NEK7 inhibitor, pharmaceutical composition and use thereof

Abstract

The present disclosure relates to an NEK7 inhibitor, a pharmaceutical composition and the use thereof. The compound has the structural formula of formula (I). The compound of the present disclosure has good NEK7 inhibitory activity, and can be used for treating or preventing 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.).

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, playing 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. NLRP3 activation 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 number of inhibitors have been widely used to interfere with effector signaling pathways involving IL-1β or IL-18 without eliminating inflammatory responses. Inhibitors that block NLRP3 inflammasome activation through the NLRP3-NEK7 interaction may have therapeutic or preventive activity in several human diseases, such as 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.).

[0006] Summary of the Invention

[0007] The present disclosure provides a compound as shown in Formula I

[0008] 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.).

[0009] The present disclosure also relates to pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0010] 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.

[0011] 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

[0012] 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.

[0013] 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.

[0014] 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.

[0015] definition

[0016] 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.

[0017] 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."

[0018] 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.

[0019] 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.

[0020] 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.

[0021] "Cyano" refers to a -CN group.

[0022] "Hydroxy" (hydroxyl) refers to an -OH group.

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

[0024] "Mercapto" refers to a -SH substituent.

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

[0026] "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.

[0027] "Alkenyl" refers to an unsaturated straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having 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.

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

[0029] "Alkoxy" 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.

[0030] "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.

[0031] "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.

[0032] "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.

[0033] "Carbocyclic" or "carbocycle" refers to a ring system in which every one of the ring atoms is carbon.

[0034] "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.

[0035] "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.

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

[0037] "Halogen" refers to bromine, chlorine, fluorine or iodine.

[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]dioxepinyl, 1,4-benzodioxalanyl, 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 of 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 pharmaceutically acceptable salts thereof may contain one or more centers of geometric asymmetry and may therefore give rise to stereoisomers, such as enantiomers, diastereomers and other stereoisomeric forms, which are defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- of an amino acid. 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 from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, 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, 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.

[0075] Compound

[0076] The present disclosure provides compounds capable of inhibiting NEK7 and / or modulating the activity of the NLRP3 inflammasome, including pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof.

[0077] The present disclosure provides a compound as shown in Formula I

[0078] or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof,

[0079] in,

[0080] 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;

[0081] R is one of the following structural formulas

[0082] Indicates the position where these structures are connected to NH in Formula I;

[0083] R4 is the following group

[0084] in,

[0085] L is a direct key, O 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] X1 for CR 31 or N;

[0088] X2 is C or N;

[0089] X3 for CR 32 or N;

[0090] X4 is C or N;

[0091] Z1 is CH or N;

[0092] Z2 is O or S;

[0093] Z3 is C or N;

[0094] Z4 is C or N;

[0095] Ring 1 Indicates the presence of a conjugated double bond in ring 1 (the position of the double bond will vary depending on the selection of X1, X2, and X4);

[0096] R1 is selected from 0-4 R 0 C 6-10 Aryl, substituted with 0-4 R 0 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 1-6Alkyl, 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 ;

[0097] R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0098] 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;

[0099] R B are each independently selected from 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 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;

[0100] 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;

[0101] R C are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0102] R 31 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0103] R 32 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0104] R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 、R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0105] R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 、R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0106] 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 70 3-10 membered heterocyclic group or substituted with 0-4 R 70 5-6 membered heteroaryl;

[0107] 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 ;

[0108] R 0 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3-8 membered heterocyclic group or NR 11 R 12 ;

[0109] 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;

[0110] 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 and the connected carbon together form C 3-6 Cycloalkyl;

[0111] n is 1 or 2.

[0112] In one embodiment, 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 A 5-6 membered monocyclic heteroaryl group.

[0113] In certain embodiments, Ring A is a divalent group selected from the group consisting of: each optionally substituted with 0-4 R Aphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl, [2.2.2]bicyclooctyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, acridinyl, benzimidazolyl, benzofuranyl, benzothiathienyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazole yl, NH-carbazolyl, carbolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl.

[0114] In one embodiment, ring A may be a benzene ring; or, ring A may be a pyridine ring; or ring A may be a pyrimidine ring.

[0115] In one embodiment, the substituent R on the A ring A Can be halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy.

[0116] In one embodiment, Ring A has one of the following structures:

[0117] In the embodiments of the above compounds, R2 may be hydrogen.

[0118] In the embodiment of the above compound, R1 is substituted with 0-4 R 0 C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R 0 3-10 membered heterocyclic group or substituted with 0-4 R 0 C 1-6 alkyl;

[0119] R 0 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0120] In the embodiments of the above compounds, R1 can be C 3-10 An example of a cycloalkyl group is a cyclopropyl group.

[0121] In the embodiments of the above compounds, R1 can be substituted with 0-1 R 0 3-10 membered heterocyclic group, substituted with 0-1 R 0 C 2-6 Alkenyl or substituted with 0-1 R 0 C 1-6 alkyl;

[0122] R 0 Each independently selected from halogen, hydroxy, cyano or C 1-3 Alkoxy.

[0123] In the embodiments of the above compounds, R1 can be one of the following groups:

[0124] In one embodiment, R can be isoxazolyl substituted with one R7, oxazolyl substituted with one R7, oxadiazolyl substituted with one R7, triazolyl substituted with one R7, thiazolyl substituted with one R7, isothiazolyl substituted with one R7, or thiadiazolyl substituted with one R7;

[0125] 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 703-10 membered heterocyclic group or substituted with 0-1 R 70 5-6 membered heteroaryl;

[0126] 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.

[0127] In one embodiment, R may have the structure

[0128] In the above structure Indicates the presence of a conjugated double bond within the ring structure (the position of the double bond will vary depending on the selection of Z2, Z3, and Z4);

[0129] Wherein, R7 is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or substituted with 0-1 R 70 C 3-6 Cycloalkyl;

[0130] 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;

[0131] Z2 is O or S;

[0132] Z3 is C or N;

[0133] Z4 is C or N.

[0134] In particular, Z2 is O, Z3 is CH, and Z4 is N; or

[0135] Z2 is N, Z3 is CH, and Z4 is O; or

[0136] Z2 is S, Z3 is CH, and Z4 is N; or

[0137] Z2 is S, Z3 is N, and Z4 is N.

[0138] In one embodiment, R may have one of the following structural formulas

[0139] Among them, R Ba C 1-6 Alkyl, C 1-6 Haloalkyl or substituted with 1 R B1a C3-6 Cycloalkyl,

[0140] where R B1a C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0141] In one embodiment, R may have the structure

[0142] 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;

[0143] R4 has the following structure

[0144] L is O, CH2, CF2, CD2 or

[0145] 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;

[0146] R C Halogen or C 1-6 alkyl.

[0147] In one embodiment, R B Can be hydrogen or C 1-6 haloalkyl such as trifluoromethyl;

[0148] L is O, CH2, CF2, CD2 or

[0149] R L To replace there is 1 R C A 3-10 membered heterocyclic group;

[0150] R C Halogen or C 1-3 alkyl.

