NEK7 inhibitor, pharmaceutical composition and use thereof

Abstract

The present application relates to an NEK7 inhibitor, a pharmaceutical composition and a use thereof. The compound has a structural formula of formula (I). The compound of the present disclosure has good NEK7 inhibitory activity, and can be used for treating or preventing inflammatory pathological disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, Crohn's disease, cancer, osteoarthritis, gout, etc.) regulated by the NLRP3 inflammasome.

Description

A NEK7 inhibitor, pharmaceutical composition and use thereof Technical Field

[0001] The present invention belongs to the field of biopharmaceuticals and specifically relates to NEK7 kinase inhibitor compounds represented by general formula (I), pharmaceutically acceptable salts, esters, stereoisomers, tautomers, and pharmaceutical compositions and formulations containing the same, as well as their uses. The compounds of the present invention selectively inhibit the NEK7 family of tyrosine kinases and can be used to treat diseases mediated by abnormal NEK7 kinase expression. Background Art

[0002] Inflammation is a protective immune response initiated by the host's innate immune system in response to stimuli such as allergens and pathogenic organisms. The innate immune response is tightly regulated by the host. Importantly, inflammation can lead to persistent infection, while excessive inflammation can cause autoimmune diseases. Inflammasomes are cytoplasmic supramolecular protein complexes whose activation activates cytokines such as IL-1β and IL-18, mediated by caspase 1, and induces inflammation and pyroptosis. They play a central role in innate immunity and inflammation. To date, four types of inflammasomes have been discovered: NLRP1, NLRP3, NLRC4, and AIM2. NLRP3 is a key downstream effector of signals triggering inflammatory responses and has been implicated in driving the onset and progression of many chronic inflammatory diseases, neurodegenerative disorders, and cardiovascular diseases. Activated NLRP3 triggers the release of proinflammatory cytokines IL-1β and IL-18 and induces a lytic cell death process known as pyroptosis. Blocking the inflammasome-mediated inflammatory response can help treat many diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, Crohn's disease, cancer, osteoarthritis, gout, etc.

[0003] NEK7 (NIMA-related kinase 7) protein kinase is the smallest of a family of 11 mammalian NEKs (NEK1-NEK11). It is expressed in numerous tissues and has been shown to be crucial in mitotic regulation and NLRP3 inflammasome activation. Inhibition of NLRP3 signaling by NEK7 prevents NLRP3 inflammasome formation, thereby inhibiting IL-1β and IL-18 production and pore-forming gasdermin D cleavage. Pyroptosis is associated with numerous inflammatory diseases, and thus, inhibitors of NLRP3 inflammasome activation that block the NLRP3-NEK7 interaction may have therapeutic or preventive activity in conditions such as chronic inflammation, neurodegenerative diseases, and cardiovascular disease.

[0004] A large number of inhibitors have been widely used to interfere with effector signaling pathways involving IL-1β or IL-18 without eliminating the inflammatory response. Inhibitors that block NLRP3 inflammasome activation by the NLRP3-NEK7 interaction may have therapeutic or preventive activity in several human diseases (e.g., type 2 diabetes, atherosclerosis, gout, and neurodegenerative diseases).

[0005] Therefore, it is necessary to develop inhibitors that selectively target NEK7 for the treatment or prevention of several inflammatory pathological diseases regulated by the NLRP3 inflammasome (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, Crohn's disease, cancer, osteoarthritis, gout, etc.). Summary of the Invention

[0006] The present disclosure provides a compound as shown in Formula I

[0007] The compounds of the present disclosure have good NEK7 inhibitory activity and can be used to treat or prevent several inflammatory pathological diseases regulated by the NLRP3 inflammasome (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, Crohn's disease, cancer, osteoarthritis, gout, etc.).

[0008] The present disclosure also relates to pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0009] The present disclosure also relates to a method for treating or preventing a disorder mediated by NEK7-NLRP3 interaction, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure to an individual in need thereof.

[0010] The present disclosure also relates to the use of the compounds of the present disclosure in the preparation of a medicament for treating or preventing a disorder mediated by the NEK7-NLRP3 interaction. DETAILED DESCRIPTION

[0011] The present invention will be further described in detail below through the following examples, through which the features and advantages of the present invention will become more clearly understood.

[0012] The word “exemplary” is used exclusively herein to mean “serving as an example, example, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0013] In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0014] definition

[0015] The chemical naming schemes and structure diagrams used herein are modified versions of the IUPAC nomenclature system, which use ACD / named software program version 9.07 and / or ChemDraw Professional version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, the substituent is typically named before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Unless described below, all bonds are identified in the chemical structure diagrams herein, but it is assumed that all bonds on some carbon atoms are bonded to enough hydrogen atoms to complete the valence.

[0016] Unless the context requires otherwise, throughout the specification and claims, the word "comprise" and variations thereof (e.g., "comprises" and "comprising") are to be construed in an open, inclusive sense, that is, to mean "including, but not limited to."

[0017] In this specification, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and where appropriate, include its fraction (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 range, value or structure shown, unless otherwise stated. It should be understood that the terms "one / a kind (a)" and "an" as used herein refer to "one / a kind or more / a variety" of the enumerated components. The use of alternatives (e.g., "or") should be understood to mean one or both of the alternatives or any combination thereof.

[0018] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrase "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.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

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

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

[0022] "Oxo" refers to a =0 substituent.

[0023] "Mercapto" refers to a -SH substituent.

[0024] "Thio" refers to a =S substituent.

[0025] "Alkyl" refers to a saturated straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms having 1 to 12 carbon atoms (C1-C 12 The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical.

[0026] "Alkenyl" refers to an unsaturated straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having 2 to 12 carbon atoms (C2-C 12 The carbon numbers mentioned relate to the main chain carbons and the side chain carbons, but do not include the carbon atoms belonging to any substituent. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted.

[0027] The term "alkynyl" refers to an unsaturated straight or branched chain hydrocarbon group having 2 to 12 carbon atoms (C2-C 12 The term "alkynyl" refers to a group having at least one carbon atom (C-C alkynyl), 2 to 9 carbon atoms (C-C alkynyl), or 2 to 6 carbon atoms (C-C alkynyl), or any value within these ranges, and having at least one carbon-carbon triple bond. Examples of alkynyl groups can be selected from ethynyl, propargyl, but-1-ynyl, but-2-ynyl, and the like. The number of carbons mentioned relates to the main chain carbons and the side chain carbons, but does not include the carbon atoms belonging to any substituent. Unless otherwise specifically stated in this specification, alkynyl groups are optionally substituted.

[0028] "Alkoxy" refers to a radical of the formula -OR, wherein R is an alkyl radical as defined above, which may contain from 1 to 12 carbon atoms (C1-C 12 Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0029] "Aromatic ring" refers to a cyclic planar molecule or portion (i.e., group) of a ring with a resonant bond that exhibits increased stability relative to other connected arrangements with the same atomic group. Typically, an aromatic ring contains a set of covalently bonded coplanar atoms and contains many π-electrons (e.g., alternating double bonds and single bonds), where the π-electrons are an even number 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, pyrimidyl, pyrazinyl, pyridyl, pyridazinyl, pyrimidyl. Unless otherwise specifically stated in the specification, "aromatic ring" includes all groups that are optionally substituted.

[0030] "Aryl" refers to a group containing 6 to 18 carbon atoms (e.g., 6 to 10 carbon atoms (C6-C 10 The term "aryl" refers to a carbocyclic ring system comprising an aryl group (an aryl group) and at least one carbocyclic aromatic ring. For the purposes of embodiments of the present invention, an aryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrene, acenaphthylene, acephenanthren, anthracene, azulene, benzene, fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenanthren, phenanthren, septaphenanthren, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, aryl groups are optionally substituted.

[0031] "Cyanoalkyl" refers to an alkyl group that contains at least one cyano substituent. The -CN substituent can be on a primary, secondary, or tertiary carbon. Unless otherwise specifically stated in the specification, a cyanoalkyl group is optionally substituted.

[0032] "Carbocyclic" or "carbocycle" refers to a ring system in which every one of the ring atoms is carbon.

[0033] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic group consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C 15 Cycloalkyl), three to ten ring carbon atoms (C3-C 10The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.

[0034] "Alkylcycloalkyl" refers to a group of the formula -R a R b A group in which R a is a cyclic hydrocarbon group and R b is alkyl as defined above. Unless stated otherwise specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0035] "Fused" refers to any ring structure described herein that is fused to another ring structure.

[0036] "Halogen" refers to bromine, chlorine, fluorine or iodine.

[0037] "Hydrogen" refers to various isotopes of hydrogen including protium, deuterium and tritium; in particular, when hydrogen appears alone, it can be any one of "protium", "deuterium" and "tritium"; when hydrogen appears with "deuterium" and / or "tritium", it sometimes refers to "protium".

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

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

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

[0041] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. The hydroxyalkyl group is attached to the backbone through an alkyl carbon atom. Unless otherwise specifically stated in the specification, a hydroxyalkyl group is optionally substituted.

[0042] "Heterocyclyl" refers to a 3-18 membered, e.g., 3-10 or 3-8 membered, non-aromatic ring group having 1 to 10 ring carbon atoms (e.g., 2 to 10) and 1 to 6 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in this specification, a heterocyclyl is a partially or fully saturated, monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic, and / or bridged ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclyl are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolazine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, heterocyclic groups are optionally substituted.

[0043] "Heteroaryl" refers to a 5-18 membered, for example, 5-6 membered, ring system radical containing 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. A heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azaquinazole, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, phenyl, 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., thiocyclopentadienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0044] Isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, thiazolyl, isothiazolyl or thiadiazolyl may include oxazolyl (ring), isoxazolyl (ring), 1,2,3-oxadiazolyl (ring), 1,2,4-oxadiazolyl (ring), 1,2,5-oxadiazolyl (ring), 1,3,4-oxadiazolyl (ring), 1,2,3-triazolyl (ring), 1,2,4-triazolyl, thiazolyl (ring), isothiazolyl (ring), 1,2,3-thiadiazolyl (ring), 1,2,4-thiadiazolyl (ring), 1,2,5-thiadiazolyl (ring) and 1,3,4-thiadiazolyl (ring), respectively refer to the following structures:

[0045] Among them, 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 respectively represented by oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl. , 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 attached to the rest of the molecule through a covalent bond to one of the carbon atoms in the ring of the oxadiazolyl group.

[0046] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxyalkyl) in which at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxy, halogen, nitro, oxo, thiol, thio, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxyalkyl substituents, each of which may be optionally substituted with one or more of the above substituents.

[0047] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound as described herein sufficient to achieve the intended application, including but not limited to the treatment of diseases as defined below. A therapeutically effective amount can vary depending on the intended therapeutic application (in vivo), or the individual and disease condition being treated, such as the weight and age of the individual, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to doses that induce a specific response in target cells, such as a decrease in platelet adhesion and / or cell migration. The specific dosage will vary depending on the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system it carries.

[0048] As used herein, "treatment" or "treat" refers to a method for obtaining a beneficial or desired result (including but not limited to a therapeutic effect and / or a preventive effect) with respect to a disease, disorder, or medical condition. A therapeutic benefit means a cure or improvement of the underlying disorder being treated. In addition, a therapeutic benefit is achieved by curing or improving one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the individual, even though the individual may still be suffering from the underlying disorder. A preventive effect includes delaying or eliminating the appearance of the disease or condition, delaying or eliminating the onset of symptoms of the disease or condition, slowing, preventing, or reversing the progression of the disease or condition, or any combination thereof. In certain embodiments, for a preventive benefit, a composition is administered to an individual at risk for a particular disease, or to an individual reporting one or more physiological symptoms of a disease, even though the disease may not yet have been diagnosed.

[0049] As used herein, the terms "co-administration," "combined administration," and grammatical equivalents thereof encompass the administration of two or more pharmaceutical agents to animals, including humans, such that both agents and / or their metabolites are present in the individual at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

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

[0051] "Pharmaceutically acceptable acid addition salts" refers 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. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for use in contact with patient tissues without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptylsulfonic acid, Acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0052] "Pharmaceutically acceptable base addition salts" refers to salts that retain the biological effectiveness of the free base, are biologically tolerable, or are otherwise biologically suitable for administration to an individual. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for use in contact with patient tissues without undue toxicity, irritation, or allergic reactions. Pharmaceutically acceptable base addition salts are prepared by adding an inorganic base or an organic base to 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, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-ethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine penicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

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

[0054] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of a protein (e.g., NLRP3 inflammasome or NEK7) or by inhibiting the association of NLRP3 inflammasome with NEK7. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological action of the target protein. Although preferred antagonists herein particularly interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway in which the target protein is a member are also particularly included in this definition. The preferred biological activity inhibited by the antagonist is associated with the development, growth, or spread of a tumor.

[0055] As used herein, the term "agonist" refers to a compound that has the ability to induce or enhance the biological function of a target protein, whether or not by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological action of the target polypeptide. Although preferred agonists herein particularly interact with (e.g., bind to) the target, compounds that induce or enhance the biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also particularly included in this definition.

[0056] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted into and within cells to elicit intracellular responses.

[0057] The term "selective inhibition" or "selectively inhibits" refers to the ability of a biologically active agent, through direct or indirect interaction with the target, such that the agent preferentially reduces target signaling activity compared to off-target signaling activity.

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

[0059] "Mammal" includes humans and livestock animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals, etc.

[0060] "Prodrug" is intended to mean a compound (e.g., a compound of structure (I)) that can be converted into a bioactive compound as 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, the prodrug is inert when applied to a subject, but is converted into an active compound in vivo, such as by hydrolysis. Prodrug compounds often provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms. The term "prodrug" also means any covalently bonded carrier that releases the active compound in vivo when such prodrugs are applied to mammalian individuals. Prodrugs of active compounds as described herein are typically prepared by modifying the functional groups present in the active compound in such a way that the modification is cleaved into the parent active compound in conventional operations or in vivo. Prodrugs include compounds wherein a hydroxyl, amino, or thiol group is connected to any group, and when the prodrug of the active compound is applied to a mammalian individual, it is cleaved to form free hydroxyl, free amino, or free thiol groups. Examples of prodrugs include, but are not limited to, acetic acid, formic acid, and benzoic acid derivatives of a hydroxy functional group or acetamide, formamide, and benzamide derivatives of an amine functional group in the active compound, and the like.

[0061] The term "in vivo" refers to events that occur within the body of an individual.

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

[0063] Certain embodiments are also intended to include in vivo metabolites of the disclosed compounds. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, embodiments include compounds produced by methods comprising administering a compound of the disclosure to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the disclosure to an animal (e.g., rat, mouse, guinea pig, monkey) or to a human, allowing sufficient time for metabolism, and isolating its conversion products from urine, blood, or other biological samples.

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

[0065] Typically, crystallization produces solvates of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the disclosure and one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the disclosure may be true solvates, while in other cases, the compounds of the disclosure retain only adventitious water or are a mixture of water plus some adventitious solvent.

[0066] "Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstances occur and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups without substituents.

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

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

[0069] "Stereoisomers" refer to compounds composed of the same atoms bonded to the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0070] The compounds of the present disclosure (i.e., compounds of structure (I)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and thus may produce 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 therefore include all such possible isomers, as well as racemic and optically pure forms thereof. Optional active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis of suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0071] Embodiments of the present disclosure include all forms and conformationally restricted states of rotational isomers of the compounds of the present invention. Also included are atropisomers, which are stereoisomers arising from hindered rotation about a single bond, where energy differences due to steric strain or other contributing factors create a rotational barrier high enough to allow separation of the individual conformers. As an example, certain compounds of the present disclosure may exist as a mixture of atropisomers, or may be purified or enriched to allow the presence of a single atropisomer.

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

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

[0074] "NEK7-NLRP3-mediated disorders" refers to diseases or pathological processes caused by the interaction between NEK7 and NLRP3, including autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases and ischemic conditions, etc.; in particular, including type 2 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 Mueller-Willi syndrome, etc. Conditions mediated by the NEK7-NLRP3 interaction include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes mellitus, type II diabetes mellitus, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndromes, cryptopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease, and cancer.

