 1H), 4.34 (t, J = 5.6 Hz, 2H), 3.72 (t, J = 5.2 Hz, 2H), 3.26 (s, 3H), 1.38 - 1.49 (m, 4H). LCMS: 520.2 [M+H].

[0788] Example 52

[0789] 1-(4-(4-Amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0790]

[0791] According to the general procedure for urea formation (Method B), starting from 2-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (D23, 0.080 g, 0.278 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.087 g, 0.278 mmol), the title compound was obtained and obtained as an off-white solid (0.011 g, 7% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.53 (bs, 1H), 8.78 (bs, 1H), 8.05 - 8.09 (m, 2H), 7.32 (s, 1H), 7.19 - 7.28 (m, 2H), 6.18 (bs, 2H), 6.13 (s, 1H), 4.90 (t, J = 5.2 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.66 - 3.69 (m, 2H), 1.31 - 1.41 (m, 4H). LCMS: 506.2 [M+H].

[0792] Example 53

[0793] 1-(4-(4-Amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0794]

[0795] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D24, 0.150 g, 0.504 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.158 g, 0.504 mmol), the title compound was obtained and 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].

[0796] Example 54

[0797] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-chlorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0798]

[0799] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-3-chlorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D25, 0.050 g, 0.167 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.052 g, 0.167 mmol), the title compound was obtained and obtained as an off-white solid (6 mg, 7% yield). 11H NMR (400 MHz, DMSO-d6) δ = 11.04 (broad singlet, 1H), 8.67 (broad singlet, 1H), 8.40 (singlet, 1H), 8.23 - 8.25 (multiplet, 1H), 7.58 - 7.60 (multiplet, 2H), 7.42 - 7.44 (multiplet, 1H), 6.21 (singlet, 1H), 3.67 - 3.73 (multiplet, 1H), 1.46 - 2.33 (multiplet, 2H), 1.37 - 1.38 (multiplet, 2H), 1.11 - 1.13 (multiplet, 4H). LCMS: 518.2 [M+H].

[0800] Example 55

[0801] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0802]

[0803] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-3-methoxyphenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D26, 0.020 g, 0.068 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.021 g, 0.068 mmol), the title compound was obtained and obtained as an off-white solid (7 mg, 19% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.96 (broad singlet, 1H), 8.65 (broad singlet, 1H), 8.23 (singlet, 1H), 8.17 (doublet, J = 8.4 Hz, 1H), 7.30 (singlet, 1H), 7.12 - 7.17 (multiplet, 1H), 7.01 - 7.04 (multiplet, 1H), 6.47 (broad singlet, 2H), 6.19 (singlet, 1H), 3.94 (singlet, 3H), 3.60 - 3.62 (multiplet, 1H), 1.45 - 1.48 (multiplet, 2H), 1.36 - 1.38 (multiplet, 2H), 1.04 - 1.07 (multiplet, 4H). LCMS: 513.9 [M+H].

[0804] Example 56

[0805] 1-(4-(4-Amino-7-(1-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0806]

[0807] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-3-fluorophenyl)-7-(1-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D27, 0.040 g, 0.123 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.036 g, 0.115 mmol), the title compound was obtained and obtained as a white solid (0.015 mg, 24% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.82 (bs, 1H), 9.07 (bs, 1H), 8.39 (s, 1H), 8.19 - 8.23 (m, 1H), 7.84 (s, 1H), 7.14 - 7.40 (m, 2H), 6.21 (s, 1H), 5.55 - 5.66 (m, 1H), 3.90 - 4.09 (m, 2H), 2.95 (bs, 4H), 2.08 (s, 3H), 1.38 - 1.49 (m, 4H). LCMS: 545.3 [M+H].