[0151] In one embodiment, R L Can have one of the following structures

[0152] Among them, RBb C 1-6 alkyl.

[0153] In one embodiment, R may have one of the following structural formulas

[0154] Wherein, L is O or CH2; R Bb C 1-3 Alkyl; R Bc is hydrogen or C 1-3 Haloalkyl is for example trifluoromethyl.

[0155] In one embodiment, R may have the structure

[0156] R4 has one of the following structures

[0157] Among them, R Bb C 1-6 alkyl;

[0158] R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 、R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0159] R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 、R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0160] n is 1 or 2.

[0161] In one embodiment, R may have the following structural formula

[0162] in,

[0163] R 51 and R 52 are each independently selected from hydrogen, halogen, deuterium or tritium, or R 51 、R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0164] R 61 and R 62 are each independently selected from hydrogen, halogen, deuterium or tritium, or R61 、R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0165] R Bb C 1-6 alkyl;

[0166] n=1 or 2.

[0167] In the embodiment of the above compound, X1 and X2 may both be N, X3 may be CH, and X4 may be C. In this case, Can be

[0168] In the embodiment of the above compound, X1, X2 and X3 can all be N, and X4 can be C. In this case, in Formula I Can be

[0169] In the embodiment of the above compound, X1 and X3 can both be CH, X2 can be C, and X4 can be N. In this case, Can be

[0170] In the embodiment of the above compound, X1 and X3 can both be CH, X2 can be N, and X4 can be C. In this case, Can be

[0171] In the embodiment of the above compound, X1 and X4 can both be N, X2 can be C, and X3 can be CH. Can be

[0172] In the embodiment of the above compound, X1 may be CH, X2 and X3 may be N, and X4 may be C. In this case, Can be

[0173] In the embodiment of the above compound, X1 can be CH, X2 can be C, and X3 and X4 can both be N. In this case, Can be

[0174] In the embodiment of the above compound, X1, X3 and X4 can all be N, and X2 can be C. In this case, Can be

[0175] In one embodiment, the compounds of the present disclosure may have the structure of Formula IA

[0176] in,

[0177] R is one of the following structural formulas

[0178] R4 is the following group

[0179] in,

[0180] L is a direct key, O or CR 21 R 22 ;

[0181] 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;

[0182] X1 for CR 31 or N;

[0183] X2 is C or N;

[0184] X3 for CR 32 or N;

[0185] X4 is C or N;

[0186] X5 for CR 33 or N;

[0187] Z1 is CH or N;

[0188] Z2 is O or S;

[0189] Z3 is C or N;

[0190] Z4 is C or N;

[0191] Ring 1 Indicates the presence of a conjugated double bond in ring 1 (the position of the double bond will vary depending on the selection of X1, X2, and X4);

[0192] R1 is selected from 0-4 R 0 C 6-10 Aryl, substituted with 0-4 R 0 C 3-10 Cyclic hydrocarbon group, substituted with 0-4 R 03-10 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 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 ;

[0193] R B are each independently selected from 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 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;

[0194] 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;

[0195] R C are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0196] R 31 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0197] R 32 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C1-6 alkyl halide;

[0198] R 33 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;

[0199] R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 、R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0200] R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 、R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0201] 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 70 3-10 membered heterocyclic group or substituted with 0-4 R 70 5-6 membered heteroaryl;

[0202] 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 ;

[0203] R 0 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group or NR11 R 12 ;

[0204] 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;

[0205] 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 connected carbon, it forms a C3-6 cycloalkyl group;

[0206] n is 1 or 2.

[0207] In one embodiment of the compound of formula IA, X5 can be CR 33 , where R 33 is fluorine, hydrogen, methoxy or trifluoromethoxy.

[0208] In one embodiment of the compound of formula IA, X5 can be N.

[0209] In one embodiment of the compound of formula IA, R1 may be substituted with 0-1 R 0 C 3-10 Cyclic hydrocarbon group, substituted with 0-1 R 0 3-10 membered heterocyclic group or substituted with 0-1 R 0 C 1-6 alkyl;

[0210] R 0 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0211] In one embodiment of the compound of formula IA, X1 and X2 are both N, X3 is CH, and X4 is C; or

[0212] X1, X2 and X3 are all N, and X4 is C; or

[0213] X1 and X3 are both CH, X2 is C, and X4 is N; or

[0214] X1 and X3 are both CH, X2 is N, and X4 is C; or

[0215] X1 and X4 are both N, X2 is C, and X3 is CH; or

[0216] X1 is CH, X2 and X3 are N, and X4 is C; or

[0217] X1 is CH, X2 is C, and X3 and X4 are both N; or

[0218] X1, X3 and X4 are all N, and X2 is C.

[0219] In one embodiment of the compound of formula IA, R may have the structure

[0220] In the above structure Indicates the presence of a conjugated double bond within the ring structure (the position of the double bond will vary depending on the selection of Z2, Z3, and Z4);

[0221] Wherein, R7 is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or substituted with 0-1 R 70 C 3-6 Cycloalkyl;

[0222] 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;

[0223] Z2 is O or S;

[0224] Z3 is C or N;

[0225] Z4 is C or N.

[0226] In particular, Z2 is O, Z3 is CH, and Z4 is N; or

[0227] Z2 is N, Z3 is CH, and Z4 is O; or

[0228] Z2 is S, Z3 is CH, and Z4 is N; or

[0229] Z2 is S, Z3 is N, and Z4 is N.

[0230] In one embodiment of the compound of formula IA, R may have one of the following structural formulas:

[0231] Among them, R Ba C 1-6 Alkyl, C 1-6Haloalkyl or substituted with 1 R B1a C 3-6 Cycloalkyl,

[0232] where R B1a C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0233] In one embodiment of the compound of formula IA, R may have the structure

[0234] 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;

[0235] R4 has the following structure

[0236] L is O, CH2, CF2, CD2 or

[0237] 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;

[0238] R C Halogen or C 1-6 alkyl.

[0239] In one embodiment of the compound of Formula IA, R B It can be hydrogen or C 1-6 haloalkyl such as trifluoromethyl;

[0240] L is O, CH2, CF2, CD2 or

[0241] R L To replace there is 1 R C A 3-10 membered heterocyclic group;

[0242] R C C 1-3 alkyl.

[0243] In one embodiment of the compound of Formula IA, R L Can have one of the following structures

[0244] Among them, R Bb C 1-6 alkyl.

[0245] In one embodiment of the compound of formula IA, R may have one of the following structural formulas:

[0246] Wherein, L is O or CH2; R Bb C 1-3 alkyl.

[0247] In one embodiment of the compound of Formula IA, R Bb It can be methyl;

[0248] R Bc is hydrogen or trifluoromethyl.

[0249] In one embodiment of the compound of formula IA, R may have the structure

[0250] R4 has one of the following structures

[0251] Among them, R Bb C 1-6 alkyl;

[0252] R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 、R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0253] R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 、R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0254] n is 1 or 2.