[0075] Compound

[0076] The present application provides a compound as shown in Formula I

[0077] or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof,

[0078] Wherein, X is O or S;

[0079] X1, X2, X3 and X4 are each independently C or N;

[0080] When X2 and X3 are N, X1 and X4 are C; when X1 and X3 are N, X2 and X4 are C; when X3 and X4 are N, X1 and X2 are C;

[0081] The dotted ring indicates the presence of two conjugated double bonds in the 5-membered ring;

[0082] Ring A is substituted with 0-4 R A C 6-10 Aryl, substituted with 0-4 R AC 3-10 Cyclic hydrocarbon group, substituted with 0-4 R A 3-10 membered heterocyclic group or substituted with 0-4 R A 5-6 membered heteroaryl;

[0083] R is one of the following structural formulas

[0084] R4 is the following group

[0085] Among them, L is a direct bond, O, CR 21 or CR 21 R 22 ;

[0086] R L To replace 0-4 R C C 6-10 Aryl, substituted with 0-4 R C C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R C 3-10 membered heterocyclic group or substituted with 0-4 R C 5-6 membered heteroaryl;

[0087] R 4 in Indicates a single bond or a double bond; when R 4 in When it represents a double bond, L is CR 21 ;

[0088] Z1 is CH or N;

[0089] Z2 is O or S or N;

[0090] Z3 is C or N or O or S;

[0091] Z4 is C or O or N;

[0092] R3 is selected from hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0093] R2 is selected from hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0094] R1 is selected from 0-4 R 0 C 6-10 Aryl, substituted with 0-4 R0 C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R 0 3-10 membered heterocyclic group, substituted with 0-4 R 0 5-6 membered heteroaryl, substituted with 0-4 R 0 C 1-6 Alkyl, substituted with 0-4 R 0 C 1-6 Halogenated alkyl, substituted with 0-4 R 0 C 1-6 Alkoxy, substituted with 0-4 R 0 C 2-6 Alkenyl, substituted with 0-4 R 0 C 2-6 Alkynyl or NR 11 R 12 ;

[0095] Alternatively, R1, R2 and the atoms to which they are attached together form a 5-membered or 6-membered ring;

[0096] R A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, hydroxy, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0097] R B are independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, substituted with 0-4 R B1 C 6-10 Aryl, substituted with 0-4 R B1 C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R B1 3-10 membered heterocyclic group or substituted with 0-4 R B1 5-6 membered heteroaryl;

[0098] R B1 are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0099] R Care independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, -C(=O)R C1 、-(CH2) k S(=O)2R C1 、-NR C2 R C3 ; or, two R C Together with the atoms to which they are attached, they form a 3- to 6-membered ring;

[0100] R C1 Each independently selected from hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyloxy;

[0101] R C2 and R C3 are each independently selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0102] R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 、R 52 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl;

[0103] R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 、R 62 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl;

[0104] R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, substituted with 0-4 R 70 C 6-10 Aryl, substituted with 0-4 R 70 C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R 703-10 membered heterocyclic group or substituted with 0-4 R 70 5-6 membered heteroaryl;

[0105] R 70 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group or NR 11 R 12 ;

[0106] R 0 Each independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, carbonyl C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 3-10 Cycloalkyl, 3-8 membered heterocyclic group or NR 11 R 12 ;

[0107] R 11 and R 12 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0108] R 21 and R 22 are each independently selected from hydrogen, halogen, deuterium, tritium, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, or R 11 and R 12 Together with the attached carbon atom, it forms C 3-6 Cycloalkyl;

[0109] n is 1 or 2;

[0110] k is 0, 1, 2, 3 or 4.

[0111] In the compounds of the present application, X may be O or S; preferably, X is O.

[0112] In the compounds of the present application,

[0113] In the part, the N atom to which R3 is connected and the N atom to which R2 is connected both carry at least one hydrogen atom, thereby forming an intramolecular hydrogen bond between the above-mentioned N atom and the hydrogen atom, which is beneficial to maintaining the stable conformation of the compound and can even further improve the biological activity and pharmacokinetic properties of the compound.

[0114] In the above ring portion, X1, X2, X3 and X4 are each independently C or N; wherein when X2 and X3 are N, X1 and X4 are C; when X1 and X3 are N, X2 and X4 are C; when X3 and X4 are N, X1 and X2 are C;

[0115] The dotted ring indicates the presence of two conjugated double bonds in the 5-membered ring.

[0116] According to the different options of X1, X2, X3 and X4, It can be one of the following structures

[0117] In the present application, R3 is selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 Preferably, R3 is hydrogen or C 1-6 Alkyl groups such as C 1-3 Alkyl groups such as methyl or deuterated methyl.

[0118] In this application, ring A is substituted with 0-4 R A C 6-10 Aryl, substituted with 0-4 R A C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R A 3-10 membered heterocyclic group or substituted with 0-4 R A 5-6 membered heteroaryl (e.g. 5-6 membered monocyclic heteroaryl). A The number can be 0, 1, 2 or 3.

[0119] In one embodiment, Ring A is substituted with 0-2 (eg, 0, 1, or 2) R A benzene ring.

[0120] In one embodiment, Ring A is substituted with 0-2 (eg, 0, 1, or 2) R A of the pyridine ring.

[0121] In one embodiment, Ring A is substituted with 0-2 (eg, 0, 1, or 2) R A pyrimidine ring.

[0122] In one embodiment, RA Halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 For example, R A It can be halogen such as fluorine, chlorine, bromine; C 1-6 Alkyl groups such as C 1-3 Alkyl such as methyl, ethyl, propyl or isopropyl, especially methyl or ethyl; C 1-6 Hydroxyalkyl such as hydroxymethyl, hydroxyethyl, etc.; C 1-6 Haloalkyl such as trifluoromethyl, difluoromethyl, monofluoromethyl; C 1-6 Alkoxy groups such as methoxy, ethoxy, etc.; C 1-6 Examples of haloalkoxy include trifluoromethoxy and the like.

[0123] In one embodiment, Ring A has one of the following structures:

[0124] In one embodiment, R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, C 2-6 Alkynyl, cyano C 1-6 Alkyl or HOC(=O)C 1-6 For example, R1 can be C 1-6 Alkyl such as methyl, ethyl, propyl, isopropyl or tert-butyl; C 1-6 Haloalkyl such as trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroisopropyl, trifluorotert-butylmethyl, etc.; C 1-6 Hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxybutyl (including hydroxy-n-butyl, hydroxy-sec-butyl, hydroxy-isobutyl, hydroxy-tert-butyl), etc.; C 1-3 Alkoxy C 1-6 Alkyl such as methoxymethyl, methoxyethyl, methoxypropyl, etc.; C 2-6 Alkynyl such as ethynyl, propynyl, etc.; cyano C 1-6 Alkyl such as cyanomethyl, cyanoethyl, etc.; HOC(=O)C 1-6 Examples of the alkyl group include HOC(=O)methyl and HOC(=O)ethyl.

[0125] In one embodiment, R1 is selected from C optionally substituted with R8 3-6 Cycloalkyl or 3-6 membered heterocyclic group optionally substituted with R8; wherein R8 are independently selected from halogen, hydroxyl, C 1-6 Alkyl, C1-6 For example, R1 can be C 3-6 Cyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; 3-6 membered heterocyclic groups such as oxetanyl, azetidinyl, azopentyl, azohexyl, etc. 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be substituted with 1-3 R8, for example halogen such as fluorine; hydroxyl; C 1-6 Alkyl such as methyl, ethyl; C 1-6 Haloalkyl is for example trifluoromethyl.

[0126] In one embodiment, each R1 is independently optionally substituted with R 10 C 1-6 Alkyl, optionally substituted with R 10 C 1-6 Haloalkyl, optionally substituted with R 10 C 1-6 Alkoxy, optionally substituted with R 10 C 2-6 Alkenyl, optionally substituted with R 10 C 2-6 Alkynyl, optionally substituted with R 10 C 3-6 Cycloalkyl or optionally substituted with R 10 3-6 membered heterocyclic group; wherein R 10 Each independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl or C 1-6 In one embodiment, R1 is -C(CH3)(CF3).

[0127] In one embodiment, R is isoxazolyl substituted with 1 R7, oxazolyl substituted with 1 R7, oxadiazolyl substituted with 1 R7, triazolyl substituted with 1 R7, thiazolyl substituted with 1 R7, isothiazolyl substituted with 1 R7, or thiadiazolyl substituted with 1 R7;

[0128] Wherein, R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, substituted with 0-1 R 70 C 6-10 Aryl, substituted with 0-1 R 70 C 3-10 Cyclic hydrocarbon group, substituted with 0-1 R 70 3-10 membered heterocyclic group or substituted with 0-1 R 70 5-6 membered heteroaryl;

[0129] R 70 are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl.

[0130] In one embodiment, R has the structure

[0131] In the above structure Indicates the presence of two conjugated double bonds within the ring structure;

[0132] Wherein, R7 is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or substituted with 0-1 R 70 C 3-6 Cycloalkyl;

[0133] R 70 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3-8 membered heterocyclic group;

[0134] Z2 is O or S or N;

[0135] Z3 is C or N or O or S;

[0136] Z4 is C or O or N.

[0137] In one embodiment, Z2 is O, Z3 is CH, and Z4 is N; that is, R is of the following structure

[0138] In one embodiment, Z2 is N, Z3 is CH, and Z4 is O; that is, R is of the following structure

[0139] In one embodiment, Z2 is S, Z3 is CH, and Z4 is N; that is, R is of the following structure

[0140] In one embodiment, Z2 is S, Z3 is N, and Z4 is N; that is, R is of the following structure

[0141] In one embodiment, Z2 is N, Z3 is O, and Z4 is N; that is, R is of the following structure

[0142] In one embodiment, Z2 is N, Z3 is S, and Z4 is N; that is, R is of the following structure

[0143] In one embodiment, Z2 is N, Z3 is N, and Z4 is N; that is, R is of the following structure

[0144] In one embodiment, R7 is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or substituted with 0-1 R 70 C 3-6 Cycloalkyl; R 70 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3-8 membered heterocyclic group. For example, R7 can be methyl, tert-butyl, trifluorotert-butyl, cyclopropyl, cyclobutyl, etc., as well as substituted cyclopropyl such as trifluoromethyl substituted cyclopropyl, methyl substituted cyclopropyl; substituted cyclobutyl such as trifluoromethyl substituted cyclobutyl, methyl substituted cyclobutyl.

[0145] In one embodiment, R has one of the following structural formulas:

[0146] Among them, R Ba C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cyclic hydrocarbon group or substituted with 1 R B1a C 3-6 Cycloalkyl,

[0147] where R B1a C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0148] For example, R Ba It can be selected from tert-butyl, trifluoro-substituted tert-butyl (such as 1,1,1-trifluoro-2-methyl-prop-2-yl, etc.) or

[0149] In one embodiment, R has the structure

[0150] Among them, R B For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0151] R4 has the following structure

[0152] L is O, C(=O), CR 41 R 42 or

[0153] R L For substitution there are 0-1 R C C 6-10 Aryl, substituted with 0-1 R C C 3-10 Cyclic hydrocarbon group, substituted with 0-1 R C 3-10 membered heterocyclic group or substituted with 0-1 R C 5-6 membered heteroaryl;

[0154] R 41 and R 42 Each independently selected from protium, deuterium, tritium, halogen or C 1-3 alkyl;

[0155] R C Halogen or C 1-6 alkyl.

[0156] Furthermore, R B is hydrogen or C 1-3 haloalkyl, such as trifluoromethyl;

[0157] L is O, C(=O), CH(CH3), CH2, CF2, CD2 or

[0158] R L To replace there is 1 R C A 4-6 membered heterocyclic group;

[0159] R C Halogen or C 1-3 alkyl.

[0160] Furthermore, R L Has one of the following structures

[0161] Among them, R Cb For hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, 3-6 membered heterocyclic group, -C(=O)R C1 、-(CH2) kS(=O)2R C1 or -NR C2 R C3 ; or two R Bb Together with the atoms to which they are attached, they form a 3- to 6-membered ring;

[0162] R C1 Each independently selected from C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0163] R C2 and R C3 are each independently selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0164] m is 0, 1, 2, 3 or 4;

[0165] k is 0, 1, or 2.

[0166] Furthermore, R L Has one of the following structures

[0167] Among them, R Cb Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, 3-6 membered heterocyclic group, -C(=O)R C1 、-(CH2) k S(=O)2R C1 or -NR C2 R C3 ;

[0168] R Cc are independently selected from hydrogen, halogen, or C 1-3 alkyl;

[0169] R C1 Each independently selected from C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0170] R C2 and R C3 are independently selected from hydrogen or C 1-3 alkyl;

[0171] k is 0, 1, or 2.

[0172] In one embodiment, R has one of the following structural formulas

[0173] Wherein, L is O or CH2; R Cb C 1-3 Alkyl; R Bd For hydrogen, C 1-3 Alkyl or C 1-3 Haloalkyl is for example trifluoromethyl.

[0174] In one embodiment, R has the structure

[0175] R4 has one of the following structures

[0176] Among them, R Cb C 1-6 alkyl;

[0177] R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 、R 52 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl;

[0178] R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 、R 62 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl;

[0179] n is 1 or 2.

[0180] In one embodiment, R has one of the following structural formulas

[0181] in,

[0182] R 51 and R 52 are each independently selected from protium, halogen, deuterium or tritium, or R 51 、R 52 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl;

[0183] R 61 and R 62 are each independently selected from protium, halogen, deuterium or tritium, or R 61 、R 62 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl;

[0184] R Cb C 1-6 alkyl;

[0185] n=1 or 2.

[0186] In one embodiment, R2 is hydrogen. In particular, R3 and R2 are both hydrogen.

[0187] In one embodiment, R1, R2 and the atoms to which they are attached together form a 6-membered ring.

[0188] In one embodiment, in Formula I

[0189] A section has one of the following structures

[0190] Among them, when X1 is C, X2 and X3 are N; when X1 is N, X2 is C and X3 is N;

[0191] Among them, R D1 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; or two R D1 Together with the carbon atoms to which they are attached, they form 0-2 R D0 3- to 6-membered ring structures;

[0192] R D0 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ;

[0193] R e1 and R e2 are each independently selected from hydrogen, C 1-6 alkyl.

[0194] In one embodiment, in Formula I

[0195] A section has one of the following structures

[0196] Among them, R D2 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ;

[0197] R e1 and R e2 are independently selected from hydrogen or C 1-6 alkyl.

[0198] In one embodiment, the compound has the structure of Formula IA or IB

[0199] Where L is a direct bond, O or CR 21 R 22 ;

[0200] R L To replace 0-4 R C C 6-10 Aryl, substituted with 0-4 R C C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R C 3-10 membered heterocyclic group or substituted with 0-4 R C 5-6 membered heteroaryl;

[0201] X is O or S;

[0202] R3 is selected from hydrogen or C 1-6 alkyl;

[0203] R2 is selected from hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0204] R1 is selected from 0-2 R 0 C 6-10 Aryl, substituted with 0-2 R 0 C 3-6 Cyclic hydrocarbon group, substituted with 0-2 R 0 3-6 membered heterocyclic group, substituted with 0-2 R 0 5-6 membered heteroaryl, substituted with 0-2 R 0 C 1-6 Alkyl, substituted with 0-2 R 0 C 1-6 Halogenated alkyl, substituted with 0-2 R 0 C 1-6 Alkoxy, substituted with 0-2 R 0 C 2-6 Alkenyl, or substituted with 0-2 R0 C 2-6 Alkynyl; or, R1, R2 and the atoms to which they are attached together form a 5-membered or 6-membered ring;

[0205] R A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, hydroxy, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0206] R B Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 haloalkyl; and two R B One of them is hydrogen;

[0207] R 0 Each independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, carbonyl C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 3-10 Cycloalkyl, 3-8 membered heterocyclic group or NR 11 R 12 ;

[0208] R 11 and R 12 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0209] R 21 and R 22 are each independently selected from hydrogen, halogen, deuterium, tritium, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, or R 11 and R 12 Together with the attached carbon atom, it forms C 3-6 Cyclic hydrocarbon group.

[0210] Furthermore, in Formulas IA and IB

[0211] A section has one of the following structures:

[0212] Among them, R D2 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ;

[0213] R e1 and R e2 are each independently selected from hydrogen, C 1-6 alkyl.

[0214] Further, R3 is hydrogen or C 1-3 Alkyl; R2 is hydrogen;

[0215] R1 is each independently optionally substituted with R 10 C 1-6 Alkyl, optionally substituted with R 10 C 1-6 Haloalkyl, optionally substituted with R 10 C 1-6 Alkoxy, optionally substituted with R 10 C 2-6 Alkenyl, optionally substituted with R 10 C 2-6 Alkynyl, optionally substituted with R 10 C 3-6 Cycloalkyl or optionally substituted with R 10 A 3-6 membered heterocyclic group;

[0216] Among them, R 10 Each independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl or C 1-6 Alkoxy.

[0217] Furthermore, the two R A All are fluorine.

[0218] Furthermore, the two R B One of them is hydrogen and the other is trifluoromethyl.