[0808] Example 57

[0809] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-yl)urea

[0810]

[0811] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.160 g, 0.565 mmol) and phenyl (5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-yl)carbamate (E25, 0.184 g, 0.565 mmol), the title compound was obtained and obtained as a white solid (0.081 mg, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.02 (bs, 1H), 8.87 (bs, 1H), 8.15 - 8.20 (m, 2H), 7.25 - 7.36 (m, 3H), 6.96 (s, 1H), 6.16 (bs, 2H), 3.55 - 3.61 (m, 1H), 2.59 - 2.68 (m, 4H), 2.03 - 2.11 (m, 2H), 1.02 - 1.11 (m, 4H). LCMS: 516.2 [M+H].

[0812] Example 58

[0813] 1-(4-(4-Amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0814]

[0815] According to the general procedure for urea formation (Method B), starting from 5-(4-amino-3-fluorophenyl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D24, 0.204 g, 0.686 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.214 g, 0.686 mmol), the title compound was obtained and obtained as an off-white solid (0.096 g, 27% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.01 (bs, 1H), 8.87 (bs, 1H), 8.14 - 8.20 (m, 2H), 7.66 (s, 1H), 7.28 - 7.39 (m, 2H), 6.91 (s, 1H), 6.18 (bs, 2H), 5.18 - 5.23 (m, 1H), 2.39 - 2.41 (m, 4H), 1.81 - 1.90 (m, 2H), 1.54 - 1.55 (m, 4H). LCMS: 516.2 [M+H].

[0816] Example 59

[0817] 1-(6-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0818]

[0819] According to the general procedure for urea formation (Method B), starting from 5-(5-aminopyridin-2-yl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D14, 0.030 g, 0.045 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.014 g, 0.045 mmol), the title compound was obtained and obtained as an off-white solid (5 mg, 23% yield). 11H NMR (400 MHz, DMSO-d6) δ = 10.67 (bs, 1H), 9.68 (bs, 1H), 9.12 (s, 1H), 8.59 - 8.60 (m, 1H), 8.09 (s, 1H), 7.92 - 8.00 (m, 2H), 7.17 (bs, 2H), 6.20 (s, 1H), 3.58 - 3.63 (m, 1H), 1.36 - 1.48 (m, 4H), 1.06 - 1.10 (m, 4H). LCMS: 485.2 [M+H].

[0820] Example 60

[0821] 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,6-difluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0822]

[0823] According to the general procedure for urea formation (Method A), starting from 5-(4-amino-3,5-difluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D15, 0.150 g, 0.498 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.155 g, 0.498 mmol), the title compound was obtained and obtained as an off-white solid (0.015 g, 6% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 11.47 (bs, 1H), 10.17 (bs, 1H), 8.18 (s, 1H), 7.42 (s, 1H), 7.18 - 7.22 (m, 2H), 6.82 (s, 1H), 6.27 (bs, 2H), 3.51 - 3.55 (m, 1H), 1.46 - 1.51 (m, 4H), 1.04 - 1.05 (m, 4H). LCMS: 520.2 [M+H].

[0824] Example 61

[0825] 1-(4-(4-Amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0826]

[0827] According to the general procedure for urea formation (Method B), starting from 2-(4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-ol (D23, 0.100 g, 0.348 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (E7, 0.109 g, 0.348 mmol), the title compound was obtained and 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].

[0828] Example 62

[0829] 1-(4-(4-Amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0830] Step 1: Synthesis of 1-cyclopropyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrrolo[3,2-c]pyridin-4-amine

[0831]

[0832] A mixture of 4-chloro-1-cyclopropyl-3-iodo-1H-pyrrolo[3,2-c]pyridine (B9, 0.300 g, 0.942 mmol) and (2,5-dimethoxyphenyl)methanamine (0.429 mL, 2.83 mmol) in n-BuOH (10 mL) was stirred at 110 °C for 12 h. After completion of the reaction (as shown by LCMS), the reaction mixture was concentrated under reduced pressure to give a crude material, which was purified by Isolera (silica gel 230 - 400 mesh, eluted with 30% EtOAc in petroleum ether). The title product was obtained as a yellow gum (0.10 g, 19% yield). LCMS: 450.0 [M+H].