[0255] In one embodiment of the compound of formula IA, R may have the following structure

[0256] in,

[0257] R 51 and R 52 are each independently selected from hydrogen, halogen, deuterium or tritium, or R51 、R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0258] R 61 and R 62 are each independently selected from hydrogen, halogen, deuterium or tritium, or R 61 、R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl;

[0259] R Bb C 1-6 alkyl;

[0260] n=1 or 2.

[0261] In one embodiment of the compound of Formula IA, R Bb It may be methyl.

[0262] The present application also provides a compound shown in Formula II

[0263] or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof,

[0264] in,

[0265] X1 for CR 31 or N;

[0266] X2 is C or N;

[0267] X3 for CR 32 or N;

[0268] X4 is C or N;

[0269] X5 for CR 33 or N;

[0270] Ring 1 This indicates the presence of a conjugated double bond within ring 1;

[0271] R1 is selected from 0-4 R 0 C 6-10 Aryl, substituted with 0-4 R 0 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 C1-6 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 ;

[0272] R 31 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0273] R 32 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 alkyl halide;

[0274] R 33 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;

[0275] R 0 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group or NR 11 R 12 ;

[0276] 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;

[0277] Ring B is a 5-membered heteroaromatic ring containing 1-3 heteroatoms selected from N, O or S, and the ring B is substituted with m R8;

[0278] R8 are each independently selected from protium, deuterium, tritium, halogen, hydroxyl, cyano, optionally substituted with R 80 C 1-6 Alkyl, optionally substituted with R 80 C 1-6Alkoxy, optionally substituted with R 80 C 3-6 Cycloalkyl, optionally substituted with R 80 C 6-10 Aryl, optionally substituted with R 80 3-10 membered heterocyclic group, -CONR 81 R 82 Or-COR 83 ;

[0279] R 80 Each independently selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0280] R 81 and R 82 are independently selected from hydrogen or C 1-6 alkyl;

[0281] R 83 Selected from C 1-6 alkyl;

[0282] m is 1, 2 or 3.

[0283] In one embodiment of the compound of formula II, Ring B is selected from one of the following structural formulas:

[0284] in, Indicates the position where the B ring is connected to the NH in the structure of formula II;

[0285] The B ring is substituted with two R8s.

[0286] In one embodiment of the compound of formula II, Ring B has the following structural formula:

[0287] The B ring is substituted with 2 to 3 R8.

[0288] In one embodiment of the compound of formula II, two R8 are optionally protium, deuterium, tritium, halogen, substituted with R 80 C 1-6 Alkyl, another R8 is optionally substituted with R 80 of aromatic groups.

[0289] In one embodiment of the compound of formula II, X5 is CR 33 , where R 33 is fluorine, hydrogen, methoxy or trifluoromethoxy.

[0290] In one embodiment of the compound of formula II, X1 and X2 are both N, X3 is CH, and X4 is C. In this case, Can be

[0291] In one embodiment of the compound of formula II, X1, X2 and X3 are all N, and X4 is C; in this case, Can be

[0292] In one embodiment of the compound of formula II, X1 and X3 are both CH, X2 is C, and X4 is N; in this case, Can be

[0293] In one embodiment of the compound of formula II, X1 and X3 are both CH, X2 is N, and X4 is C; in this case, Can be

[0294] In one embodiment of the compound of formula II, X1 and X4 are both N, X2 is C, and X3 is CH; in this case, Can be

[0295] In one embodiment of the compound of formula II, X1 is CH, X2 and X3 are N, and X4 is C; in this case, Can be

[0296] In one embodiment of the compound of formula II, X1 is CH, X2 is C, and X3 and X4 are both N; in this case, Can be

[0297] In one embodiment of the compound of formula II, X1, X3 and X4 are all N, and X2 is C. In this case, Can be

[0298] In one embodiment of the compound of formula II, X1 and X2 are both N, X3 is CH, and X4 is C.

[0299] In one embodiment of the compound of formula II, the compound has the structural formula II-1

[0300] Wherein R1 is substituted with 0-1 R 0 C 3-10 Cyclic hydrocarbon group, substituted with 0-1 R 03-10 membered heterocyclic group or substituted with 0-1 R 0 C 1-6 alkyl;

[0301] R 0 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 alkyl halide;

[0302] R 33 Halogen or C 1-6 alkyl;

[0303] R 91 is optionally substituted with R 90 C 1-6 Alkyl, optionally substituted with R 90 C 3-6 Cycloalkyl, optionally substituted with R 90 C 3-6 Cycloalkyl, optionally substituted with R 90 3-10 membered heterocyclic group;

[0304] R 92 is optionally substituted with R 90 Phenyl or optionally substituted with R 90 A 3-10 membered heterocyclic group;

[0305] R 93 For protium, deuterium, tritium, halogen or C 1-6 alkyl;

[0306] R 90 Each independently selected from protium, deuterium, tritium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl.

[0307] In one embodiment of the compound of formula II-1, R1 is C 3-6 Cycloalkyl groups include, for example, cyclopropyl.

[0308] In one embodiment of the compound of formula II-1, R 91 C 1-6 Alkyl groups such as tert-butyl,

[0309] R 92 is optionally substituted with R 90 Phenyl, R 90 are each independently selected from halogen such as fluorine, C 1-6 Alkyl such as methyl, ethyl or isopropyl, or C 1-6 alkoxy groups such as methoxy;

[0310] R93 For protium.

[0311] In one embodiment of the compound of formula II-1, R 91 is optionally substituted with R 90 C 3-6 Cycloalkyl, R 90 Each independently selected from C 1-6 Haloalkyl, such as R 91 for

[0312] R 92 is optionally substituted with R 90 Phenyl, R 90 are each independently selected from halogen such as fluorine, C 1-6 Alkyl such as methyl, ethyl or isopropyl, or C 1-6 alkoxy groups such as methoxy;

[0313] R 93 For protium.

[0314] In one embodiment of the compound of formula II-1, R 92 One of the following structures:

[0315] The compounds of the present disclosure may be selected from one of the following:

[0316] Pharmaceutical composition

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] Provided herein are pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0325] 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).

[0326] 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.

[0327] 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.

[0328] 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.

[0329] application

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] Example

[0338] Synthesis of intermediates

[0339] Intermediate 1: 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline

[0340] Step A: 1-Methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine

[0341] 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 h. 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: DCM / MeOH = 97 / 3) to give the product (5.4 g, yield 78%).

[0342] LC-MS (ESI), m / z: [M+1]+ =304.

[0343] Step B: 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline

[0344] 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 h. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. 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.

[0345] LC-MS (ESI), m / z: [M+1] + =274.

[0346] Intermediate 2: 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline

[0347] Step A: 1-Methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine

[0348] 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 temperature was raised to room temperature, and 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 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, concentrated under reduced pressure, and purified by column chromatography to give the product (3.5 g, yield 61%).

[0349] LC-MS (ESI), m / z: [M+1] + =305.

[0350] Step B: 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline

[0351] 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 h. 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.