[0219] Furthermore, R L Has one of the following structures:

[0220] Among them, R Cb Each independently selected from hydrogen, halogen, hydroxyl, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, 3-6 membered heterocyclic group, -C(=O)R C1 、-(CH2) k S(=O)2R C1 or -NR C2 R C3 ;

[0221] R Cc are independently selected from hydrogen, halogen, or C 1-3 alkyl;

[0222] R C1 Each independently selected from C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0223] R C2 and R C3 are independently selected from hydrogen or C 1-3 alkyl;

[0224] k is 0, 1, or 2.

[0225] The present application also provides a compound as shown in Formula II

[0226] Wherein, X is O or S;

[0227] R3 is selected from hydrogen or C 1-6 alkyl;

[0228] R2 is selected from hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0229] R1 is selected from 0-2 R 0 C 6-10 Aryl, substituted with 0-2 R 0 C 3-6 Cyclic hydrocarbon group, substituted with 0-2 R 0 3-6 membered heterocyclic group, substituted with 0-2 R 0 5-6 membered heteroaryl, substituted with 0-2 R 0 C 1-6 Alkyl, substituted with 0-2 R 0 C 1-6 Halogenated alkyl, substituted with 0-2 R 0 C 1-6 Alkoxy, substituted with 0-2 R0 C 2-6 Alkenyl, or substituted with 0-2 R 0 C 2-6 Alkynyl; or, R1, R2 and the atoms to which they are attached together form a 5-membered or 6-membered ring;

[0230] R G1 and R G2 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, hydroxy, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0231] R 0 Each independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, carbonyl C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 3-10 Cycloalkyl, 3-8 membered heterocyclic group or NR 11 R 12 ;

[0232] R 11 and R 12 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0233] R F1 Selected from hydrogen, hydroxyl, C 1-6 Alkoxy, cyano, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cyclic hydrocarbon group or substituted with 1 R F1a C 3-6 Cycloalkyl,

[0234] R F2 To replace 0-4 R F2a C 6-10 Aryl C 6-10 Aryl, substituted with 0-4 R F2a C 3-6 Cyclic hydrocarbon group, substituted with 0-4 R F2a 3-6 membered heterocyclic group or substituted with 0-4 R F2a 5-6 membered heteroaryl;

[0235] where R F1a Selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; R F2a Selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0236] In one embodiment, A section has one of the following structures

[0237] Among them, R D2 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ;

[0238] R e1 and R e2 are each independently selected from hydrogen, C 1-6 alkyl.

[0239] For example, A section can have the following structure

[0240] In one embodiment,

[0241] R3 is hydrogen;

[0242] R2 is hydrogen;

[0243] R1 is each independently optionally substituted with R 10 C 1-6 Alkyl, optionally substituted with R 10 C 1-6 Haloalkyl, optionally substituted with R 10 C 1-6 Alkoxy, optionally substituted with R 10 C 2-6 Alkenyl, optionally substituted with R 10 C 2-6 Alkynyl, optionally substituted with R 10 C 3-6 Cycloalkyl or optionally substituted with R 10 A 3-6 membered heterocyclic group;

[0244] Among them, R 10 Each independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C1-6 Alkyl or C 1-6 Alkoxy.

[0245] In one embodiment, R1 is C 3-6 Cyclic hydrocarbon groups are for example cyclopropyl or cyclobutyl.

[0246] In one embodiment, R G1 is a halogen such as F, R G2 For hydrogen.

[0247] In one embodiment, R F1 tert-butyl, trifluoro-substituted tert-butyl (e.g., 1,1,1-trifluoro-2-methyl-prop-2-yl, etc.) or

[0248] R F2 is phenyl or halogen-substituted phenyl (eg fluorine-substituted phenyl such as 4-fluoro-phenyl, etc.).

[0249] In the above compounds, preferably, X is O.

[0250] In the present application, the compound is selected from one of the following:

[0251] Pharmaceutical composition

[0252] The present disclosure also relates to pharmaceutical compositions. The pharmaceutical compositions comprise any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In more embodiments, the pharmaceutical compositions comprise a compound disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0253] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0254] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, typically in the form of a depot formulation or a sustained release formulation. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in the form of a quick-release formulation, an extended-release formulation, or an intermediate-release formulation. In other embodiments, the compounds described herein are administered topically.

[0255] 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 dosage can be determined by methods such as modeling, dose escalation studies or clinical trials, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder or condition, the individual's previous or ongoing therapy, the individual's health status and response to drugs, and the judgment of the treating physician.

[0256] The compounds of the present disclosure are effective over a wide dosage range. For example, in the treatment of adults, dosages of 10 to 5000 mg / day, 100 to 5000 mg / day, 1000 to 4000 mg / day, and 1000 to 3000 mg / day are examples of dosages used in some embodiments. The exact dosage depends on the route of administration, the compound form administered, the subject to be treated, the weight of the subject to be treated, the preference and experience of the attending physician.

[0257] 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, to allow for rapid introduction of the agent. However, other routes may be used as appropriate. A single dose of a compound of the present disclosure may also be used to treat acute conditions.

[0258] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate processing of the disclosed compounds into pharmaceutically acceptable formulations. Appropriate formulations depend on the chosen route of administration.

[0259] Provided herein are pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0260] Provided herein is a pharmaceutical composition comprising one or more compounds selected from the compound of structure (I) and a pharmaceutically acceptable diluent, excipient, and carrier. In certain embodiments, the compound is administered as a pharmaceutical composition, wherein one or more compounds selected from the compound of structure (I) are mixed with other active ingredients, such as in a combination therapy. All combinations of the active substances described in the combination therapy section below and all combinations of the active substances described in the disclosure are contemplated herein. In a specific embodiment, the pharmaceutical composition includes one or more compounds of structure (I).

[0261] As used herein, pharmaceutical composition refers to a mixture of one or more compounds selected from the compound of structure (I) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. In certain embodiments, pharmaceutical composition promotes the administration of compound to organisms. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compound of structure (I) provided herein is applied to a mammal suffering from a disease to be treated, a disease or a medical condition in a pharmaceutical composition. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount varies according to the severity of the disease, the age and relative health status of the individual, the efficacy of the compound used and other factors. Compounds as described herein are used as components of a mixture alone or in combination with one or more therapeutic agents.

[0262] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated into oral dosage forms including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0263] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if desired) to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other substances, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, a disintegrant is optionally added. By way of example only, disintegrants include cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0264] application

[0265] The present disclosure also relates to methods for treating disorders mediated by the NEK7-NLRP3 interaction, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition of the present disclosure.

[0266] As demonstrated in the disclosure, the compounds disclosed herein have NEK7 enzymatic inhibitory activity and can therefore be used to treat or prevent NEK7-NLRP3-mediated disorders, as well as to prepare drugs for treating or preventing NEK7-NLRP3-mediated disorders.

[0267] The host or patient can be of any mammalian species, such as primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are interesting for experimental research and provide models for treating human diseases.

[0268] The NEK7-NLRP3 interaction-mediated disorder can be selected from autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases and ischemic conditions.

[0269] The NEK7-NLRP3-interacting disorder can be 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 Mueller-Weiss syndrome.

[0270] The NEK7-NLRP3 interactively mediated disorder can be selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndromes, cryptopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease and cancer.

[0271] The examples and formulations provided below further illustrate and exemplify the compounds of the present disclosure and methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and formulations. In the following examples, and throughout the specification and claims, unless otherwise indicated, molecules with a single stereocenter exist as a racemic mixture. Unless otherwise indicated, those molecules with two or more stereocenters exist as a racemic mixture of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0272] Example

[0273] Synthesis of intermediates

[0274] Intermediate 1: 1-(4-isocyanato-2-(trifluoromethyl)benzyl)-4-methylpiperazine

[0275] Step A: 1-Methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine

[0276] To a solution of 4-nitro-2-(trifluoromethyl)benzaldehyde (5.0 g, 22.8 mmol) in dichloromethane (50 mL) were added 1-methylpiperazine (2.7 g, 27.0 mmol) and sodium triacetoxyborohydride (14.4 g, 68.0 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution, then extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 97 / 3) to give the product (5.4 g, yield 78%).

[0277] LC-MS (ESI), m / z: [M+1]+ =304.

[0278] Step B: 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline

[0279] To a solution of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (4.8 g, 15.8 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (1.0 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product (4.3 g, 99% yield), which was used directly in the next step without purification.

[0280] LC-MS (ESI), m / z: [M+1] + =274.

[0281] Intermediate 2: 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline

[0282] Step A: 1-Methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine

[0283] To a solution of 1-methyl-4-piperidinol in N,N-dimethylformamide (2.4 g, 20.8 mmol) was slowly added sodium hydride (1.5 g, 38.0 mmol, 60% dispersion in mineral oil) at 0°C, and the mixture was stirred at this temperature for 1 hour. 2-Fluoro-5-nitrobenzotrifluoride (4.0 g, 19.0 mmol) was then slowly added, and the reaction was allowed to warm to room temperature and stirred at room temperature for 16 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was made alkaline with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (3.5 g, 61% yield).

[0284] LC-MS (ESI), m / z: [M+1] + =305.

[0285] Step B: 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline

[0286] To a solution of 1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (3.5 g, 11.5 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (500 mg) at room temperature, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product (3.0 g, 95% yield), which was used directly in the next step without purification.

[0287] LC-MS (ESI), m / z: [M+1] + =275.

[0288] Intermediate 3: 3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-amine

[0289] Step A: 3-Oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile

[0290] Sodium hydride (220 mg, 5.6 mmol, 60%) was added to anhydrous tetrahydrofuran (5 mL) at room temperature and stirred for 10 minutes. Ethyl 1-trifluoromethylcyclopropane-1-carboxylate (500 mg, 2.8 mmol) and anhydrous acetonitrile (169 mg, 4.1 mmol) were then added sequentially. The mixture was stirred at 70°C under nitrogen for 1 hour. TLC and LC-MS monitoring indicated the disappearance of the starting material. The reaction mixture was cooled to 0°C, ice water and methyl tert-butyl ether were added, and the organic phase was separated. The aqueous phase was extracted twice with methyl tert-butyl ether. The combined organic phases were washed once with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product (802 mg) as a pale yellow solid.

[0291] LC-MS (ESI), m / z: [M-1] - =176.

[0292] Step B: 3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-amine

[0293] To a mixture of sodium hydroxide (217 mg, 5.4 mmol) in ethanol and water (10 mL, 1 / 1) at room temperature were added hydroxylamine sulfate (446 mg, 2.7 mmol) and 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile (802 mg, 4.5 mmol). The mixture was stirred at 80°C under nitrogen for 6 hours. TLC and LC-MS monitoring indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature, and methyl tert-butyl ether was added to separate the organic phase. The aqueous phase was extracted twice with methyl tert-butyl ether. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1) to afford the product as a white solid (444 mg, 51% yield).

[0294] LC-MS (ESI), m / z: [M+1] + =193.

[0295] Referring to the synthesis method of the above intermediates, the intermediates in the table below were synthesized as follows:

[0296] Intermediate A1: 2-(methoxy(4-nitrophenyl)methylene)malononitrile

[0297] Step A: 2-(Hydroxy(4-nitrophenyl)methylene)malononitrile

[0298] To a solution of 4-nitrobenzoic acid (5 g, 29.9 mmol) in ethyl acetate (25 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.5 g, 39.1 mmol), 1-hydroxybenzotriazole (5.3 g, 39.2 mmol), malononitrile (2.4 g, 36.4 mmol) and triethylamine (9.1 g, 89.8 mmol) at room temperature; the mixture was stirred at room temperature for 16 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was made alkaline with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (6.0 g, yield 93%).

[0299] LC-MS (ESI), m / z: [M+1] + =216.

[0300] Step B: 2-(Methoxy(4-nitrophenyl)methylene)malononitrile

[0301] To a solution of 2-(hydroxy(4-nitrophenyl)methylene)malononitrile (6.0 g, 27.9 mmol) in 1,4-dioxane (50 mL) at room temperature were added sodium bicarbonate (12.7 g, 151.0 mmol) and dimethyl sulfate (7.6 g, 60.3 mmol). The reaction mixture was heated to 80°C and stirred at 80°C for 2 h. TLC and LC-MS monitoring revealed the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 73 / 27) to obtain the product (4.1 g, 64% yield).

[0302] LC-MS (ESI), m / z: [M+1] + =230.

[0303] 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=8.8Hz,2H),7.98(d,J=8.8Hz,2H),3.87(s,3H).

[0304] Intermediate A2: 2-((3-fluoro-4-nitrophenyl)(methoxy)methylene)malononitrile

[0305] Step A: 2-((3-Fluoro-4-nitrophenyl)(hydroxy)methylene)malononitrile

[0306] To a solution of 3-fluoro-4-nitrobenzoic acid (20.0 g, 108.0 mmol) in ethyl acetate (50 mL) were added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (26.9 g, 140.4 mmol), 1-hydroxybenzotriazole (18.9 g, 140.4 mmol), triethylamine (32.8 g, 324.0 mmol) and malononitrile (8.6 g, 129.6 mmol) at room temperature; the mixture was stirred at room temperature for 16 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was made alkaline with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (25.2 g, yield 100%).

[0307] LC-MS (ESI), m / z: [M+1] + =234.

[0308] Step B: 2-((3-Fluoro-4-nitrophenyl)(methoxy)methylene)malononitrile

[0309] To a solution of 2-((3-fluoro-4-nitrophenyl)(hydroxy)methylene)malononitrile (19.0 g, 81.5 mmol) in 1,4-dioxane (200 mL) were added dimethyl sulfate (51.4 g, 407.5 mmol) and sodium bicarbonate (34.2 g, 407.5 mmol) at room temperature; the reaction solution was heated to 80°C and stirred at 80°C for 2 h; the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1) to give the product (12.9 g, yield 64%).

[0310] LC-MS (ESI), m / z: [M+1] + =248.

[0311] 1 H NMR (400MHz, DMSO-d6) δ8.41(t,J=8.0Hz,1H),8.11(dd,J=11.3Hz,1.6Hz,1H),7.82(d,J=8.5Hz,1H),3.94(s,3H).

[0312] Intermediate A3: 2-((3,5-difluoro-4-nitrophenyl)(methoxy)methylene)malononitrile

[0313] Step A: 2-((3,5-difluoro-4-nitrophenyl)(hydroxy)methylene)malononitrile

[0314] To a solution of 3,5-difluoro-4-nitrobenzoic acid (4.9 g, 24.1 mmol) in ethyl acetate (50 mL) were added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.0 g, 31.3 mmol), 1-hydroxybenzotriazole (4.2 g, 31.3 mmol), triethylamine (7.3 g, 72.3 mmol), and malononitrile (1.9 g, 28.9 mmol) in sequence at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was made alkaline with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (9.5 g).

[0315] LC-MS (ESI), m / z: [M+1] + =252.

[0316] Step B: 2-((3,5-difluoro-4-nitrophenyl)(methoxy)methylene)malononitrile

[0317] To a solution of 2-((3,5-difluoro-4-nitrophenyl)(hydroxy)methylene)malononitrile (9.5 g, 37.8 mmol) in 1,4-dioxane (100 mL) were added dimethyl sulfate (14.3 g, 113.5 mmol) and sodium bicarbonate (9.5 g, 113.5 mmol) at room temperature; the reaction solution was heated to 80°C and stirred at 80°C for 3 h; the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product (990 mg, yield 15%).

[0318] LC-MS (ESI), m / z: [M+1] + =266.

[0319] Intermediate A4: 2-((2,5-difluoro-4-nitrophenyl)(methoxy)methylene)malononitrile

[0320] Step A: 2-((2,5-difluoro-4-nitrophenyl)(hydroxy)methylene)malononitrile

[0321] To a solution of 2,5-difluoro-4-nitrobenzoic acid (10 g, 49.2 mmol) in ethyl acetate (100 mL) were added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (12.3 g, 64.0 mmol), 1-hydroxybenzotriazole (8.7 g, 64.0 mmol), triethylamine (15.0 g, 147.7 mmol), and malononitrile (3.9 g, 59.1 mmol) in sequence at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was made alkaline with saturated aqueous sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (21.0 g).

[0322] LC-MS (ESI), m / z: [M+1] + =252.

[0323] Step B: 2-((2,5-difluoro-4-nitrophenyl)(methoxy)methylene)malononitrile

[0324] To a solution of 2-((2,5-difluoro-4-nitrophenyl)(hydroxy)methylene)malononitrile (9.5 g, 37.8 mmol) in 1,4-dioxane (100 mL) were added dimethyl sulfate (14.3 g, 113.5 mmol) and sodium bicarbonate (9.5 g, 113.5 mmol) at room temperature; the reaction solution was heated to 80°C and stirred at 80°C for 3 h; the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product (3.6 g, yield 54%).

[0325] LC-MS (ESI), m / z: [M+1] + =266.