[0833] Step 2: Synthesis of 3-(4-amino-3-fluorophenyl)-1-cyclopropyl-N-(2,4-dimethoxybenzyl)-1H-pyrrolo[3,2-c]pyridin-4-amine

[0834]

[0835] According to a similar procedure as described for Intermediate D8, the title compound was obtained from 1-cyclopropyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrrolo[3,2-c]pyridin-4-amine (0.190 g, 0.423 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.100 g, 0.423 mmol), and obtained as a brown gum (0.080 g, 41% yield). LCMS: 433.2 [M+H].

[0836] Step 3: Synthesis of 1-(4-(1-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0837]

[0838] According to the general procedure for urea formation (Method B), starting from 3-(4-amino-3-fluorophenyl)-1-cyclopropyl-N-(2,4-dimethoxybenzyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (0.080 g, 0.185 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.058 g, 0.185 mmol), the title compound was obtained and obtained as an off-white solid (0.027 g, 17% yield). LCMS: 651.3 [M+H].

[0839] Step 4: Synthesis of 1-(4-(4-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0840]

[0841] Triethylsilane (4.8 mg, 0.041 mmol) and TFA (4.7 mg, 0.041 mmol) were added to a solution of 1-(4-(1-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (0.027 g, 0.041 mmol) in DCM (2 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 12 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 preparative HPLC (gradient elution with 0.1% TFA in water) to afford the title product as an off-white solid (5 mg, 24% yield). 1 1H 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].

[0842] Biological Example 1

[0843] Biochemical Assay of Compounds

[0844] The inhibitory activities of representative compounds against NEK7 and IL-1β release were tested according to the above procedure. The results are given in the following table.

[0845] Table 2. Activities of Representative Compounds

[0846]

[0847]

[0848] For NEK7 IC in Table 2 50 Activity:

[0849] * IC 50 Greater than 1500 nM

[0850] ** IC 50 Is 501–1500 nM

[0851] *** IC 50 Is 301–500 nM

[0852] **** IC 50 Is 151–300 nM

[0853] ***** IC 50 Less than 150 nM

[0854] For the IL-1β IC in Table 2 50 Activity:

[0855] + IC 50 Greater than 1000 nM

[0856] ++ IC 50 Is 301–500 nM

[0857] +++ IC 50 Is 151–300 nM

[0858] ++++ IC 50 Less than 150 nM

[0859] - indicates that no value was measured

[0860] 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 referred to in this specification and / or listed in the application data sheet, including but 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, are hereby incorporated by reference in their entirety. Aspects of the embodiments may be modified, if necessary, to employ the concepts of the various patents, applications, and publications to provide other embodiments.

[0861] These and other changes may be made to the embodiments in light of the above detailed description. In general, in the claims, the terms used should not be construed as limiting the claims to the specific embodiments disclosed in this specification and the claims, but should be construed to include all possible embodiments together with all ranges of equivalents to such claims. Thus, the claims are not limited by the disclosure.

Claims

1. A compound having the following structure (I): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: A is each optionally substituted by one or more R 6 substituted phenyl, pyridyl, pyrimidinyl, saturated cyclohexyl or unsaturated cyclohexyl; X is N; Y is NH; R 1 is H; R 2 is a C3-C4 cycloalkyl group, a 3- to 8-membered heterocyclic group, or a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclic groups; R 3 is H; R 4 is a heteroaryl selected from: oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl; R 5 is H; and R 6 is independently, at each occurrence, halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxyalkyl or C1-C6 haloalkyl; Wherein the term "amino group" in "amino group" and "amino C1-C6 alkyl C3-C8 cycloalkyl group" refers to the group of formula -NR a R b , wherein R a and R b are each independently H or C1-C6 alkyl.

2. The compound according to claim 1, wherein R 2 is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl or oxetanyl, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclic group.