[0352] LC-MS (ESI), m / z: [M+1]+=275.

[0353] Other amino intermediates used in the preparation of the examples are as follows:

[0354] Intermediate B1: (1s,3s)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutane-1-ol

[0355] Step A: (1s,3s)-3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutane-1-ol

[0356] To a solution of 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutan-1-one (3.0 g, 10.0 mmol) in tetrahydrofuran was added methylmagnesium bromide (8 mL, 24 mmol, 3 M) at -70°C, and the reaction mixture was stirred for 3 hours; the reaction was monitored by TLC and LC-MS, and the starting material disappeared; saturated ammonium chloride solution was added to quench 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 to give the product (1.8 g, yield 57%).

[0357] LC-MS (ESI), m / z: [M+1] + =316.

[0358] Step B: (1s,3s)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutane-1-ol

[0359] To a solution of (1s,3s)-3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutan-1-ol (1.5 g, 4.7 mmol) in isopropanol was added aqueous ammonia (8.3 g, 237 mmol) at room temperature. The reaction temperature was raised to 90°C and stirred for 16 h. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The product was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, and concentrated to give the product (1.2 g, 85% yield).

[0360] LC-MS (ESI), m / z: [M+1] + =297.

[0361] Intermediate B2: 7-cyclopropyl-5-iodoimidazo[5,1-f][1,2,4]triazine-4-amine

[0362] The synthesis method of intermediate B2 can be found in CN114075190A.

[0363] Referring to the synthesis method of the above intermediates, the intermediates in the table below were synthesized as follows:

[0364] Intermediate A1: 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate

[0365] 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.

[0366] LC-MS (ESI), m / z: [M+1] + =439.

[0367] Intermediate A2: 4-nitrophenyl-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)carbamate

[0368] 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.

[0369] LC-MS (ESI), m / z: [M+1] + =440.

[0370] Referring to the synthesis method of the above intermediates, the intermediates in the table below were synthesized as follows:

[0371] Synthesis of Examples

[0372] Example 1: 1-(4-(8-amino-3-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea formate

[0373] Step A: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0374] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.1 mmol) in 1,4-dioxane (10 mL) were added N,N-diisopropylethylamine (818 mg, 6.3 mmol) and 4-nitrophenyl-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamate (Intermediate A1, 1.1 g, 2.5 mmol) at room temperature; the reaction was stirred at room temperature overnight. TLC and LCMS confirmed 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 (155 mg, 14% yield).

[0375] LC-MS (ESI), m / z: [M+1]+ =537.

[0376] Step B: 1-(4-(8-amino-3-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea formate

[0377] To a solution of (1s,3s)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutan-1-ol (Intermediate B1, 150 mg, 0.4 mmol) in 1,4-dioxane (10 mL) were added potassium carbonate (166 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (107 mg, 0.5 mmol) at room temperature; the mixture was heated to 100°C and stirred for 3 hours. The reaction was detected by TLC and LCMS, and the starting material disappeared and the product was generated; the mixture was concentrated under reduced pressure, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography Prep-HPLC was used to obtain 1-(4-(8-amino-3-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea formate (31 mg, yield 11%).

[0378] LC-MS (ESI), m / z: [M+1] + =627.

[0379] 1 H NMR (400MHz, DMSO-d6) δ9.53(s,1H),8.83(s,1H),8.27(t,1H),8.18(s,1H),8.02(s,1H),7.65(d,J=8.4Hz,1H),7.56(d,1H),7.51-7.3 9(m,3H),7.03(s,1H),6.07(s,2H),5.24-5.00(br,1H),3.55(s,2H),3.45-3.41(m,2H),2.51-2.24(m,11H),2.20(s,3H),1.40(s,3H).

[0380] Example 2: 1-(4-(8-amino-3-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0381] Step A: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0382] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (300 mg, 1.3 mmol) in 1,4-dioxane (10 mL) were added N,N-diisopropylethylamine (491 mg, 3.8 mmol) and 4-nitrophenyl-(4-((1-methylpiperazin-1-yl)oxy)-3-(trifluoromethyl)phenyl)carbamate (Intermediate A2, 667 mg, 1.5 mmol) at room temperature; the reaction was stirred at room temperature overnight. TLC and LCMS confirmed 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 (363 mg, 54% yield).

[0383] LC-MS (ESI), m / z: [M+1] + =538.

[0384] Step B: 1-(4-(8-amino-3-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0385] To a solution of (1s,3s)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutan-1-ol (250 mg, 0.8 mmol) in 1,4-dioxane (10 mL) were added potassium carbonate (325 mg, 2.4 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (537 mg, 1.0 mmol) at room temperature; the temperature was raised to 100°C and stirred for 2 hours. The reaction was monitored by TLC and LCMS, indicating that the starting material disappeared and the product was generated. The mixture was concentrated under reduced pressure, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography Prep-HPLC was used to obtain 1-(4-(8-amino-3-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (67 mg, yield 17%).

[0386] LC-MS (ESI), m / z: [M+1] + =628.

[0387] 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.67(s,1H),8.27(t,1H),7.87(s,1H) ,7.54-7.38(m,4H),7.27(d,J=9.2Hz,1H),7.02(d,J=4.8Hz,1H),6.06(s,2 H),5.14(s,1H),4.53(s,1H),3.45-3.41(m,1H),2.51-2.42(m,6H),2.24-2 .20(m,2H),2.17(s,3H),1.93-1.88(m,2H),1.70-1.66(m,2H),1.40(s,3H).

[0388] Example 4: 1-(5-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)pyridin-2-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0389] Step A: 4-Nitrophenyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate

[0390] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (400 mg, 1.8 mmol) and pyridine (285 mg, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise p-nitrophenyl chloroformate (363 mg, 1.8 mmol) at 0°C under nitrogen. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. After completion of the reaction, the product was used directly in the next step without purification.

[0391] LC-MS (ESI), m / z: [M+1] + =386.

[0392] Step B: (6-(3-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)pyridin-3-yl)boronic acid

[0393] At room temperature, the reaction solution from the previous step was slowly added dropwise to a solution of 4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (301 mg, 1.1 mmol) and N,N-diisopropylethylamine (711 mg, 5.5 mmol) in anhydrous tetrahydrofuran (10 mL). The temperature was raised to 60°C under a nitrogen atmosphere and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was quenched with water and diluted, 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, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 1 / 1) to give a light yellow solid product (200 mg, yield 42%).

[0394] LC-MS (ESI), m / z: [M+1] + =438.

[0395] Step C: 1-(5-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)pyridin-2-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0396] To a mixed solution of (1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (127 mg, 0.5 mmol) and (6-(3-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)pyridin-3-yl)boronic acid (219 mg, 0.5 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) were added potassium carbonate (208 mg, 1.5 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmole) at room temperature. ol), after nitrogen replacement three times, the temperature was raised to 100°C and the reaction was stirred for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction system was cooled to room temperature, diluted with saturated sodium chloride aqueous solution, 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 product (50 mg, yield 18%).