[0326] Referring to the synthesis method of the above intermediates, the intermediates in the table below were synthesized as follows:

[0327] Intermediate B1: 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate

[0328] To a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (4.3 g, 15.7 mmol) in dichloromethane (50 mL) at 0°C were added pyridine (3.7 g, 47.1 mmol) and p-nitrophenyl chloroformate (3.8 g, 18.9 mmol); the mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was quenched with water and diluted, extracted three times with dichloromethane, and the organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (6.8 g), which was used directly in the next step without further purification.

[0329] LC-MS (ESI), m / z: [M+1] + =439.

[0330] Intermediate B2: 4-nitrophenyl-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)carbamate

[0331] To a solution of 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline (3.0 g, 10.9 mmol) in dichloromethane (30 mL) at 0°C were added pyridine (2.6 g, 32.7 mmol) and p-nitrophenyl chloroformate (2.6 g, 13.1 mmol); the mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was quenched with water and diluted, extracted three times with dichloromethane, and the organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (4.8 g), which was used directly in the next step without further purification.

[0332] LC-MS (ESI), m / z: [M+1] + =440.

[0333] Referring to the synthesis method of the above intermediates, the intermediates in the table below were synthesized as follows:

[0334] Example 1: 5-amino-1-cyclopropyl-3-(4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0335] Step A: 5-amino-1-cyclopropyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile

[0336] To a solution of 2-(methoxy(4-nitrophenyl)methylene)malononitrile (2.0 g, 8.7 mmol) in ethanol (5 mL) were added triethylamine (4.4 g, 43.5 mmol) and cyclopropylhydrazine hydrochloride (945 mg, 8.7 mmol) at room temperature; the reaction temperature was raised to 80°C and stirred for 16 h; the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material; the reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (mobile phase: DCM / MeOH = 20 / 1) to give the product (2.0 g, yield 85%).

[0337] LC-MS (ESI), m / z: [M+1] + =270.

[0338] Step B: 5-amino-3-(4-aminophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile

[0339] To a solution of 5-amino-1-cyclopropyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (2.0 g, 7.4 mmol) in methanol (30 mL) at room temperature were added zinc powder (2.4 g, 37.0 mmol) and saturated aqueous ammonium chloride (26 mL). The reaction temperature was raised to 60°C and stirred for 16 h. TLC and LC-MS monitoring revealed the disappearance of the starting material. The mixture was adjusted to a weak alkaline state by adding saturated aqueous sodium bicarbonate solution, filtered, and the filtrate was concentrated under reduced pressure to remove methanol. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 97 / 3) to afford the product (1.3 g, 73% yield).

[0340] LC-MS (ESI), m / z: [M+1] + =240.

[0341] Step C: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0342] To a solution of 5-amino-3-(4-aminophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (500 mg, 2.1 mmol) in tetrahydrofuran (5 mL) were added triethylamine (634 mg, 6.3 mmol) and 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate (1.1 g, 2.5 mmol) at room temperature. The reaction temperature was raised to 50°C and stirred for 3 h. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Water was added to quench and dilute the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 87 / 13) to give the product (140 mg, yield 12%).

[0343] LC-MS (ESI), m / z: [M+1] + =539.

[0344] Step D: 5-amino-1-cyclopropyl-3-(4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0345] To a mixed solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (130 mg, 0.2 mmol) in ethanol (2 mL) and water (1 mL) was added (dimethylphosphonic acid) platinum (II) hydrogen complex (9 mg, 0.02 mmol) at room temperature, the reaction temperature was raised to 80°C and stirred for 16 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; water was added to quench and dilute the reaction, and the reaction was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Prep-HPLC column chromatography (column model: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% The product (29 mg, yield 26%) was purified by filtration by adding TFA (gradient: 20%-50%, flow rate: 20 mL / min).

[0346] LC-MS (ESI), m / z: [M+1] + =557.

[0347] 1 H NMR (400MHz, CD3OD) δ7.92(s,1H),7.70(s,2H),7.63(d,J=8.4Hz,2H),7.48(d,J=8.5Hz,2H),3.77(s,2H),3.42-3.40 (m,2H),3.27-3.14(m,2H),3.11-2.95(m,1H),2.93(s,3H),2.89-2.75(m,2H),2.73-2.38(m,2H),1.13-1.12(m,4H).

[0348] Example 2: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0349] Step A: 5-amino-1-cyclopropyl-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile

[0350] To a solution of 2-((3-fluoro-4-nitrophenyl)(methoxy)methylene)malononitrile (1.0 g, 4.0 mmol) in anhydrous ethanol (12 mL) were added cyclopropylhydrazine hydrochloride (521 mg, 4.8 mmol) and triethylamine (1.2 g, 11.2 mmol) at room temperature; the reaction temperature was raised to 60°C and stirred for 1 h; the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material; the residue was concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 95 / 5) to give the product (1.0 g, yield 87%).

[0351] LC-MS (ESI), m / z: [M+1] + =288.

[0352] Step B: 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile

[0353] To a solution of 5-amino-1-cyclopropyl-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile (1.0 g, 3.5 mmol) in anhydrous methanol (10 mL) were added zinc powder (1.1 g, 17.0 mmol) and saturated ammonium chloride solution (8 mL) at room temperature. The reaction temperature was raised to 60°C and stirred for 16 h. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Saturated aqueous sodium bicarbonate solution was added to adjust the solution to a weak base, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove methanol. The mixture was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 95 / 5) to give the product (0.5 g, yield 56%).

[0354] LC-MS (ESI), m / z: [M+1] + =258.

[0355] Step C: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0356] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (200 mg, 0.8 mmol) in tetrahydrofuran (10 mL) were added triethylamine (236 mg, 2.3 mmol) and 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate (702 mg, 1.6 mmol) at room temperature. The reaction temperature was raised to 70°C and stirred for 2 h. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The product was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 80 / 20) to give the product (100 mg, yield 23%).

[0357] LC-MS (ESI), m / z: [M+1] + =557.

[0358] Step D: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0359] To a mixed solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (100 mg, 0.2 mmol) in anhydrous ethanol (4 mL) and water (2 mL) was added (dimethylphosphonic acid) platinum (II) hydrogen complex (15.4 mg, 0.03 mmol) at room temperature, the reaction temperature was raised to 80° C. and stirred for 16 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; water was added to quench and dilute the reaction, and the reaction was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Prep-HPLC column chromatography (column model: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H 2 O (0.1% The product (17 mg, yield 16%) was purified by filtration using TFA (gradient: 20%-50%, flow rate: 20 mL / min).

[0360] LC-MS (ESI), m / z: [M+1] + =575.

[0361] 1H NMR (400MHz, CD3OD) δ8.27(t,J=8.5Hz,1H),7.91(s,1H),7.71(s,2H),7.35(d,J=4.0Hz,1H),7.33(s,1H),3.76(s,2H),3.5 0-3.44(m,2H),3.25-3.20(m,2H),3.18-3.16(m,1H),3.15-3.03(m,2H),2.93(s,3H),2.50-2.44(m,2H),1.14-1.11(m,4H).

[0362] Examples 3 and 4: 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate and 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate

[0363] Step A: 3-Hydrazino-1-methylcyclobutan-1-ol hydrochloride

[0364] To a solution of tert-butyl 2-(3-hydroxy-3-methylcyclobutyl)hydrazine-1-carboxylate (3.0 g, 13.9 mmol) in dichloromethane (10 mL) was added a solution of HCl (g) in 1,4-dioxane (6.9 mL, 27.8 mmol, 4 M) at room temperature; the reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give 3-hydrazino-1-methylcyclobutane-1-ol hydrochloride (2.5 g), which was used directly in the next reaction without purification.

[0365] LC-MS (ESI), m / z: [M+1] + =117.

[0366] Step B: 5-amino-3-(3-fluoro-4-nitrophenyl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0367] To a solution of 2-((3-fluoro-4-nitrophenyl)(methoxy)methylene)malononitrile (2.0 g, 8.1 mmol) in ethanol (20 mL) were added N,N-diisopropylethylamine (5.2 g, 40.4 mmol) and 3-hydrazino-1-methylcyclobutane-1-ol hydrochloride (1.2 g, 10.5 mmol) in sequence at room temperature; the reaction was stirred at 70°C for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The mixture was concentrated under reduced pressure to remove ethanol, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (1.3 g, yield 65%).

[0368] LC-MS (ESI), m / z: [M+1] + =332.

[0369] Step C: 5-amino-3-(4-amino-3-fluorophenyl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile

[0370] To a solution of 5-amino-3-(3-fluoro-4-nitrophenyl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (1.3 g, 3.9 mmol) in ethanol (20 mL) was added ammonium chloride (2.1 g, 39 mmol) and iron powder (1.1 g, 19.5 mmol) sequentially at room temperature. The mixture was heated to 80°C and stirred for 1.5 hours. TLC and LCMS analysis revealed the disappearance of the starting material and the formation of the product. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford the product (1.1 g, 94% yield).

[0371] LC-MS (ESI), m / z: [M+1] + =302.

[0372] Step D: 1-(4-(5-amino-4-cyano-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0373] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (1.1 g, 3.6 mmol) in 1,4-dioxane (20 mL) were added N,N-diisopropylethylamine (1.4 g, 10.8 mmol) and 4-nitrophenyl(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate (1.8 g, 4.0 mmol) at room temperature; the reaction was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (650 mg, 30% yield).

[0374] LC-MS (ESI), m / z: [M+1] + =601.

[0375] Step E: 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate and 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate

[0376] To a mixed solution of 1-(4-(5-amino-4-cyano-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (650 mg, 1.1 mmol) in ethanol (10 mL) and water (2 mL) was added platinum dimethylphosphonate (87 mg, 0.2 mmol) at room temperature under nitrogen protection; the temperature was raised to 80°C and stirred overnight. The reaction was monitored by TLC and LCMS, indicating that the starting material disappeared and the product was generated. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by Prep-HPLC to give 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (223 mg, yield 31%) and 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (187 mg, yield 26%).

[0377] LC-MS (ESI), m / z: [M+1] + =619.

[0378] 1 H NMR (400 MHz, DMSO-d6, Example 3) δ 9.46 (s, 1H), 8.76 (s, 1H), 8.24-8.18 (m, 1H), 8.00 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.38-7.29 (m, 2H), 6.95-5.56 (m, 4H), 4.96-4.84 (m, 2H), 3.55 (s, 2H), 2.47-2.35 (m, 11H), 2.21 (s, 3H), 1.76 (s, 1H), 1.34 (s, 3H).

[0379] 1H NMR (400 MHz, DMSO-d6, Example 4) δ 9.51 (s, 1H), 8.76 (s, 1H), 8.24-8.15 (m, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 6.29-5.46 (m, 4H), 5.17 (s, 1H), 4.43-4.39 (m, 1H), 3.57 (s, 2H), 2.67-2.46 (m, 5H), 2.43-2.29 (m, 9H), 1.74 (s, 1H), 1.33 (s, 3H).

[0380] Examples 5 and 6: 5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate and 5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate

[0381] Step A: 1-(4-(5-amino-4-cyano-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0382] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (1.1 g, 3.6 mmol) in 1,4-dioxane (20 mL) were added N,N-diisopropylethylamine (1.4 g, 10.8 mmol) and 4-nitrophenyl-(4-((1-methylpiperazin-1-yl)oxy)-3-(trifluoromethyl)phenyl)carbamate (1.8 g, 4.1 mmol) at room temperature; the reaction was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (590 mg, yield 27%).

[0383] LC-MS (ESI), m / z: [M+1] + =602.

[0384] Step B: 5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate and 5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate

[0385] To a mixed solution of 1-(4-(5-amino-4-cyano-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (590 mg, 1.0 mmol) in ethanol (10 mL) and water (2 mL) was added platinum dimethylphosphonate (87 mg, 0.2 mmol) at room temperature under nitrogen protection; the temperature was raised to 80°C and stirred overnight. The reaction was monitored by TLC and LCMS, indicating that the starting material disappeared and the product was generated. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by Prep-HPLC to give 5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate (193 mg, yield 29%) and 5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide formate (180 mg, yield 27%).

[0386] LC-MS (ESI), m / z: [M+1] + =620.

[0387] 1H NMR (400 MHz, DMSO-d6, Example 5) δ 9.31-9.22 (m, 1H), 8.71-8.67 (m, 1H), 8.19-8.16 (m, 2H), 7.86 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.33-7.25 (m, 2H), 6.67 (s, 1H ),6.26(s,2H),4.95-4.84(m,1H),4.56(s,1H),2.58-2.49(m,2H),2.46-2.38(m,2H),2. 37-2.35(m,4H),2.34-2.21(m,3H),1.95(s,2H),1.76(s,1H),1.71(s,2H),1.34(s,3H).

[0388] 1 H NMR (400 MHz, DMSO-d6, Example 6) δ 9.21 (s, 1H), 8.66 (s, 1H), 8.23-8.15 (m, 2H), 7.86 (s, 1H), 7.53-7.50 (m, 1H), 7.37-7.30 (m, 1H), 7.28-7.26 (m, 2H), 6.29-6.26 (m, 3H), 5.17 (s, 1H), 4.56 (s, 1H), 4.42-4.38 (m, 1H), 2.68-2.40 (m, 4H), 2.39-2.33 (m, 4H), 2.24 (s, 3H), 1.95 (d, J = 4 Hz, 2H), 1.76-1.70 (m, 2H), 1.33 (s, 3H).

[0389] Example 7: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0390] Step A: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0391] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (230 mg, 0.9 mmol) in 1,4-dioxane (10 mL) were added N,N-diisopropylethylamine (347 mg, 2.7 mmol) and 4-nitrophenyl-(4-((1-methylpiperazin-1-yl)oxy)-3-(trifluoromethyl)phenyl)carbamate (432 mg, 1.0 mmol) at room temperature; the reaction was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (200 mg, 40% yield).

[0392] LC-MS (ESI), m / z: [M+1] + =558.

[0393] Step B: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0394] To a solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (167 mg, 0.3 mmol) in ethanol (10 mL) and water (2 mL) at room temperature under nitrogen was added platinum dimethylphosphonate (38 mg, 0.1 mmol). The mixture was heated to 80°C and stirred overnight. TLC and LCMS analysis revealed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by Prep-HPLC to afford the product (72 mg, 42% yield).

[0395] LC-MS (ESI), m / z: [M+1] + =576.

[0396] 1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.74(s,1H),8.22-8.16(m,2H),7.86(s,1H),7.54-7.51(m,1H),7.34-7.26(m,3H),6.96-5.576(m,3 H),4.58(s,1H),3.32-3.27(m,1H),2.62(s,2H),2.52-2.50(m,2H),2.26(s,3H),1.97-1.92(m,2H),1.76-1.74(m,2H),1.02-0.95(m,4H).

[0397] Example 8: 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide

[0398] Step A: 5-amino-3-(3-fluoro-4-nitrophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile

[0399] To a solution of 2-((3-fluoro-4-nitrophenyl)(methoxy)methylene)malononitrile (1.0 g, 4.1 mmol) in ethanol (20 mL) were added N,N-diisopropylethylamine (2.6 g, 20.2 mmol) and (1,1,1-trifluoropropan-2-yl)hydrazine hydrochloride (674 mg, 5.3 mmol) in sequence at room temperature. The reaction was stirred at 70°C for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The mixture was concentrated under reduced pressure to remove ethanol, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (1.2 g, yield 86%).

[0400] LC-MS (ESI), m / z: [M+1] + =344.

[0401] Step B: 5-amino-3-(4-amino-3-fluorophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile

[0402] To a solution of 5-amino-3-(3-fluoro-4-nitrophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile (1.1 g, 3.2 mmol) in ethanol (20 mL) was added ammonium chloride (1.7 g, 32.0 mmol) and iron powder (895 mg, 16.0 mmol) at room temperature. The mixture was heated to 80°C and stirred for 1.5 hours. TLC and LCMS analysis revealed the disappearance of the starting material and the formation of the product. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford the product (1.0 g, 99% yield).

[0403] LC-MS (ESI), m / z: [M+1] + =314.

[0404] Step C: 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0405] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carbonitrile (200 mg, 0.6 mmol) in 1,4-dioxane (10 mL) was added N,N-diisopropylethylamine (248 mg, 1.9 mmol) and 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate (336 mg, 0.8 mmol) under nitrogen at room temperature; the reaction was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (154 mg, 42% yield).

[0406] LC-MS (ESI), m / z: [M+1] + =613.