3. The compound according to claim 2, wherein R 2 is unsubstituted.

4. The compound according to claim 1, wherein R 2 has one of the following structures:

5. The compound according to claim 1, wherein R 4 is an 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 group, each optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

6. The compound according to claim 5, wherein R 4 is an isoxazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

7. The compound according to claim 5, wherein R 4 is a thiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

8. The compound according to claim 5, wherein R 4 is an isothiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

9. The compound according to claim 5, wherein R 4 is a 1,2,4-thiadiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

10. The compound according to claim 5, wherein R 4 is a 1,3,4-thiadiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

11. The compound according to claim 5, wherein R 4 is a 1,2,4-triazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

12. The compound according to claim 5, wherein R 4 is a 1,3,4-oxadiazolyl group optionally substituted with one or more substituents selected from: 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 heterocyclic group, C1-C6 haloalkyl C3-C8 cycloalkyl, amino C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, 3-8 membered heterocyclic group C1-C6 alkyl, C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl, 3-8 membered halocyclic group C1-C6 alkyl and C3-C8 halocycloalkyl and combinations thereof.

13. The compound according to claim 1, wherein R 4 is substituted by a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C8 cycloalkyl group, a cyano group, an amino group, a C1-C6 hydroxyalkyl group, a C1-C6 cyanoalkyl group, a 3-8 membered heterocyclic group, a C1-C6 haloalkyl C3-C8 cycloalkyl group, an amino C1-C6 alkyl C3-C8 cycloalkyl group, a C1-C6 alkyl C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group C1-C6 alkyl, a C1-C6 alkyl 3-8 membered heterocyclic group C3-C8 cycloalkyl group, a 3-8 membered haloheterocyclic group C1-C6 alkyl or a C3-C8 halocycloalkyl group or a combination thereof.

14. The compound according to claim 1, wherein R 4 has one of the following structures:

15. The compound according to claim 1, wherein R 2 is a C3-C4 cycloalkyl group, a 3- to 8-membered heterocyclic group, or a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclic group; and R 4 has one of the following structures:

16. The compound according to claim 1, wherein A is phenyl.

17. The compound according to claim 1, wherein A is a saturated cycloalkyl group or an unsaturated cycloalkyl group.

18. The compound according to claim 1, wherein A is pyridyl.

19. The compound according to claim 1, wherein A is pyrimidinyl.

20. The compound according to claim 1, wherein A is unsubstituted.

21. The compound according to claim 1, wherein A is substituted by one or more R 6 substituents.

22. The compound according to claim 21, wherein R 6 is a halogen.

23. The compound according to claim 22, wherein the halogen is chlorine or fluorine.

24. The compound according to claim 21, wherein R 6 is C1-C6 hydroxyalkyl.

25. The compound according to claim 24, wherein the C1-C6 hydroxyalkyl group is -CH2CH2OH.

26. The compound according to claim 21, wherein R 6 is cyano.

27. The compound according to claim 21, wherein R 6 is C1-C6 alkoxy.

28. The compound according to claim 27, wherein the C1-C6 alkoxy group is methoxy.

29. The compound according to claim 1, wherein A has one of the following structures:

30. The compound according to claim 1, wherein the compound has the following structure (IA): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 2a is a C3-C4 cycloalkyl group optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclic group; R 4a is an isoxazolyl group optionally substituted by one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.

31. The compound according to claim 30, wherein R 2a has the following structure:

32. The compound according to claim 30, wherein R 4a has one of the following structures:

33. The compound according to claim 1, wherein the compound has one of the following structures, or a pharmaceutically acceptable salt or stereoisomer thereof:

34. A pharmaceutical composition comprising the compound according to any one of claims 1 to 33 and a pharmaceutically acceptable carrier, diluent or excipient.

35. Use of the compound according to any one of claims 1 to 33 or the pharmaceutical composition according to claim 34 in the preparation of a medicament for the treatment of NLRP3-mediated disorders.

36. The use according to claim 35, wherein the disorders are selected from autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, transplant rejection, lung injury, respiratory diseases and ischemic conditions.

37. The use according to claim 35, wherein the disorders are selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis and Muckle-Wells syndrome.

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