[0397] LC-MS (ESI), m / z: [M+1] + =566.

[0398] 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),9.67(s,1H),8.48(d,J=4.0Hz,1H),8.07 (s,1H),7.93(dd,J=8.0,4.0Hz,1H),7.73(d,J=4.0Hz,1H),7.69-7.65(m,2H),7 .61(d,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),6.11(s,2H),3.55(s,2H),2.39-2.3 1(m,8H),2.16(s,3H),2.03-1.97(m,1H),1.09-1.04(m,2H),1.01-0.97(m,2H).

[0399] 19 F NMR(376MHz,DMSO-d6)δ-57.92.

[0400] Example 10: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0401] Step A: (3-chloropyrazin-2-yl)methanamine

[0402] To a solution of 3-chloropyrazine-2-carbonitrile (8.0 g, 57.3 mmol) in glacial acetic acid (30 mL) was added Raney nickel (3.4 g, 57.3 mmol) at room temperature. The mixture was replaced with a hydrogen balloon three times, and the reaction mixture was then heated to 60°C for 18 hours. TLC and LC-MS monitoring indicated the disappearance of the starting material. The catalyst was removed by filtration, and the acetic acid was removed by concentration under reduced pressure. Ethyl acetate was added, and the organic phase was washed repeatedly with saturated sodium carbonate solution until alkaline, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 5 / 1) to afford the product as a blue-green oily liquid (3.1 g, 38% yield).

[0403] LC-MS (ESI), m / z: [M+1] + =144.

[0404] Step B: N-((3-chloropyrazin-2-yl)methyl)cyclopropanecarboxamide

[0405] To a solution of cyclopropylcarboxylic acid (100 mg, 1.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (574 mg, 1.5 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, and then N,N-diisopropylethylamine (450 mg, 3.5 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then a solution of (3-chloropyrazin-2-yl)methylamine (183 mg, 1.3 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise to the reaction system. The reaction was stirred at room temperature for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction solution was quenched with water and diluted, 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, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 80 / 1) to give a light yellow oily product (190 mg, yield 77%).

[0406] LC-MS (ESI), m / z: [M+1] + =212.

[0407] Step C: 8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine

[0408] To a solution of N-((3-chloropyrazin-2-yl)methyl)cyclopropanecarboxamide (100 mg, 0.5 mmol) in anhydrous 1,4-dioxane (6 mL) at room temperature was added phosphorus oxychloride (94 mg, 0.6 mmol). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C with stirring for 2 hours. TLC and LC-MS monitoring revealed the disappearance of the starting material. The reaction solution was concentrated to remove 1,4-dioxane and phosphorus oxychloride, diluted with ethyl acetate, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 50 / 1) to afford the product as a pale yellow solid (80 mg, 87% yield).

[0409] LC-MS (ESI), m / z: [M+1] + =194.

[0410] Step D: 1-Bromo-8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine

[0411] To a solution of 8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine (550 mg, 2.8 mmol) in anhydrous N,N-dimethylformamide (6 mL) at 0°C was added N-bromosuccinimide (607 mg, 3.4 mmol). The atmosphere was purged with nitrogen three times, and the reaction mixture was warmed to room temperature and stirred for 18 hours. TLC and LC-MS monitoring revealed the disappearance of the starting material. The reaction mixture was quenched with water and diluted, then extracted three times with ethyl acetate. The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (mobile phase: petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) afforded the product as a pale yellow solid (400 mg, 52% yield).

[0412] LC-MS (ESI), m / z: [M+1] + =272.

[0413] Step E: 1-Bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine

[0414] To a solution of 1-bromo-8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine (270 mg, 1.0 mmol) in isopropanol (10 mL) was added aqueous ammonia (12 mL, 297 mmol, 30%) at room temperature. The reaction mixture was heated to 95°C and stirred for 18 hours. TLC and LC-MS monitoring revealed the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure to dryness to obtain the crude product, which was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 5 / 1) to afford a pale yellow solid (200 mg, 79% yield).

[0415] LC-MS (ESI), m / z: [M+1] + =253.

[0416] Step F: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0417] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (60 mg, 0.2 mmol) in 1,4-dioxane (6 mL) and water (2 mL) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (140 mg, 0.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (38.7 mg, 0.05 mmol) and potassium carbonate (131 mg, 1.0 mmol) at room temperature. After nitrogen was replaced, the temperature was raised to 100°C and the reaction was carried out for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction solution was quenched with water and diluted, 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 product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70%, 55 minutes; flow rate: 70 mL / min) to give a white solid product (28 mg, yield 19%).

[0418] LC-MS (ESI), m / z: [M+1] + =583.

[0419] 1H NMR (400MHz, DMSO-d6) δ9.46 (s, 1H), 8.77 (d, J = 4.0Hz, 1H), 8.25 (t, J = 8.0Hz, 1H), 8 .01(d,J=4.0Hz,1H),7.72(d,J=4.0Hz,1H),7.65(d,J=8.0Hz,1H),7.55(dd,J=8.0,4 .0Hz,1H),7.43-7.35(m,2H),7.07(d,J=4.0Hz,1H),6.08(s,2H),3.54(s,2H),2.38 -2.30(m,8H),2.16(s,3H),1.25-1.20(m,1H),1.08-1.02(m,2H),1.00-0.97(m,2H).

[0420] 19 F NMR(376MHz,DMSO-d6)δ-58.03,-129.40.

[0421] Example 21: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0422] Step A: 3-Oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile

[0423] 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.

[0424] LC-MS (ESI), m / z: [M-1] - =176.

[0425] Step B: 3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-amine

[0426] 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).

[0427] LC-MS (ESI), m / z: [M+1] + =193.

[0428] Step C: Phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate

[0429] To a solution of 3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-amine (416 mg, 2.2 mmol) in anhydrous tetrahydrofuran (10 mL) at 0°C was added phenyl chloroformate (508 mg, 3.2 mmol) and pyridine (274 mg, 3.5 mmol). The mixture was allowed to warm to room temperature and stirred for 18 hours. TLC and LC-MS monitoring revealed the disappearance of the starting material. The reaction was quenched and diluted with ice water, then extracted twice with ethyl acetate. 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: petroleum ether / ethyl acetate = 10 / 1) to afford the product as a white solid (426 mg, 63% yield).

[0430] LC-MS (ESI), m / z: [M+1] + =313.

[0431] Step C: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0432] To a solution of phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (426 mg, 1.4 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature were added 4-amino-3-fluorophenylboronic acid pinacol ester (323 mg, 1.4 mmol), 4-dimethylaminopyridine (8 mg, 68.2 μmol), and N,N-diisopropylethylamine (264 mg, 2.0 mmol). The mixture was stirred at 60°C under nitrogen for 2 hours. TLC and LC-MS monitoring indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature, quenched with ice water, and diluted. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once 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 = 10 / 1) to afford the product as a white solid (359 mg, 58% yield).

[0433] LC-MS (ESI), m / z: [M+1] + =456.