[0407] Step D: 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide

[0408] To a mixed solution of 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (123 mg, 0.2 mmol) in ethanol (10 mL) and water (2 mL) was added platinum dimethylphosphonate (40 mg, 0.1 mmol) at room temperature under nitrogen protection; the mixture was heated to 80°C and stirred overnight. The reaction was monitored by TLC and LCMS, indicating that the starting material disappeared and the product was generated. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by Prep-HPLC to give 5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide (54 mg, 43% yield).

[0409] LC-MS (ESI), m / z: [M+1] + =631.

[0410] 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.75(d,J=2.4Hz,1H),8.23(t,J=17.2Hz,1H),8.00(s,1H),7.65(d,J=8.4Hz,1H),7.55(d,J= 8.4Hz,1H),7.37-7.30(m,2H),6.62(s,2H),5.33-5.26(m,1H),3.54(s,2H),2.39-2.33(m,8H),2.16(s,3H),1.62(d,J=7.2Hz,3H).

[0411] Example 9: 5-amino-3-(3,5-difluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide

[0412] Step A: 5-amino-3-(3,5-difluoro-4-nitrophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile

[0413] To a solution of 2-((3,5-difluoro-4-nitrophenyl)(methoxy)methylene)malononitrile (900 mg, 3.4 mmol) in ethanol (10 mL) were added N,N-diisopropylethylamine (2.2 g, 17.0 mmol) and (1,1,1-trifluoropropan-2-yl)hydrazine hydrochloride (565 mg, 4.4 mmol) in sequence at room temperature. The reaction was stirred at 70°C for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The mixture was concentrated under reduced pressure to remove ethanol, and water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (640 mg, yield 55%).

[0414] LC-MS (ESI), m / z: [M+1] + =362.

[0415] Step B: 5-amino-3-(4-amino-3,5-difluorophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile

[0416] To a solution of 5-amino-3-(3,5-difluoro-4-nitrophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile (550 mg, 1.5 mmol) in ethanol and water (10 / 1, 11 mL) was added ammonium chloride (814 mg, 15.2 mmol) and iron powder (425 mg, 7.6 mmol) at room temperature. The temperature was raised to 80°C and stirred for 1.5 hours. TLC and LCMS analysis revealed the disappearance of the starting material and the formation of the product. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product (520 mg), which was used directly in the next step without purification.

[0417] LC-MS (ESI), m / z: [M+1] + =332.

[0418] Step C: 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0419] To a solution of 5-amino-3-(4-amino-3,5-difluorophenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carbonitrile (200 mg, 0.6 mmol) in 1,4-dioxane (10 mL) were added N,N-diisopropylethylamine (234 mg, 1.8 mmol) and 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate (292 mg, 0.7 mmol) at room temperature; the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (124 mg, yield 33%).

[0420] LC-MS (ESI), m / z: [M+1] + =631.

[0421] Step D: 5-amino-3-(3,5-difluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide

[0422] To a solution of 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2,6-difluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (124 mg, 0.2 mmol) in ethanol (10 mL) and water (2 mL) was added platinum dimethylphosphonate (7 mg, 0.02 mmol) at room temperature under nitrogen. The mixture was heated to 80°C and stirred overnight. TLC and LCMS analysis revealed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by Prep-HPLC to afford the product (18 mg, 17% yield).

[0423] LC-MS (ESI), m / z: [M+1] + =649.

[0424] 1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.41(s,1H),7.94(s,1H),7.62(s,2H),7.31-7.27(m,2H),6.95 -6.13(m,4H),5.36-5.29(m,1H),3.53(s,2H),2.38-2.34(m,8H),2.16(s,3H),1.63(d,J=6.8Hz,3H).

[0425] Example 10: 5-amino-3-(2,5-difluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide

[0426] Step A: 5-amino-3-(2,5-difluoro-4-nitrophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile

[0427] To a solution of 2-((2,5-difluoro-4-nitrophenyl)(methoxy)methylene)malononitrile (1.0 g, 3.8 mmol) in ethanol (10 mL) were added N,N-diisopropylethylamine (2.5 g, 19.0 mmol) and (1,1,1-trifluoropropan-2-yl)hydrazine hydrochloride (628 mg, 4.9 mmol) in sequence at room temperature. The reaction was stirred at 70°C for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The mixture was concentrated under reduced pressure to remove ethanol, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (1.0 g, yield 77%).

[0428] LC-MS (ESI), m / z: [M+1] + =362.

[0429] Step B: 5-amino-3-(4-amino-2,5-difluorophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile

[0430] To a solution of 5-amino-3-(2,5-difluoro-4-nitrophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbonitrile (1 g, 2.8 mmol) in ethanol and water (10 / 1, 11 mL) was added ammonium chloride (1.5 g, 27.7 mmol) and iron powder (773 mg, 13.9 mmol) at room temperature. The mixture was heated to 80°C and stirred for 1.5 hours. TLC and LCMS analysis revealed the disappearance of the starting material and the formation of the product. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product (980 mg), which was used directly in the next step without purification.

[0431] LC-MS (ESI), m / z: [M+1] + =332.

[0432] Step C: 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)-2,5-difluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0433] To a solution of 5-amino-3-(4-amino-2,5-difluorophenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carbonitrile (200 mg, 0.6 mmol) in 1,4-dioxane (10 mL) were added N,N-diisopropylethylamine (234 mg, 1.8 mmol) and 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate (292 mg, 0.7 mmol) at room temperature; the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC and LCMS, indicating the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (103 mg, yield 27%).

[0434] LC-MS (ESI), m / z: [M+1] + =631.

[0435] Step D: 5-amino-3-(2,5-difluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide

[0436] To a solution of 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2,5-difluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (103 mg, 0.2 mmol) in ethanol (10 mL) and water (2 mL) at room temperature under nitrogen was added platinum dimethylphosphonate (7 mg, 0.02 mmol). The mixture was heated to 80°C and stirred overnight. TLC and LCMS analysis revealed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by Prep-HPLC to afford the product (17 mg, 16% yield).

[0437] LC-MS (ESI), m / z: [M+1] + =649.

[0438] 1 H NMR (400MHz, DMSO-d6) δ9.47(s,1H),8.95(s,1H),8.13-8.09(m,1H),7.99(s,1H),7.66(d,J=8.8Hz,1H),7.55(d,J=8.8Hz,1H) ,7.32-7.27(m,1H),6.94-5.65(m,4H),5.35-5.28(m,1H),3.55(s,2H),2.51-2.49(m,8H),2.16(s,3H),1.61(d,J=7.2Hz,3H).

[0439] Referring to the above examples and the synthesis methods of the intermediates, the examples in the table below were synthesized as follows:

[0440] Example 142: 2-(3-Fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

[0441] Step A: 5-amino-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile

[0442] To a solution of 2-((3-fluoro-4-nitrophenyl)(methoxy)methylene)malononitrile (4.1 g, 16.6 mmol) in anhydrous ethanol (50 mL) was added hydrazine hydrate (1.5 g, 24.9 mmol, 80%) at room temperature and stirred at room temperature for 1 hour. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 97 / 3) to give the product (3.6 g, yield 88%).

[0443] LC-MS (ESI), m / z: [M+1] + =248.

[0444] Step B: 2-(3-Fluoro-4-nitrophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0445] To a solution of 5-amino-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile (3 g, 12.1 mmol) in N,N-dimethylacetamide (30 mL) were added 1,3-dibromopropane (24.4 g, 120.9 mmol) and triethylamine (3.7 g, 36.3 mmol) at room temperature; the reaction temperature was raised to 120°C and stirred for 1 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; water was added to quench and dilute the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 99 / 1) to give the product (0.7 g, yield 20%).

[0446] LC-MS (ESI), m / z: [M+1] + =288.

[0447] Step C: 2-(4-amino-3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0448] To a solution of 2-(3-fluoro-4-nitrophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (700 mg, 2.4 mmol) in anhydrous methanol (10 mL) were added zinc powder (797 mg, 12.2 mmol) and saturated ammonium chloride solution (5 mL) at room temperature; the reaction temperature was raised to 60°C and stirred for 16 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; saturated aqueous sodium bicarbonate solution was added to adjust to weak alkalinity, filtered, and the filtrate was concentrated under reduced pressure to remove methanol. The product was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 95 / 5) to give the product (350 mg, yield 57%).

[0449] LC-MS (ESI), m / z: [M+1] + =258.

[0450] Step D: 1-(4-(3-cyano-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0451] To a solution of 2-(4-amino-3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (150 mg, 0.6 mmol) in tetrahydrofuran (10 mL) were added triethylamine (172 mg, 1.7 mmol) and 1-(4-isocyanate-2-(trifluoromethyl)benzyl)-4-methylpiperazine (360 mg, 1.2 mmol) at room temperature; the reaction temperature was raised to 70°C and stirred for 2 h; the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material; the reaction solution was quenched and diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 50) to give the product (120 mg, yield 36%).

[0452] LC-MS (ESI), m / z: [M+1] + =557.

[0453] Step E: 2-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

[0454] To a mixed solution of 1-(4-(3-cyano-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (120 mg, 0.2 mmol) in anhydrous ethanol (4 mL) and water (2 mL) was added (dimethylphosphonic acid) platinum(II) hydrogen complex (9 mg, 0.02 mmol) at room temperature; the reaction temperature was raised to 80°C and stirred for 16 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; water was added to quench and dilute the reaction, and the reaction was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Prep-HPLC column chromatography (column model: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% TFA), gradient: 30%-50%, flow rate: 20 mL / min) to obtain the product (22 mg, yield 20%).

[0455] LC-MS (ESI), m / z: [M+1] + =575.

[0456] 1 H NMR (400MHz, CD3OD) δ8.26(t,J=8.3Hz,1H),7.91(s,1H),7.71(s,2H),7.37(d,J=4.8Hz,1H),7.35(s,1H),4.09(t,J=6.1Hz,2H),3.76(s ,2H),3.44(t,J=6.1Hz,2H),3.40-3.37(m,2H),3.27-3.20(m,2H),3.04-3.00(m,2H),2.93(s,3H),2.50-2.43(m,2H),2.23-2.16(m,2H).

[0457] Example 143: 2'-(3-Fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0458] Step A: Ethyl 2-cyclopropylmethyleneacetate

[0459] To a solution of (1-ethoxycyclopropyloxy)trimethylsilane (5.0 g, 28.7 mmol) in toluene (15 mL) were added ethyl (triphenylphosphinothiomethylene)acetate (13.0 g, 37.3 mmol) and benzoic acid (460 mg, 3.8 mmol) at room temperature; the reaction temperature was raised to 90°C and stirred for 20 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1) to give the product (750 mg, yield 21%).

[0460] 1 H NMR (400MHz, DMSO-d6) δ6.22(dd,J=3.7,1.9Hz,1H),4.12(q,J=7.1Hz,2H),1.43-1.38(m,2H),1.31-1.25(m,2H),1.22(t,J=7.1Hz,3H).

[0461] Step B: 2'-(3-Fluoro-4-nitrophenyl)-5'-oxo-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carbonitrile

[0462] To a solution of 5-amino-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile (1.5 g, 6.1 mmol) in N-methylpyrrolidone (10 mL) were added ethyl 2-cyclopropylmethyleneacetate (0.9 g, 7.1 mmol) and potassium carbonate (2.5 g, 18.1 mmol) at room temperature; the reaction temperature was raised to 80°C and stirred for 16 h; the reaction was monitored by TLC and LC-MS, quenched with water and diluted, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 4) to give the product (800 mg, 40% yield).

[0463] LC-MS (ESI), m / z: [M+1] + =328.

[0464] Step C: 2'-(3-Fluoro-4-nitrophenyl)-5'-oxo-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0465] To a mixed solution of 2'-(3-fluoro-4-nitrophenyl)-5'-oxo-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carbonitrile (800 mg, 2.4 mmol) in ethanol (4 mL) and water (2 mL) was added (dimethylphosphonic acid) platinum(II) hydrogen complex (80 mg, 0.2 mmol) at room temperature; the reaction temperature was raised to 80°C and stirred for 16 h; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; water was added to quench and dilute the reaction, and the reaction was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to give the product (500 mg, yield 60%).

[0466] LC-MS (ESI), m / z: [M+1] + =346.

[0467] Step D: 2'-(3-Fluoro-4-nitrophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0468] To a solution of 2'-(3-fluoro-4-nitrophenyl)-5'-oxo-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (480 mg, 1.4 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise borane-tetrahydrofuran solution (7.0 mL, 7.0 mmol) at 0°C; the reaction temperature was raised to room temperature and stirred for 1 hour; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; methanol was added to quench the reaction, the mixture was diluted with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to give the product (280 mg, yield 60%).

[0469] LC-MS (ESI), m / z: [M+1] + =332.

[0470] Step E: 2'-(4-amino-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0471] To a solution of 2'-(3-fluoro-4-nitrophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (260 mg, 0.8 mmol) in methanol (5 mL) were added zinc powder (257 mg, 4.0 mmol) and saturated aqueous ammonium chloride (3 mL) at room temperature; the reaction temperature was raised to 60°C and stirred for 16 hours; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; saturated aqueous sodium bicarbonate was added to adjust the solution to weak alkalinity, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove methanol; the mixture was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 97 / 3) to give the product (100 mg, yield 43%).

[0472] LC-MS (ESI), m / z: [M+1] + =302.

[0473] Step F: 2'-(3-Fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-5',6'-2H-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0474] To a solution of 2'-(4-amino-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (90 mg, 0.3 mmol) in tetrahydrofuran (5 mL) were added triethylamine (91 mg, 0.9 mmol) and 1-(4-isocyanate-2-(trifluoromethyl)benzyl)-4-methylpiperazine (150 mg, 0.5 mmol) at room temperature; the reaction temperature was raised to 50°C and stirred for 3 hours; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; water was added to quench and dilute the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Prep-HPLC column chromatography (column model: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% The product (3 mg, yield 2%) was purified by addition of TFA (gradient: 30%-50%, flow rate: 20 mL / min).

[0475] LC-MS (ESI), m / z: [M+1] + =601.

[0476] 1H NMR (400MHz, CD3OD) δ8.52(brs,2H),8.25(t,J=8.3Hz,1H),7.91(s,1H),7.69(q,J=8.5Hz,2H),7.33(d,J=10.0Hz,2H),3.71(s,2H),3 .55-3.49(m,2H),3.10-3.04(m,4H),2.71(s,3H),2.70-2.60(m,4H),2.16-2.13(m,2H),1.52(t,J=6.0Hz,2H),0.89(t,J=6.1Hz,2H).

[0477] Referring to the above examples and the synthesis methods of the intermediates, the examples in the table below were synthesized as follows:

[0478] Examples 188 and 189: (R)-5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and (S)-5-amino-3-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide

[0479] 1 gram of the sample of Example 8 was subjected to SFC separation to obtain Example 188 (150 mg) and Example 189 (150 mg), both of which were white solids.

[0480] LC-MS (ESI), m / z: [M+1] + =631.

[0481] 1 H NMR (400 MHz, DMSO-d6, Example 188) δ 9.42 (s, 1H), 8.75 (d, J = 2.8 Hz, 1H), 8.23 ​​(t, J = 8.5 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.42-7.26 (m, 2H), 6.62 (s, 2H), 5.35-5.28 (m, 1H), 3.54 (s, 2H), 2.48-2.23 (m, 8H), 2.17 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H).

[0482] 19 F NMR (376 MHz, DMSO-d6, Example 188) δ -58.03, -73.56, -129.64.

[0483] 1 H NMR (400 MHz, DMSO-d6, Example 189) δ 9.41 (s, 1H), 8.75 (d, J = 2.8 Hz, 1H), 8.23 ​​(t, J = 8.5 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.40-7.26 (m, 2H), 6.62 (s, 2H), 5.35-5.26 (m, 1H), 3.54 (s, 2H), 2.44-2.33 (m, 8H), 2.17 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H).

[0484] 19 F NMR (376 MHz, DMSO-d6, Example 189) δ -58.04, -73.56, -129.66.

[0485] Examples 190 and 191: (R)-5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperazin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and (S)-5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperazin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide

[0486] Step A: 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0487] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carbonitrile (500 mg, 1.6 mmol) in 1,4-dioxane (10 mL) was added N,N-diisopropylethylamine (206 mg, 1.6 mmol) and 4-nitrophenyl (4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)carbamate (912 mg, 2.1 mmol) at room temperature under nitrogen protection. The reaction was stirred at room temperature overnight. TLC and LCMS analysis showed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product (500 mg, yield 51%).

[0488] LC-MS (ESI), m / z: [M+1] + =614.

[0489] Step B: (R)-5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperazin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and (S)-5-amino-3-(3-fluoro-4-(3-(4-((1-methylpiperazin-4-yl)oxy)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide

[0490] Under nitrogen, 1-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (440 mg, 0.7 mmol) and potassium carbonate (484 mg, 3.5 mmol) were dissolved in dimethyl sulfoxide (10 mL). Hydrogen peroxide solution (793 mg, 7.0 mmol, 30 wt%) was slowly added dropwise at 60°C, and the reaction was continued for 3 hours. The mixture was diluted with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by Pre-HPLC to obtain the product (146 mg, 32% yield). Chiral SFC separation gave Example 190 (50 mg) and Example 191 (50 mg), both as white solids.

[0491] LC-MS (ESI), m / z: [M+1] + =632.

[0492] 1H NMR (400 MHz, DMSO-d6, Example 190) δ 9.19 (s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 8.22 (t, J = 8.5 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.52 (dd, J = 9.0, 2.7 Hz, 1H), 7.42-7.22 (m, 3H), 6.62 (s, 2H), 5.32-5.28 (m, 1H), 4.55-4.52 (m, 1H), 2.61-2.50 (m, 2H), 2.29-2.19 (m, 2H), 2.17 (s, 3H), 1.94-1.87 (m, 2H), 1.72-1.67 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H).

[0493] 19 F NMR (376 MHz, DMSO-d6, Example 190) δ -60.60, -73.56, -129.78.

[0494] 1 H NMR (400 MHz, DMSO-d6, Example 191) δ 9.26 (s, 1H), 8.73 (d, J = 2.7 Hz, 1H), 8.20 (t, J = 4.3 Hz, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.53 (dd, J = 9.0, 2.7 Hz, 1H), 7.41-7.22 (m, 3H), 6.62 (s, 2H), 5.33-5.26 (m, 1H), 4.58-4.53 (m, 1H), 2.65-2.54 (m, 2H), 2.37-2.26 (m, 2H), 2.22 (s, 3H), 1.96-1.89 (m, 2H), 1.74-1.66 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H).

[0495] 19 F NMR (376 MHz, DMSO-d6, Example 191) δ -60.59, -73.56, -129.64.

[0496] Example 192: 5-amino-3-(4-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)-1-cyclopropyl-1H-pyrazine-4-carboxamide

[0497] Step A: 5-amino-1-cyclopropyl-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile

[0498] To a solution of 2-((3-fluoro-4-nitrophenyl)(methoxy)methylene)malononitrile (3.0 g, 12.1 mmol) in anhydrous ethanol (30 mL) were added cyclopropylhydrazine hydrochloride (1.6 g, 14.6 mmol) and triethylamine (3.7 g, 36.3 mmol) in sequence at room temperature. The temperature was raised to 50°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 80 / 1) to give a light yellow solid (1.0 g, yield 29%).

[0499] LC-MS (ESI), m / z: [M+1] + =288.

[0500] Step B: 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile

[0501] To a mixed solution of 5-amino-1-cyclopropyl-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile (1.8 g, 6.3 mmol) in methanol (60 mL) and water (10 mL) at 0°C were added zinc powder (2.0 g, 31.5 mmol) and ammonium chloride (3.4 g, 63 mmol) in sequence. The temperature was raised to 60°C and stirred for 3 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The product was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a light yellow solid (900 mg, yield 56%).

[0502] LC-MS (ESI), m / z: [M+1] + =258.

[0503] Step C: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazin-5-yl)urea

[0504] At 0°C, under nitrogen protection, to a solution of 3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-amine (373 mg, 1.6 mmol) in anhydrous tetrahydrofuran (15 mL) were added p-nitrophenyl chloroformate (464 mg, 2.3 mmol) and pyridine (253 mg, 3.2 mmol), and the mixture was warmed to room temperature and stirred for 1 hour. The reaction system was then added dropwise to another flask containing 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (412 mg, 1.6 mmol), N, A solution of N-diisopropylethylamine (620 mg, 4.8 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask and heated to 60° C. under a nitrogen atmosphere with stirring for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. Water was added to the mixture to quench and dilute it, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a white solid (450 mg, yield 54%).

[0505] LC-MS (ESI), m / z: [M+1] + =517.

[0506] Step D: 5-amino-3-(4-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)-1-cyclopropyl-1H-pyrazine-4-carboxamide

[0507] To a solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazin-5-yl)urea (450 mg, 0.9 mmol) in dimethyl sulfoxide (10 mL) was slowly added hydrogen peroxide (1.5 g, 44 mmol) and potassium carbonate (249 mg, 1.8 mmol) in sequence at room temperature under nitrogen protection. The temperature was raised to 60°C and stirred for 1 hour. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium chloride solution, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (170 mg, 37% yield).

[0508] LC-MS (ESI), m / z: [M+1] + =535.

[0509] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.89(s,1H),8.17(t,J=8.0Hz,1H),7.60-7.55(m,2H),7.42-7.36( m,2H),7.32-7.24(m,2H),6.41(s,1H),6.26(s,2H),3.31-3.26(m,1H),1.28(s,9H),0.99-0.97(m,4H).

[0510] 19 F NMR(376MHz,DMSO-d6)δ-114.53,-129.47.

[0511] Example 193: 5-amino-3-(4-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)-1-cyclopropyl-1H-pyrazine-4-carboxamide

[0512] Step A: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazin-5-yl)urea

[0513] At 0°C, under nitrogen protection, to a solution of 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine (670 mg, 3.1 mmol) in anhydrous tetrahydrofuran (15 mL) were added p-nitrophenyl chloroformate (990 mg, 4.6 mmol) and pyridine (490 mg, 6.2 mmol), and the mixture was warmed to room temperature and stirred for 1 hour. The reaction system was then added dropwise to another flask containing 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (800 mg, 3.1 mmol), N,N- A solution of diisopropylethylamine (1.2 g, 9.3 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask and heated to 60° C. under a nitrogen atmosphere with stirring for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. Water was added to the mixture to quench and dilute it, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a white solid (1.1 g, yield 71%).

[0514] LC-MS (ESI), m / z: [M+1] + =499.

[0515] Step B: 5-amino-3-(4-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)-1-cyclopropyl-1H-pyrazine-4-carboxamide

[0516] To a solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazin-5-yl)urea (1.1 g, 2.2 mmol) in dimethyl sulfoxide (10 mL) was slowly added hydrogen peroxide (12.0 g, 40.0 mmol) and potassium carbonate (608 mg, 4.4 mmol) in sequence at room temperature under nitrogen protection. The temperature was raised to 60°C and stirred for 1 hour. T The reaction was monitored by LC and LC-MS, and the starting material disappeared. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium chloride solution, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give a white solid (374 mg, 33% yield).

[0517] LC-MS (ESI), m / z: [M+1] + =517.

[0518] 1 H NMR(400MHz, DMSO-d6)δ9.05(s,1H),8.90(s,1H),8.18(t,J=8.5Hz,1H),7.59-7.51(m,4H),7.44(ddt,J=8.6,6 .0,1.9Hz,1H),7.34-7.24(m,2H),6.42(s,1H),6.27(s,2H),3.31-3.26(m,1H),1.29(s,9H),1.03-0.92(m,4H).

[0519] 19 F NMR(376MHz,DMSO-d6)δ-129.49.

[0520] Example 194: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0521] Step A: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0522] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (180 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) were slowly added phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (219 mg, 0.7 mmol), 4-dimethylaminopyridine (13 mg, 0.1 mmol) and N,N-diisopropylethylamine (271 mg, 2.1 mmol) at room temperature. The mixture was refluxed and stirred at 60°C for 1 hour. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a light yellow solid (200 mg, yield 60%).

[0523] LC-MS (ESI), m / z: [M+1] + =476.

[0524] Step B: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0525] To a solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (190 mg, 0.4 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (110 mg, 0.8 mmol) at 0°C under nitrogen protection. Hydrogen peroxide (2 g, 16 mmol) was then slowly added dropwise to the reaction system. The mixture was allowed to warm to room temperature and the mixture was allowed to stand for 2 h. The reaction was stirred for 16 hours, and the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The product was diluted with saturated sodium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give a white solid (63 mg, 32% yield).

[0526] LC-MS (ESI), m / z: [M+1] + =494.

[0527] 1 H NMR (400MHz, DMSO-d6) δ8.52 (s, 1H), 8.19 (t, J = 8.5Hz, 1H), 7.35-7.21 (m, 2H) ,6.27(s,2H),6.12(s,1H),2.52(s,1H),1.45-1.31(m,4H),0.99-0.96(m,4H).

[0528] 19 F NMR(376MHz,DMSO-d6)δ-69.43,-129.72.

[0529] Example 195: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0530] Step A: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0531] To a solution of 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (180 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) were slowly added phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (219 mg, 0.7 mmol), 4-dimethylaminopyridine (13 mg, 0.1 mmol) and N,N-diisopropylethylamine (271 mg, 2.1 mmol) at room temperature. The mixture was refluxed and stirred at 60°C for 1 hour. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a light yellow solid (150 mg, yield 45%).

[0532] LC-MS (ESI), m / z: [M+1] + =476.

[0533] Step B: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0534] To a solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea (143 mg, 0.3 mmol) in dimethyl sulfoxide (10 mL) at 0°C under nitrogen was added potassium carbonate (83 mg, 0.6 mmol). Hydrogen peroxide (2 g, 16 mmol) was slowly added dropwise to the reaction system, and the mixture was warmed to room temperature and stirred for 16 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The mixture was diluted with saturated sodium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (7 mg, 5% yield).

[0535] LC-MS (ESI), m / z: [M+1] + =494.

[0536] 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H),8.89(d,J=2.6Hz,1H),8.16(t,J=8.4Hz,1H),7.41-7.25 (m,2H),6.90(s,1H),6.27(s,2H),3.28(d,J=5.2Hz,1H),1.62-1.43(m,4H),0.99-0.96(m,4H).

[0537] 19 F NMR(376MHz,DMSO-d6)δ-67.62,-129.47.

[0538] Example 196: 2'-(4-(3-(tert-Butyl)-1-phenyl-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0539] To a solution of 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine (179 mg, 0.8 mmol) in anhydrous tetrahydrofuran (10 mL) was added p-nitrophenyl chloroformate (200 mg, 1 mmol) and pyridine (100 mg, 1.2 mmol) at 0°C under nitrogen protection. The mixture was warmed to room temperature and stirred for 1 hour. The reaction system was then added dropwise to another 4-well plate containing 2'-(4-amino-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (250 mg, 0.8 mmol), N,N-diisopropyl A solution of ethylamine (321 mg, 2.5 mmol) in tetrahydrofuran (10 mL) was placed in a round-bottom flask and heated to 60°C under a nitrogen atmosphere with stirring for 2 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared. Water was added to the mixture to quench and dilute it, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (190 mg, yield 42%).

[0540] LC-MS (ESI), m / z: [M+1] + =543.

[0541] 1 H NMR (400MHz, DMSO-d6) δ9.05(d,J=2.6Hz,1H),8.90(s,1H),8.17(t,J=8.4Hz,1H),7.61-7.49(m,4H),7.44(tt,J=6.1,1.9Hz,1H),7.35-7. 22(m,2H),6.64(d,J=2.4Hz,1H),6.42(s,1H),3.42-3.39(m,2H),2.04(t,J=5.6Hz,2H),1.40-1.35(m,2H),1.29(s,9H),0.87-0.80(m,2H).

[0542] 19 F NMR(376MHz,DMSO-d6)δ-129.48.

[0543] Example 197: 2'-(4-(3-(tert-Butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0544] Step A: 3-(tert-Butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-amine

[0545] To a solution of 4,4-dimethyl-3-oxopentanonitrile (1.0 g, 8.0 mmol) and 4-fluorophenyl)hydrazine hydrochloride (1.3 g, 8.0 mmol) in ethanol (15 mL) was added concentrated hydrochloric acid (6.6 mL, 79.2 mmol, 12 N) at room temperature. The temperature was raised to 85°C and stirred overnight. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was cooled to room temperature, diluted with water, and adjusted to a weak alkaline state with saturated aqueous sodium bicarbonate solution. The solution was extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale yellow solid crude product (1.5 g), which was used directly in the next step without purification.

[0546] LC-MS (ESI), m / z: [M+1]+=234.

[0547] Step B: 2'-(4-(3-(tert-Butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0548] To a solution of 3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-amine (200 mg, 0.9 mmol) in anhydrous tetrahydrofuran (10 mL) was added p-nitrophenyl chloroformate (259 mg, 1.3 mmol) and pyridine (203 mg, 2.6 mmol) at 0°C under nitrogen protection. The mixture was warmed to room temperature and stirred for 1 hour. The reaction system was then added dropwise to another flask containing 2'-(4-amino-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (258 mg, 0.9 mmol), N,N -Diisopropylethylamine (443 mg, 3.4 mmol) in tetrahydrofuran (10 mL) was placed in a round-bottom flask and heated to 60 ° C. under a nitrogen atmosphere with stirring for 2 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared; water was added to the mixture to quench and dilute it, and it was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (210 mg, yield 44%).

[0549] LC-MS (ESI), m / z: [M+1]+ =561.

[0550] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.86(s,1H),8.16(t,J=8.5Hz,1H),7.59-7.55(m,2H),7.39(t,J=8.8Hz,2H),7.33-7.25(m ,2H),6.65(s,1H),6.41(s,1H),3.42-3.39(m,2H),2.04(t,J=5.6Hz,2H),1.37(q,J=4.7Hz,2H),1.28(s,9H),0.86-0.82(m,2H).

[0551] 19 F NMR(376MHz,DMSO-d6)δ-114.49,-129.48.

[0552] Example 198: 2'-(3-Fluoro-4-(3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)ureido)phenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0553] To a solution of 2'-(4-amino-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (200 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added phenyl(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (249 mg, 0.8 mmol) and N,N-diisopropylethylamine (361 mg, 2.8 mmol) at room temperature. mol), refluxed and stirred at 60°C for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (150 mg, yield 27%).

[0554] LC-MS (ESI), m / z: [M+1] + =520.

[0555] 1H NMR (400MHz, DMSO-d6) δ10.01(s,1H),8.89(s,1H),8.15(t,J=8.5Hz,1H),7.38-7.28(m,2H),6.90(s,1H),6.65(s,1H ),3.41-3.38(m,2H),2.06-2.00(m,2H),1.57-1.54(m,2H),1.51-1.48(m,2H),1.39-1.36(m,2H),0.86-0.83(m,2H).

[0556] 19 F NMR(376MHz,DMSO-d6)δ-67.62,-129.51.

[0557] Example 199: 2'-(3-Fluoro-4-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)ureido)phenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0558] To a solution of 2'-(4-amino-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (200 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added phenyl(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (249 mg, 0.8 mmol) and N,N-diisopropylethylamine (361 mg, 2.8 mmol) at room temperature. mol), refluxed and stirred at 60°C for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (133 mg, yield 25%).

[0559] LC-MS (ESI), m / z: [M+1] + =520.

[0560] 1H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.86(s,1H),8.12(t,J=8.4Hz,1H),7.39-7.30(m,2H),6.65(s,1H),6 .19(s,1H),3.42-3.39(m,2H),2.06-1.98(m,2H),1.48-1.43(m,2H),1.41-1.36(m,4H),0.86-0.83(m,2H).

[0561] 19 F NMR(376MHz,DMSO-d6)δ-67.43,-129.14.

[0562] Example 200: 2'-(3-Fluoro-4-(3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0563] Step A: 3-Oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile

[0564] To a solution of ethyl 1-(trifluoromethyl)cyclopropane-1-carboxylate (2.0 g, 11.0 mmol) in anhydrous tetrahydrofuran were added sodium hydride (926 mg, 22.0 mmol, 57%) and acetonitrile (681 mg, 16.6 mmol) at 0°C. The mixture was heated to 70°C under a nitrogen atmosphere and stirred for 2 hours. The reaction was monitored by TLC and LCMS. The starting material disappeared. The mixture was quenched with water and diluted, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product (1.6 g), which was used directly in the next step without further purification.

[0565] LC-MS (ESI), m / z: [M+1] + =178.

[0566] Step B: 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine

[0567] To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile (1.1 g, 6.0 mmol) in anhydrous ethanol (16 mL) were added phenylhydrazine (650 mg, 6.0 mmol) and concentrated hydrochloric acid (5.0 mL, 60.0 mmol) at room temperature. The temperature was raised to 85°C under a nitrogen atmosphere and stirred for 12 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared. Water was added to the mixture, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The inorganic salts were filtered off and concentrated to give a crude product. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 1 to 5 / 1) to give a yellow solid (1.4 g, yield 87%).

[0568] LC-MS (ESI), m / z: [M+1] + =268.