[0434] Step E: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0435] To a mixed solution of (1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (100 mg, 0.40 mmol) in 1,4-dioxane (6 mL) and water (2 mL) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (189 mg, 0.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (70 mg, 0.1 mL) at room temperature. mol) and potassium carbonate (218 mg, 1.6 mmol). After nitrogen was replaced, the temperature was raised to 100°C and the reaction was allowed to proceed for 3 hours. TLC and LC-MS monitoring of the reaction indicated the disappearance of the starting material. The reaction solution was quenched with water and diluted, extracted three times with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% over 55 minutes; flow rate: 70 mL / min) to afford the product as a white solid (30 mg, 15% yield).

[0436] LC-MS (ESI), m / z: [M+1] + =502.

[0437] 1H NMR (400MHz, DMSO-d6) δ10.69(brs,1H),8.96(s,1H),8.20-8.15(m,1H),7.73(d,J=4.0Hz,1H),7.46-7.38(m,2H),7.08(d,J=4.0H z,1H),6.21(s,1H),6.09(brs,2H),2.37-2.31(m,1H),1.48-1.45(m,2H),1.42-1.36(m,2H),1.08-1.02(m,2H),1.00-0.97(m,2H).

[0438] 19 F NMR(376MHz,DMSO-d6)δ-67.43,-128.79.

[0439] Example 22: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0440] Step A: 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine

[0441] To a solution of sodium hydroxide (2.5 g, 63.0 mmol) in water (100 mL) at room temperature under nitrogen was added 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile (8.6 g, 48.6 mmol). After dissolution, hydroxylamine sulfate (8.8 g, 53.6 mmol) was added and the pH was adjusted to 7-8. The temperature was raised to 45°C and stirred for 24 hours. Concentrated hydrochloric acid (6.5 mL, 78.1 mmol) was added to the reaction system, and the temperature was raised to 50°C and stirred for 2.5 hours. TLC and LC-MS monitoring of the reaction indicated the disappearance of the starting material. The reaction system was cooled to room temperature, and the pH was adjusted to 11 with 30% aqueous sodium hydroxide solution. The product 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 column chromatography (mobile phase: dichloromethane / methanol = 100 / 1) to give a white solid (1.6 g, yield 17%).

[0442] LC-MS (ESI), m / z: [M+1] + =193.

[0443] Step B: Phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate

[0444] To a solution of 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (1.0 g, 5.2 mmol) in anhydrous tetrahydrofuran (20 mL) at 0°C were added phenyl chloroformate (2.0 g, 12.8 mmol) and pyridine (1.2 g, 15.2 mmol). The mixture was naturally warmed to room temperature and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Ice water was slowly added to dilute and quench the reaction. 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 column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to give a white solid (1.1 g, yield 68%).

[0445] LC-MS (ESI), m / z: [M+1] + =313.

[0446] Step C: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0447] To a solution of phenyl (5- (1- (trifluoromethyl) cyclopropyl) isoxazol-3-yl) carbamate (1.3 g, 4.2 mmol) in anhydrous tetrahydrofuran (25 mL) was added 2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (987 mg, 4.2 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and N,N-dimethylaminopyridine (20 mg, 0.2 mmol) in succession at room temperature under nitrogen protection. Isopropylethylamine (1.1 g, 8.5 mmol) was heated to 60°C and stirred for 16 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Ice water was slowly added to dilute and quench the reaction, 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: petroleum ether / ethyl acetate = 5 / 1) to give a white solid (1.0 g, yield 52%).

[0448] LC-MS (ESI), m / z: [M+1] + =456.

[0449] Step D: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0450] To a solution of (1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (76 mg, 0.3 mmol) in 1,4-dioxane / water (8 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea (137 mg, 0.3 mmol), potassium carbonate (124 mg, 0.9 mmol) and 1,1'-bis(diphenylphosphine) at room temperature. Ferrocene] palladium dichloride (73 mg, 0.1 mmol), nitrogen replacement three times, raised to 90 ° C and stirred for 2 hours, TLC and LC-MS monitoring of the reaction, the starting material disappeared; the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, washed 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 (22 mg, yield 15%).

[0451] LC-MS (ESI), m / z: [M+1] + =502.

[0452] 1 H NMR (400MHz, DMSO-d6) δ9.18(s,1H),8.39(s,1H),8.18(t,J=12.0Hz,1H),7.72(d,J=4.0Hz,1H),7.44-7.36(m,2H),7.08(d,J=4.0 Hz,1H),6.90(s,1H),6.07(s,2H),2.37-2.30(m,1H),1.57-1.54(m,2H),1.51-1.48(m,2H),1.08-1.03(m,2H),1.01-0.97(m,2H).

[0453] 19 F NMR(376MHz,DMSO-d6)δ-67.63,-128.68.

[0454] Example 33: 1-(4-(4-amino-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0455] Step A: 7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0456] To a solution of 7-bromopyrrolo[1,2-f][1,2,4]triazin-4-amine (2.0 g, 9.4 mmol) in 1,4-dioxane (15 mL) and water (5 mL) at room temperature were added cyclopropylboronic acid (1.2 g, 14.0 mmol), tetrakistriphenylphosphine palladium (1.1 g, 1.0 mmol), and potassium carbonate (3.9 g, 28.1 mmol). The atmosphere was purged with nitrogen three times and stirred at 140°C overnight. TLC and LC-MS monitoring indicated the disappearance of the starting material. The reaction mixture was quenched with water and diluted, then 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 product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to afford a beige solid (700 mg, 42% yield).

[0457] LC-MS (ESI), m / z: [M+1] + =175.

[0458] Step B: 5-Bromo-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0459] To a solution of 7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (700 mg, 4.0 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added a solution of dibromohydantoin (574 mg, 2.0 mmol) in anhydrous tetrahydrofuran at -78°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. TLC and LC-MS monitoring revealed the disappearance of the starting material. The reaction mixture was quenched with water and diluted, then extracted three times with ethyl acetate. The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to afford a beige solid (330 mg, 32% yield).

[0460] LC-MS (ESI), m / z: [M+1] + =253.

[0461] Step C: 1-(4-(4-amino-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0462] To a mixed solution of 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (100 mg, 0.2 mmol) in 1,4-dioxane (6 mL) and water (2 mL) were added 5-bromo-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (47 mg, 0.2 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (15 mg, 0.02 mmol) and potassium carbonate (77 mg, 0.6 mmol) at room temperature. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 100°C for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction solution was quenched with water and diluted, 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 product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70%, 55 minutes; flow rate: 70 mL / min) to give a white solid product (12 mg, 10% yield).

[0463] LC-MS (ESI), m / z: [M+1] + =583.

[0464] 1 H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.88-8.71(m,1H),8.29-8.17(m,2H),8.01 (d,J=2.0Hz,1H),7.91(s,1H),7.65(d,J=8.5Hz,1H),7.60-7.49(m,1H),7.30(dd ,J=12.2,1.8Hz,1H),7.25-7.15(m,1H),6.41(s,1H),4.19-3.01(m,3H),2.48-2. 26(m,8H),2.21(s,3H),1.25-1.19(m,1H),1.06-0.95(m,2H),0.83-0.75(m,2H).