[0569] Step C: 2'-(3-Fluoro-4-(3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0570] At 0°C, under nitrogen protection, to a solution of 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (200 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) were added p-nitrophenyl chloroformate (226 mg, 1.1 mmol) and pyridine (178 mg, 2.2 mmol), the mixture was warmed to room temperature and stirred for 1 hour, and the above reaction system was added dropwise to another 4-amino-3-fluorophenyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (203 mg, 0.6 mmol), N, A solution of N-diisopropylethylamine (387 mg, 3.0 mmol) in tetrahydrofuran (10 mL) was placed in a round-bottom flask and heated to 60° C. under a nitrogen atmosphere with stirring for 2 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared. Water was added to the mixture to quench and dilute it, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (190 mg, yield 43%).

[0571] LC-MS (ESI), m / z: [M+1] + =595.

[0572] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),9.03(s,1H),8.17(t,J=8.5Hz,1H),7.61-7.47(m,5H),7.34-7.25(m,2H),6.65(s ,1H),6.62(s,1H),3.42-3.39(m,2H),2.04(t,J=5.6Hz,2H),1.38-1.34(m,4H),1.32-1.29(m,2H),0.86-0.82(m,2H).

[0573] 19 F NMR(376MHz,DMSO-d6)δ-67.48,-129.40.

[0574] Example 201: 2'-(3-Fluoro-4-(3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0575] Step A: 1-(4-Fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine

[0576] To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile (1.3 g, 7.3 mmol) in anhydrous ethanol (16 mL) were added p-fluorophenylhydrazine (921 mg, 7.3 mmol) and concentrated hydrochloric acid (4.0 mL, 48.0 mmol) at room temperature. The temperature was raised to 88°C under a nitrogen atmosphere and stirred for 12 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared. Water was added to the mixture, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The inorganic salts were filtered off and concentrated to obtain a crude product. The residue was separated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 1 to 5 / 1) to obtain a light yellow solid (1.4 g, yield 67%).

[0577] LC-MS (ESI), m / z: [M+1] + =286.

[0578] Step B: 2'-(3-fluoro-4-(3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide

[0579] To a solution of 1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (200 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) was added p-nitrophenyl chloroformate (212 mg, 1.1 mmol) and pyridine (166 mg, 2.1 mmol) at 0°C under nitrogen. The mixture was warmed to room temperature and stirred for 1 hour. The reaction system was then added dropwise to another flask containing 2'-(4-amino-3-fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrimidine]-3'-carboxamide (190 mg, 0.6 mmol). , a solution of N,N-diisopropylethylamine (362 mg, 2.8 mmol) in tetrahydrofuran (10 mL) was placed in a round-bottom flask, heated to 60°C under a nitrogen atmosphere, and stirred for 2 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared; water was added to the mixture to quench and dilute it, and it was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (200 mg, yield 47%).

[0580] LC-MS (ESI), m / z: [M+1] + =613.

[0581] 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 9.00 (s, 1H), 8.16 (t, J = 8.5Hz, 1H), 7.61-7.58 (m, 2H), 7.49-7.40 (m, 2H), 7.34-7.25 (m, 2H) ),6.65(s,1H),6.60(s,1H),3.41-3.39(m,2H),2.04(t,J=5.6Hz,2H),1.38-1.34(m,4H),1.31-1.28(m,2H),0.85-0.82(m,2H).

[0582] 19 F NMR(376MHz,DMSO-d6)δ-67.48,-113.41,-129.36.

[0583] Example 202: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0584] Step A: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0585] At 0°C, under nitrogen protection, to a solution of 1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (200 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) were added p-nitrophenyl chloroformate (211 mg, 1.0 mmol) and pyridine (83 mg, 1.0 mmol), and the mixture was warmed to room temperature and stirred for 1 hour. The above reaction system was added dropwise to another 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (180 mg, 0.7 mmol). A solution of N,N-diisopropylethylamine (271 mg, 2.0 mmol) in tetrahydrofuran (10 mL) was placed in a round-bottom flask and heated to 60°C under a nitrogen atmosphere with stirring for 2 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared. Water was added to the mixture to quench and dilute it, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness. The residue was separated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a light yellow solid (320 mg, yield 76%).

[0586] LC-MS (ESI), m / z: [M+1] + =569.

[0587] Step B: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0588] To a solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (320 mg, 0.6 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (156 mg, 1.1 mmol) at 0°C under nitrogen protection, and then hydrogen peroxide (3.3 g, 22 mmol) was slowly added dropwise to the reaction system. ), raised to 50 ° C and stirred for 1 hour, the reaction was monitored by TLC and LC-MS, and the starting material disappeared; saturated sodium chloride solution was added for dilution, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (160 mg, yield 48%).

[0589] LC-MS (ESI), m / z: [M+1] + =587.

[0590] 1 H NMR(400MHz, DMSO-d6)δ9.08(s,1H),9.01(s,1H),8.17(t,J=8.0Hz,1H),7.61-7.58(m,2H),7.44-7.40(m,2H),7.33 -7.25(m,2H),6.60(s,1H),6.27(s,2H),3.32-3.26(m,1H),1.37-1.34(m,2H),1.31-1.28(m,2H),0.98-0.96(m,4H).

[0591] 19 F NMR(376MHz,DMSO-d6)δ-67.48,-113.39,-129.35.

[0592] Example 203: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0593] Step A: 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0594] To a solution of 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (188 mg, 0.7 mmol) in anhydrous tetrahydrofuran (10 mL) at 0°C under nitrogen, p-nitrophenyl chloroformate (211 mg, 1.0 mmol) and pyridine (83 mg, 1.0 mmol) were added. The mixture was warmed to room temperature and stirred for 1 hour. The reaction system was then added dropwise to another flask containing 5-amino-3-(4-amino-3-fluorophenyl)-1-cyclopropyl-1H-pyrazole-4-carbonitrile (180 mg, 0.7 mmol), N,N -Diisopropylethylamine (271 mg, 2.0 mmol) in tetrahydrofuran (10 mL) was placed in a round-bottom flask and heated to 60 ° C. under a nitrogen atmosphere with stirring for 2 hours. The reaction was monitored by TLC and LCMS, and the starting material disappeared; water was added to the mixture to quench and dilute it, and it was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a light yellow solid (340 mg, yield 84%).

[0595] LC-MS (ESI), m / z: [M+1] + =551.

[0596] Step B: 5-amino-1-cyclopropyl-3-(3-fluoro-4-(3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-pyrazole-4-carboxamide

[0597] To a solution of 1-(4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-2-fluorophenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (340 mg, 0.6 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (170 mg, 1.2 mmol) at 0°C under nitrogen protection. Hydrogen peroxide (3.4 g, 22 mmol) was then slowly added dropwise to the reaction system. The mixture was heated to 40°C. The mixture was heated to 50° C. and stirred for 1 hour. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Saturated sodium chloride solution was added for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (160 mg, 48% yield).

[0598] LC-MS (ESI), m / z: [M+1] + =587.

[0599] 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),9.05(s,1H),8.18(t,J=8.0Hz,1H),7.61-7.47(m,5H),7.33-7.25(m, 2H),6.62(s,1H),6.27(s,2H),3.30-3.26(m,1H),1.37-1.34(m,2H),1.32-1.29(m,2H),0.99-0.97(m,4H).

[0600] 19 F NMR(376MHz,DMSO-d6)δ-67.48,-129.37.

[0601] Effect evaluation

[0602] The NEK7 enzyme inhibitory activity (IC 50 ) detection

[0603] The compound was diluted with DMSO (manufacturer: Sigma, catalog number: D4540). SYSTEM) Transfer 40 nL of compound to a 384-well plate (Manufacturer: Greiner, Catalog No. 784075). Prepare a 2x kinase solution using 1x kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 2 mM DTT). Transfer 2 μL of NEK7 (working concentration: 10 nM, Manufacturer: Carna, Catalog No. 05-131) solution to the 384-well plate. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 10 minutes. Prepare a 2x mixture of Casein substrate (working concentration: 0.1 mg / mL) and ATP (working concentration: 15 μM, Manufacturer: Promega, Catalog No. V915B) in kinase reaction buffer. Add 2 μL of the substrate and ATP mixture to the plate to initiate the reaction. Centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 60 minutes, add 4 μL of ADP-Glo ​​Reagent (manufacturer: Promega, catalog number: V9103) incubated at 25°C to each well of the 384 reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 40 minutes. Add 8 μL of Detection Reagent (manufacturer: Promega, catalog number: V9103) incubated at 25°C to each well of the 384 reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 40 minutes. Use a multifunctional microplate reader (manufacturer: BMG, model: PHERAstar FSX) to read the chemiluminescence signal. Each reaction was tested in duplicate, and IC was analyzed using GraphPad Prism 8.0 software. 50 .

[0604] Experimental manipulation of IL-1β secretion by THP-1 cells

[0605] THP-1 cells were cultured in 1640 medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO2. At the start of the experiment, the cell suspension was gently shaken and transferred to a centrifuge tube for counting. The required volume was removed and added to fresh culture medium. 40 μL of polylysine diluted in sterile water was added to a 96-well plate and incubated at 37°C and 5% CO2 for 30 minutes. The plate was then washed twice with 100 μL of the solution. 50,000 cells were seeded per well of the THP-1 cell suspension (100 μL) at 50 ng / mL PMA (phorbol 12-myristate 13-acetate) in the 96-well plate prepared in step 1 and incubated at 37°C and 5% CO2 for 24 hours. The medium in the 96-well plate was removed and the cells were washed once with 37°C prewarmed PBS. 85 μL of serum-free medium containing 25 ng / mL LPS was added and the cells were incubated at 37°C and 5% CO2 for 3 hours. Add 5 μL of compounds of different concentrations (DMSO concentration is uniformly 1‰) and continue to incubate the cells at 37°C & 5% CO2 for 30 minutes. Add 5 μL of diluted Nigericin to make the working concentration of Nigericin 5 μg / mL and continue to incubate the cells at 37°C & 5% CO2 for 1 hour. Collect the cell supernatant, store it at -80°C, and use ELISA kit to detect the secretion of IL-1β. Calculate the IL-1β concentration based on the standard curve, calculate the inhibition rate, fit the compound action curve, and calculate the IC 50 .

[0606] Table 1: NEK7 kinase inhibitory activity and IL-1β release inhibitory activity of compounds Note: 1nM <A<10nM;10nM<B<100nM;100nM<C<1000nM;D> 1000nM;

[0607] The example compounds of the present invention have a strong inhibitory effect on NEK7 kinase activity and IL-1β secretion by THP-1 cells. The inhibition of NLRP3 signaling by NEK7 can prevent the formation of NLRP3 inflammasomes, thereby inhibiting the production of IL-1β and IL-18 and the cleavage of pore-forming gasdermin D.

[0608] Pharmacokinetic evaluation

[0609] Pharmacokinetic evaluation in mice

[0610] Male ICR mice were divided into groups of 3 per group and were orally administered with a single oral gavage of the example compound (10 mg / kg). The animals were fasted overnight before the experiment, and the fasting period was from 10 hours before administration to 4 hours after administration. Blood was collected from the oral group at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration. 0.05 mL of whole blood was collected after isoflurane anesthesia using a small animal anesthesia machine and placed in a heparin anticoagulant tube. The sample was centrifuged at 4°C and 4000 rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis. The sample in the plasma was extracted using protein precipitation, and the extract was analyzed by LC-MS / MS.

[0611] Table 2: Pharmacokinetic parameters of different compounds after oral administration to mice at 10 mg / kg

[0612] Conclusion: The example compounds of the present invention have good pharmacokinetic properties in mice.

[0613] Safety evaluation of hERG cardiotoxicity

[0614] The test substance and positive control concentrations were prepared by diluting the 10 mM solution of Example 1 sequentially with DMSO to 3.33 mM, 1 mM, 0.33 mM, 0.1 mM, 0.033 mM, and 0.01 mM. The test substance dilutions were then diluted sequentially with extracellular fluid to 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, and 0.03 μM, ensuring a DMSO concentration of 0.3%. All concentrations were ultrasonicated for 20 minutes. The 10 mM solution of Cisapride (positive control) was diluted sequentially with DMSO to 1 mM, 333.33 μM, 33.33 μM, 3.33 μM, 0.33 μM, and 0.033 μM dilutions. The five concentrations of Cisapride were diluted in sequence with extracellular fluid to prepare working solutions of 1000 nM, 100 nM, 10 nM, 1 nM and 0.1 nM, ensuring that the DMSO concentration was 0.3%.

[0615] Experimental equipment: HEKA EPC 10 patch clamp amplifier.

[0616] Experimental Methods: This experiment uses manual patch clamp technology to detect the blocking effect of compounds on the current of HEK-293 cell lines stably expressing hERG channels, and evaluates the risk of compound inhibition of cardiac hERG potassium channels by fitting the concentration-effect relationship.

[0617] Experimental Procedure: Patch clamping involves first pulling a recording electrode from a glass capillary using a microelectrode puller. The electrode, filled with intracellular fluid, is then inserted into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in extracellular fluid and record the electrode resistance (Rpip). The electrode is then gently brought into contact with the cell surface, and negative pressure is applied to form a GΩ seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied. Drug administration is initiated after the whole-cell hERG current has stabilized. Each drug concentration is tested after approximately 5 minutes of exposure (or until the current stabilizes). Multiple concentrations of each test compound are tested. A coverslip containing cells is placed in the recording bath under an inverted microscope. A blank control solution and the test compound working solution are gravity-flown through the recording bath, sequentially applying the solution from low to high concentrations. A peristaltic pump is used for fluid exchange during recording. The current measured in each cell in the presence of compound-free external solution served as its own control. Each concentration was tested in triplicate. All electrophysiological experiments were performed at room temperature.

[0618] Experimental data analysis method: First, normalize the current after each drug concentration and the blank control current Then calculate the inhibition rate corresponding to each drug concentration The mean (Mean), standard deviation (SD) and standard error (SE) of the inhibition rate at each concentration were calculated;

[0619] Among them, Peak tail current compound Peak tail current control Represents the peak-to-tail current of the blank control.

[0620] Table 3: Inhibitory effect of compounds on cardiac hERG potassium channels

[0621] Conclusion: Examples 192 and 201 of the present invention have weaker inhibitory effects on cardiac hERG potassium channels and are relatively safe.

[0622] The present application has been described above in conjunction with preferred embodiments, but these embodiments are merely exemplary and serve only as an illustrative example. On this basis, various replacements and improvements can be made to the present application, all of which fall within the scope of protection of the present application.

Claims

1. A compound represented by Formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotopically labeled compound, isomer or prodrug thereof, wherein, X is O or S; X1, X2, X3 and X4 are each independently C or N; wherein when X2 and X3 are N, X1 and X4 are C; when X1 and X3 are N, X2 and X4 are C; when X3 and X4 are N, X1 and X2 are C; the dashed ring indicates the presence of two conjugated double bonds in the 5-membered ring; Ring A is substituted with 0-4 R A C 6-10 Aryl, substituted with 0-4 R A C 3-10 Cycloalkyl, substituted with 0-4 R A 3-10 membered heterocyclic group or substituted with 0-4 R A A 5-6 membered heteroaryl group; R is one of the following structural formulas Or, R4 is the following group wherein, L is a direct key, O, CR 21 or CR 21 R 22 ; R L is for substituting C with 0 - 4 Rs C of 6-10 aryl, C substituted with 0 - 4 Rs C of 3-10 cycloalkyl, 3 - 10 membered heterocyclic group substituted with 0 - 4 Rs C or 5 - 6 membered heteroaryl substituted with 0 - 4 Rs C ; R 4 in represents a single bond or a double bond; when R 4 in When representing a double bond, L is CR 21 ; Z1 is CH or N; Z2 is O or S or N; Z3 is C or N or O or S; Z4 is C or O or N; R3 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R2 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R1 is selected from C aryl substituted with 0 - 4 Rs 0 ; C 6-10 cycloalkyl substituted with 0 - 4 Rs 0 ; C 3-10 3 - 10 membered heterocyclic group substituted with 0 - 4 Rs 0 ; 5 - 6 membered heteroaryl substituted with 0 - 4 Rs 0 ; C 0 alkyl substituted with 0 - 4 Rs 1-6 ; C 0 haloalkyl substituted with 0 - 4 Rs 1-6 ; C 0 alkoxy substituted with 0 - 4 Rs 1-6 ; C 0 ; C 2-6 alkenyl substituted with 0 - 4 Rs 0 ; C 2-6 alkynyl or NR 11 R 12 ; alternatively, R1, R2 and the atoms to which they are attached together form a 5- or 6-membered ring; R A Each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R B Each independently selected from hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C substituted with 0 - 4 R B1 s, C 6-10 aryl, C substituted with 0 - 4 R B1 s, C 3-10 cycloalkyl, C substituted with 0 - 4 R B1 s, a 3 - 10 membered heterocyclic group or a 5 - 6 membered heteroaryl substituted with 0 - 4 R B1 s; R B1 Each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R C Each independently selected from hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, -C(=O)R C1 , -(CH2) k S(=O)2R C1 , -NR C2 R C3 ; or, two R C together with the atoms to which they are attached form a 3- to 6-membered ring; R C1 Each independently selected from hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy; R C2 and R C3 each independently selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; R 51 and R 52 each independently is hydrogen, halogen, deuterium, tritium or C 1-6 alkyl, or R 51 , R 52 and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group; R 61 and R 62 each independently is hydrogen, halogen, deuterium, tritium or C 1-6 alkyl, or R 61 , R 62 and the carbon atom to which they are attached together form a C 3-6 cycloalkyl group; R7 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C substituted with 0 - 4 R 70 's 6-10 aryl, C substituted with 0 - 4 R 70 's 3-10 cycloalkyl, 3 - 10 - membered heterocyclic group substituted with 0 - 4 R 70 or 5 - 6 - membered heteroaryl substituted with 0 - 4 R 70 ; R 70 selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 8-membered heterocyclic group or NR 11 R 12 ; R 0 each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, carbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 3-10 cycloalkyl, 3- to 8-membered heterocyclic group or NR 11 R 12 ; R 11 and R 12 each independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R 21 and R 22 each independently selected from hydrogen, halogen, deuterium, tritium, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or R 11 and R 12 together with the attached carbon atom form a C 3-6 cycloalkyl group; n is 1 or 2; k is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein Ring A is a C A aryl substituted with 0 - 4 Rs, 6-10 a C A cycloalkyl substituted with 0 - 4 Rs, 3-10 a 3 - 10 membered heterocyclic group substituted with 0 - 4 Rs or A a 5 - 6 membered monocyclic heteroaryl substituted with 0 - 4 Rs. A ​ 3. The compound according to claim 2, wherein, Ring A is a benzene ring substituted with 0-2 R A .