[0465] 19 F NMR(376MHz,DMSO-d6)δ-58.02,-128.93.

[0466] Example 45: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0467] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (100 mg 0.4 mmol) in 1,4-dioxane (6 mL) and water (2 mL) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-(((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (212 mg 0.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (65 mg 0.4 mmol) at room temperature. The mixture was stirred for 2 h at room temperature for 3 hours. The mixture was stirred for 2 h at room temperature for 3 hours. The mixture was stirred for 3 hours. The reaction mixture was quenched with water and diluted, 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 product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% over 55 minutes; flow rate: 70 mL / min) to afford the product as a white solid (70 mg, 70% yield).

[0468] LC-MS (ESI), m / z: [M+1] + =584.

[0469] 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.67 (d, J = 2.4Hz, 1H), 8.24 (t, J = 8.0Hz, 1H), 7.87 (d, J = 4.0Hz, 1H), 7. 72(d,J=4.0Hz,1H),7.52(dd,J=8.0,4.0Hz,1H),7.41(d,J=12.0Hz,1H),7.35(d,J=8.0Hz,1H),7.27(d,J=8 .0Hz,1H),7.07(d,J=4.0Hz,1H),6.08(s,2H),4.55-4.53(m,1H),2.37-2.30(m,2H),2.26-2.23(m,2H),2.1 7(s,3H),1.94-1.87(m,2H),1.72-1.64(m,2H),1.24(d,J=4.0Hz,1H),1.08-1.04(m,2H),1.00-0.98(m,2H).

[0470] 19 F NMR(376MHz,DMSO-d6)δ-60.61,-129.58.

[0471] Example 46: 1-(4-(4-amino-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0472] To a mixed solution of 5-bromo-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (47 mg, 0.2 mmol) in 1,4-dioxane (6 mL) and water (2 mL) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-(((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (100 mg, 0.2 mmol), 1,1-bis(diphenylphosphino)dichloroferric palladium (15 mg) and 4-nitropropane-1,2-dioxane-2,4-dioxane-3,4-dioxaborolan-2-yl)phenyl)-3-(4-(((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (100 mg, 0.2 mmol), 1,1-bis(diphenylphosphino)dichloroferric palladium (15 mg) and 4-nitropropane-1,2-dioxane-3,4-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)phenyl)urea (100 mg, 0.2 mmol) and 1,1-bis(diphenylphosphino)dichloroferric palladium (15 mg) at room temperature. The product was added with 1% ethyl acetate (0.5% hydroxyethyl ester, 0.1% hydroxypropyl methyl ester, 0.02 mmol) and potassium carbonate (77 mg, 0.6 mmol), the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C for 3 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was quenched with water and diluted, 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 product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% over 55 minutes; flow rate: 70 mL / min) to give the product as a white solid (15 mg, 13% yield).

[0473] LC-MS (ESI), m / z: [M+1] + =584.

[0474] 1 H NMR (400MHz, DMSO-d6) δ9.18 (s, 1H), 8.64 (d, J = 2.7Hz, 1H), 8.20 (t, J = 8.6Hz, 1H), 7.91 (s, 1H), 7.86(d,J=2.7Hz,1H),7.51(dd,J=9.0,2.7Hz,1H),7.35-7.24(m,2H),7.20(dd,J=8.5,2.0Hz,1H ),6.40(s,1H),4.61-4.48(m,1H),2.36-2.19(m,4H),2.17(s,3H),1.90(ddt,J=11.3,7.0,3.5H z,2H),1.69(tt,J=8.1,3.7Hz,2H),1.24(d,J=3.1Hz,1H),1.07-0.94(m,2H),0.88-0.73(m,2H).

[0475] 19F NMR(376MHz,DMSO-d6)δ-60.61,-129.21.

[0476] Example 47: 1-(4-(4-amino-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0477] To a mixed solution of 5-bromo-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (45 mg, 0.2 mmol) in 1,4-dioxane (6 mL) and water (2 mL) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (80 mg, 0.2 mmol), 1,1-bis(diphenylphosphino)diboraneferronichloridopalladium (14 mg, 0.02 mmol) and potassium carbonate (80 mg, 0.6 mmol) at room temperature. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 100°C for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction solution was quenched with water and diluted, 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 product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70%, 55 minutes; flow rate: 70 mL / min) to give a white solid product (8 mg, 8% yield).

[0478] LC-MS (ESI), m / z: [M+1] + =502.

[0479] 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.95(d,J=2.6Hz,1H),8.19(t,J=8.5Hz,1H),8.06(s,1H),7.39(d,J=1.8Hz,1H),7.27(dd,J=8.4 ,1.5Hz,1H),6.54(s,1H),6.20(s,1H),2.35-2.30(m,1H),1.51-1.43(m,2H),1.36-1.39(m,2H),1.10-1.01(m,2H),0.90-0.82(m,2H).

[0480] 19 F NMR(376MHz,DMSO-d6)δ-67.43,-74.20,-128.43.

[0481] Referring to the above examples and the synthesis methods of the intermediates, the examples in the table below were synthesized as follows:

[0482] Example 48: 1-(4-(4-amino-7-cyclopropylimidazo[5,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0483] To a solution of 7-cyclopropyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine (151 mg, 0.5 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (322 mg, 0.6 mmol), sodium carbonate (212 mg, 2.0 mmol) and 1,1'-bis(diphenylphosphino)dioxadiene at room temperature. [Fe] palladium dichloride (73 mg, 0.1 mmol), after nitrogen replacement three times, the temperature was raised to 100 ° C. and the reaction was stirred for 16 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction system was cooled to room temperature, diluted with saturated sodium chloride aqueous 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 minutes; flow rate: 70 mL / min) to give a white solid product (24 mg, yield 8%).

[0484] LC-MS (ESI), m / z: [M+1] + =584.

[0485] 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.75(d,J=4.0Hz,1H),8.28(t,J=12.0Hz,1H),8.01(d,J=4.0Hz,1H),7.92(s,1H),7.66 (d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.44-7.35(m,2H),3.56(s,2H),2.49-2.41(m,9H),2.26(s,3H),1.22-1.07(m,4H).

[0486] 19 F NMR(376MHz,DMSO-d6)δ-57.97,-129.25.

[0487] Example 49: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0488] Step A: N,N-dimethyl-1-(4-nitro-2-(trifluoromethyl)benzyl)pyrrolidin-3-amine

[0489] To a solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (2.0 g, 7.0 mmol) in N,N-dimethylformamide (20 mL) were added N,N-dimethylpyrrolidin-3-amine (880 mg, 7.7 mmol) and potassium carbonate (2.9 g, 21.0 mmol) at room temperature and stirred at room temperature for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The mixture was diluted with saturated aqueous 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 to give a crude yellow oily liquid (2.2 g), which was used directly in the next step without purification.