4. The compound according to claim 2, wherein, Ring A is a pyridine ring substituted with 0-2 Rs A .

5. The compound according to claim 2, wherein Ring A is a pyrimidine ring substituted with 0-2 Rs A .

6. The compound according to any one of claims 1-5, wherein, R A is halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.

7. The compound according to any one of claims 1-5, wherein Ring A has one of the following structures:

8. The compound according to any one of claims 1-7, wherein, R3 is hydrogen or C 1-3 alkyl group.

9. The compound according to any one of claims 1-8, wherein R1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, hydroxy C 1-6 alkyl, C 1-3 alkoxy C 1-6 alkyl, C 2-6 alkynyl, cyano C 1-6 alkyl or HOC(=O)C 1-6 alkyl.

10. The compound according to any one of claims 1-8, wherein, R1 is selected from a C 3-6 cycloalkyl group optionally substituted with R8 or a 3- to 6-membered heterocyclic group optionally substituted with R8; Among them, each R8 is independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl.

11. The compound according to any one of claims 1-10, wherein, R is an isoxazolyl group substituted with one R7, an oxazolyl group substituted with one R7, an oxadiazolyl group substituted with one R7, a triazolyl group substituted with one R7, a thiazolyl group substituted with one R7, an isothiazolyl group substituted with one R7 or a thiadiazolyl group substituted with one R7; wherein, R7 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C substituted with 0-1 R 70 , C 6-10 aryl, C substituted with 0-1 R 70 , C 3-10 cycloalkyl, 3-10 membered heterocyclic group substituted with 0-1 R 70 or 5-6 membered heteroaryl substituted with 0-1 R 70 ; R 70 Each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl or C 1-6 haloalkyl.

12. The compound according to any one of claims 1-10, wherein, R has the following structure In the above structure indicating the presence of two conjugated double bonds within the ring structure; wherein, R7 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 70 cycloalkyl substituted with 0-1 R 3-6 ; R 70 selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or a 3- to 8-membered heterocyclic group; Z2 is O or S or N; Z3 is C or N or O or S; Z4 is C or O or N.

13. The compound according to claim 12, wherein, Z2 is O, Z3 is CH, Z4 is N; or Z2 is N, Z3 is CH, Z4 is O; or Z2 is S, Z3 is CH, Z4 is N; or Z2 is S, Z3 is N, Z4 is N; or Z2 is N, Z3 is O, Z4 is N; or Z2 is N, Z3 is S, Z4 is N; or Z2 is N, Z3 is N, Z4 is N.

14. The compound according to claim 12, wherein, R has one of the following structural formulas Among them, R Ba is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or C B1a cycloalkyl substituted with one R 3-6 ; wherein R B1a is C 1-6 alkyl or C 1-6 haloalkyl.

15. The compound according to claim 14, wherein, R Ba selected from tert-butyl, trifluoro-substituted tert-butyl or 16. The compound according to any one of claims 1-10, wherein, R has the following structure wherein, R B is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R4 has the following structure L is O, C(=O), CR 41 R 42 or R L is C aryl substituted with 0 - 1 R C , C cycloalkyl substituted with 0 - 1 R 6-10 , 3 - 10 membered heterocyclic group substituted with 0 - 1 R C or 5 - 6 membered heteroaryl substituted with 0 - 1 R; 3-10 is C cycloalkyl substituted with 0 - 1 R C , 3 - 10 membered heterocyclic group substituted with 0 - 1 R C or 5 - 6 membered heteroaryl substituted with 0 - 1 R; R 41 and R 42 each independently selected from protium, deuterium, tritium, a halogen, or C 1-3 alkyl; R C is a halogen or a C 1-6 alkyl group.

17. The compound according to claim 16, wherein, R B is hydrogen or C 1-3 haloalkyl, such as trifluoromethyl; L is O, C(=O), CH(CH3), CH2, CF2, CD2 or R L is a 4- to 6-membered heterocyclic group substituted with 1 R C ; R C is a halogen or a C 1-3 alkyl group.

18. The compound according to any one of claims 1-17, wherein, R L has one of the following structures or wherein, R Cb is hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, 3- to 6-membered heterocyclic group, -C(=O)R C1 , -(CH2) k S(=O)2R C1 or -NR C2 R C3 ; or two R Bb together with the atoms to which they are attached form a 3- to 6-membered ring; R C1 each independently selected from C 1-6 alkyl or C 3-6 cycloalkyl; R C2 and R C3 each independently selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; m is 0, 1, 2, 3 or 4; k is 0, 1, or 2.

19. The compound according to claim 18, wherein, R L has one of the following structures Among them, R Cb are each independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, 3- to 6-membered heterocyclic group, -C(=O)R C1 , -(CH2) k S(=O)2R C1 or -NR C2 R C3 ; R Cc each independently selected from hydrogen, halogen, or C 1-3 alkyl; R C1 each independently selected from C 1-3 alkyl or C 3-6 cycloalkyl; R C2 and R C3 each independently selected from hydrogen or C 1-3 alkyl; k is 0, 1, or 2.

20. The compound according to claim 16, wherein R has one of the following structural formulas Wherein, L is O or CH2; R Cb is C 1-3 alkyl; R Bd is hydrogen, C 1-3 alkyl or C 1-3 haloalkyl such as trifluoromethyl.

21. The compound according to any one of claims 1-10, wherein, R has the following structure R4 has one of the following structures Or Among them, R Cb is C 1-6 alkyl; R 51 and R 52 each independently is hydrogen, a halogen, deuterium, tritium or a C 1-6 alkyl group, or R 51 , R 52 and the carbon atom to which they are attached together form a C 3-6 cycloalkyl group; R 61 and R 62 each independently is hydrogen, halogen, deuterium, tritium or C 1-6 alkyl, or R 61 , R 62 and the carbon atom to which they are attached together form a C 3-6 cycloalkyl group; n is 1 or 2.

22. The compound according to claim 21, wherein, R has the following structural formula Or Wherein, R 51 and R 52 are each independently selected from protium, halogen, deuterium or tritium, or R 51 , R 52 and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group; R 61 and R 62 are each independently selected from protium, a halogen, deuterium or tritium, or R 61 , R 62 and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group; R Cb is C 1-6 alkyl; n = 1 or 2.

23. The compound according to claim 1, wherein R3 and R2 are hydrogen.

24. The compound according to claim 1, wherein, R1, R2 and the atoms to which they are attached together form a 6-membered ring.

25. The compound according to claim 24, wherein, The part in Formula I has one of the following structures wherein when X1 is C, X2 and X3 are N; when X1 is N, X2 is C and X3 is N; Among them, R D1 are each independently selected from hydrogen, halogen, hydroxyl group, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; or two R D1 together with the carbon atoms to which they are attached form a 3- to 6-membered ring structure substituted with 0-2 R D0 ; R D0 Each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ; R e1 and R e2 each independently selected from hydrogen, C 1-6 alkyl 26. The compound according to claim 24, wherein, The part in Formula I has one of the following structures wherein, R D2 each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ; R e1 and R e2 each independently selected from hydrogen or C 1-6 alkyl.

27. The compound according to claim 1, wherein, Each R1 is independently an optionally R-substituted 10 C 1-6 alkyl group, an optionally R-substituted 10 C 1-6 haloalkyl group, an optionally R-substituted 10 C 1-6 alkoxy group, an optionally R-substituted 10 C 2-6 alkenyl group, an optionally R-substituted 10 C 2-6 alkynyl group, an optionally R-substituted 10 C 3-6 cycloalkyl group or an optionally R-substituted 10 3- to 6-membered heterocyclic group; Among them, R 10 are each independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C 1-6 alkyl or C 1-6 alkoxy group.

28. The compound according to claim 27, wherein, R1 is -C(CH3)(CF3).

29. The compound according to claim 1, wherein The compound has a structure of the following formula IA or IB wherein, L is a direct key, O, or CR 21 R 22 ; R L is for substituting C with 0 - 4 Rs C of 6-10 aryl, C substituted with 0 - 4 Rs C of 3-10 cycloalkyl, C substituted with 0 - 4 Rs C of 3 - 10 - membered heterocyclic group or 5 - 6 - membered heteroaryl substituted with 0 - 4 Rs C ; X is O or S; R3 is selected from hydrogen or C 1-6 alkyl; R2 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R1 is selected from 0-2 R 0 C 6-10 Aryl, substituted with 0-2 R 0 C 3-6 Cycloalkyl, substituted with 0-2 R 0 3-6 membered heterocyclic group, substituted with 0-2 R 0 5-6 membered heteroaryl, substituted with 0-2 R 0 C 1-6 Alkyl, substituted with 0-2 R 0 C 1-6 Haloalkyl, substituted with 0-2 R 0 C 1-6 Alkoxy, substituted with 0-2 R 0 C 2-6 Alkenyl, or substituted with 0-2 R 0 C 2-6 Alkynyl; or, R1, R2 and the atoms to which they are attached together form a 5-membered or 6-membered ring; R A each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R B each independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl; and one of the two Rs B is hydrogen; R 0 each independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, carbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 3-10 cycloalkyl, 3- to 8-membered heterocyclic group or NR 11 R 12 ; R 11 and R 12 each independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R 21 and R 22 each independently selected from hydrogen, halogen, deuterium, tritium, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or R 11 and R 12 together with the attached carbon atom form a C 3-6 cycloalkyl group.

30. The compound according to claim 29, wherein, In formulas IA and IB, the moiety has one of the following structures: wherein, R D2 each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ; R e1 and R e2 each independently selected from hydrogen, C 1-6 alkyl.

31. The compound according to claim 29, wherein, R3 is hydrogen; R2 is hydrogen; Each R1 is independently an optionally R-substituted 10 C 1-6 alkyl, an optionally R-substituted 10 C 1-6 haloalkyl, an optionally R-substituted 10 C 1-6 alkoxy, an optionally R-substituted 10 C 2-6 alkenyl, an optionally R-substituted 10 C 2-6 alkynyl, an optionally R-substituted 10 C 3-6 cycloalkyl or an optionally R-substituted 10 3- to 6-membered heterocyclic group; Among them, R 10 are each independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C 1-6 alkyl or C 1-6 alkoxy group.

32. The compound according to claim 29, wherein, Two Rs A are both fluorine.

33. The compound according to claim 29, wherein, One of the two Rs B is hydrogen and the other is trifluoromethyl.

34. The compound according to claim 29, wherein, R L has one of the following structures wherein, R Cb is independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, 3- to 6-membered heterocyclic group, -C(=O)R C1 , -(CH2) k S(=O)2R C1 or -NR C2 R C3 ; R Cc each independently selected from hydrogen, halogen, or C 1-3 alkyl; R C1 each independently selected from C 1-3 alkyl or C 3-6 cycloalkyl; R C2 and R C3 each independently selected from hydrogen or C 1-3 alkyl; k is 0, 1, or 2.

35. A compound as shown in Formula II Among them, X is O or S; R3 is selected from hydrogen or C 1-6 alkyl; R2 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R1 is selected from 0-2 R 0 C 6-10 Aryl, substituted with 0-2 R 0 C 3-6 Cycloalkyl, substituted with 0-2 R 0 3-6 membered heterocyclic group, substituted with 0-2 R 0 5-6 membered heteroaryl, substituted with 0-2 R 0 C 1-6 Alkyl, substituted with 0-2 R 0 C 1-6 Haloalkyl, substituted with 0-2 R 0 C 1-6 Alkoxy, substituted with 0-2 R 0 C 2-6 Alkenyl, or substituted with 0-2 R 0 C 2-6 Alkynyl; or, R1, R2 and the atoms to which they are attached together form a 5-membered or 6-membered ring; R G1 and R G2 each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R 0 each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, carbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 3-10 cycloalkyl, 3- to 8-membered heterocyclic group or NR 11 R 12 ; R 11 and R 12 each independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R F1 selected from hydrogen, hydroxyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or C F1a substituted with one R 3-6 cycloalkyl, R F2 is for substituting C with 0 - 4 R F2a of 6-10 aryl C 6-10 aryl, substituting C with 0 - 4 R F2a of 3-6 cycloalkyl, substituting with 0 - 4 R F2a of 3 - 6 membered heterocyclic group or substituting with 0 - 4 R F2a of 5 - 6 membered heteroaryl; wherein R F1a is selected from halogen, hydroxy, cyano, C 1-6 alkyl or C 1-6 haloalkyl; R F2a is selected from halogen, hydroxy, cyano, C 1-6 alkyl or C 1-6 haloalkyl.

36. The compound according to claim 35, wherein, The part has one of the following structures wherein, R D2 each independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)OR e1 or -C(=O)NR e1 R e2 ; R e1 and R e2 each independently selected from hydrogen, C 1-6 alkyl groups.

37. The compound according to claim 36, wherein, The part has the following structure 38. The compound according to claim 35, wherein, R3 is hydrogen; R2 is hydrogen; Each R1 is independently optionally substituted with R 10 C 1-6 alkyl, optionally substituted with R 10 C 1-6 haloalkyl, optionally substituted with R 10 C 1-6 alkoxy, optionally substituted with R 10 C 2-6 alkenyl, optionally substituted with R 10 C 2-6 alkynyl, optionally substituted with R 10 C 3-6 cycloalkyl or optionally substituted with R 10 3- to 6-membered heterocyclic group; Among them, R 10 are each independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C 1-6 alkyl or C 1-6 alkoxy group.

39. The compound according to claim 37, wherein, R1 is C 3-6 a cycloalkyl group such as cyclopropyl or cyclobutyl.

40. A compound according to any one of claims 35 - 39, wherein, R G1 is a halogen such as F, and R G2 is hydrogen.

41. A compound according to any one of claims 35 - 40, wherein, R F1 selected from tert-butyl, trifluoro-substituted tert-butyl or R F2 is phenyl or phenyl substituted with fluorine, such as 4-fluoro-phenyl.

42. The compound according to any one of claims 1-41, wherein, X is O.

43. The compound according to any one of claims 1-42, wherein The compound is selected from one of the following:

44. A pharmaceutical composition comprising the compound according to any one of claims 1 to 43 and a pharmaceutically acceptable carrier, diluent or excipient.

45. A method of treating or preventing an NEK7-NLRP3-mediated disorder, comprising administering to an individual in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 43 or the pharmaceutical composition according to claim 44.

46. The method according to claim 45, wherein the disease condition is selected from autoimmune diseases, inflammatory conditions, cardiovascular diseases, neurodegenerative conditions, 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.

47. The method according to claim 45 or 46, wherein the disease condition is selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, and Muckle-Wells syndrome.

48. The method according to claim 45 or 46 or 47, wherein the NEK7-NLRP3-mediated disease conditions 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.

49. Use of a compound according to any one of claims 1 to 43 for the preparation of a medicament for the treatment or prevention of NEK7-NLRP3-mediated disease conditions.

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