[0490] LC-MS (ESI), m / z: [M+1] + =318.

[0491] Step B: 1-(4-amino-2-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidin-3-amine

[0492] To a mixed solution of N,N-dimethyl-1-(4-nitro-2-(trifluoromethyl)benzyl)pyrrolidin-3-amine (2.2 g, 6.9 mmol) in ethanol / water (21 mL, 2 / 1) were added zinc powder (2.2 g, 34.5 mmol) and ammonium chloride (1.8 g, 34.5 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h, then heated to 60°C and stirred for 3 h. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction mixture was cooled to room temperature and filtered under reduced pressure. The filter cake was washed with ethanol (15 mL). The mother liquors were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to give the yellow solid product (1.3 g, yield 66%).

[0493] LC-MS (ESI), m / z: [M+1] + =288.

[0494] Step C: (4-(3-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenyl)boronic acid

[0495] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (996 mg, 4.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added triphosgene (504 mg, 1.7 mmol) at room temperature. The temperature was raised to 60°C and stirred for 1 hour. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with tetrahydrofuran (10 mL), and placed in a constant pressure dropping funnel. To a solution of 1-(4-amino-2-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidin-3-amine (1.2 g, 4.2 mmol) in anhydrous tetrahydrofuran (10 mL) were added triethylamine (1.3 g, 12.8 mmol) and a freshly prepared tetrahydrofuran solution of isocyanate. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°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 concentrated under reduced pressure, and the crude product was purified by preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 60 mL / min) to give an off-white solid (1.0 g, 51% yield).

[0496] LC-MS (ESI), m / z: [M+1] + =469.

[0497] Step D: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0498] To a mixed solution of (1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) and (4-(3-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenyl)boronic acid (281 mg, 0.6 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) were added potassium carbonate (166 mg, 1.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol), the atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C, and the reaction was stirred for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction system was cooled to room temperature, diluted with saturated sodium chloride aqueous solution, 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% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid product (93 mg, yield 39%).

[0499] LC-MS (ESI), m / z: [M+1] + =597.

[0500] 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.75(d,J=2.7Hz,1H),8.25(t,J=8.5Hz,1H),8.00(d,J=2.2Hz ,1H),7.72(d,J=5.0Hz,1H),7.64(d,J=8.5Hz,1H),7.56(dd,J=8.5,2.3Hz,1H),7.45-7.34(m,2H), 7.07(d,J=4.9Hz,1H),6.08(s,2H),3.67-3.64(m,2H),2.79(t,J=7.4Hz,1H),2.69-2.55(m,2H),2. 49(s,1H),2.39-2.30(m,2H),2.12(s,6H),1.93-1.83(m,1H),1.69-1.58(m,1H),1.11-0.94(m,4H).

[0501] 19 F NMR(376MHz,DMSO-d6)δ-58.13,-129.45.

[0502] Example 50: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0503] Step A: 1-(Bromomethyl)-4-nitro-2-(trifluoromethyl)benzene

[0504] To a solution of 1-methyl-4-nitro-2-(trifluoromethyl)benzene (24.0 g, 117 mmol) in 1,2-dichloroethane (240 mL) were added N-bromosuccinimide (20.8 g, 117 mmol) and azobisisobutyronitrile (2.0 g, 12.2 mmol) at room temperature. The atmosphere was protected by nitrogen and replaced three times. The temperature was raised to 80°C and stirred overnight. 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: petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to give the product as a light yellow oily liquid (21.0 g, yield 63%).

[0505] LC-MS (ESI), m / z: [M+1] + =284.

[0506] 1 H NMR (400MHz, CDCl3) δ8.53(d,J=4.0Hz,1H),8.41(dd,J=8.0,4.0Hz,1H),7.83(d,J=8.0Hz,1H),4.66(s,2H).

[0507] Step B: N,N-dimethyl-1-(4-nitro-2-(trifluoromethyl)benzyl)piperidin-4-amine

[0508] To a solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (3.5 g, 12.3 mmol) in dichloromethane (40 mL) were added N,N-dimethylpiperidin-4-amine (1.9 g, 14.8 mmol) and potassium carbonate (3.4 g, 24.6 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was quenched with water and diluted, and extracted three times with dichloromethane. 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 crude yellow oily liquid product (4.0 g), which was used directly in the next step without purification.

[0509] LC-MS (ESI), m / z: [M+1] + =332.

[0510] Step C: 1-(4-amino-2-(trifluoromethyl)benzyl)-N,N-dimethylpiperidin-4-amine

[0511] To a mixed solution of N,N-dimethyl-1-(4-nitro-2-(trifluoromethyl)benzyl)piperidin-4-amine (4.0 g, 12.1 mmol) in ethanol / water (30 mL, 2 / 1) were added zinc powder (4.0 g, 60.4 mmol) and ammonium chloride (3.2 g, 60.4 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour, then heated to 60°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction mixture was cooled to room temperature and filtered under reduced pressure. The filter cake was washed with ethanol (15 mL). The mother liquors were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to give a yellow solid product (2.9 g, yield 80%).

[0512] LC-MS (ESI), m / z: [M+1] + =302.

[0513] Step D: (4-(3-(4-(dimethylamino)piperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenyl)boronic acid

[0514] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (800 mg, 3.3 mmol) in anhydrous tetrahydrofuran (10 mL) was added triphosgene (400 mg, 1.3 mmol) at room temperature, and the mixture was heated to 60°C and stirred for 1 hour; The reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, diluted with anhydrous tetrahydrofuran (20 mL), and placed in a constant pressure dropping funnel; triethylamine (1.0 g, 10.0 mmol) was added to a solution of 1-(4-amino-2-(trifluoromethyl)benzyl)-N,N-dimethylpiperidin-4-amine (1.0 g, 3.3 mmol) in anhydrous tetrahydrofuran (20 mL), and the atmosphere was replaced with nitrogen three times. The freshly prepared isocyanate tetrahydrofuran solution was slowly added dropwise to the constant pressure dropping funnel. After the addition was completed, the temperature was raised to 60°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction solution was directly concentrated under reduced pressure to dryness to obtain a crude product, which was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 to 1 / 1) to obtain a yellow solid product (1.3 g, yield 82%).

[0515] LC-MS (ESI), m / z: [M+1] + =483.

[0516] Step E: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0517] To a mixed solution of (1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) and (4-(3-(4-(dimethylamino)piperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenyl)boronic acid (286 mg, 0.6 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) were added potassium carbonate (166 mg, 1.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) at room temperature. l), replaced with nitrogen three times, heated to 100 ° C and stirred for 3 hours, the reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction system was cooled to room temperature, diluted with saturated sodium chloride aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, washed 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% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid product (120 mg, yield 49%).

[0518] LC-MS (ESI), m / z: [M+1] + =611.

[0519] 1 H NMR (400MHz, DMSO-d6) δ9.41 (s, 1H), 8.74 (d, J = 2.7Hz, 1H), 8.24 (t, J = 8.5Hz, 1H), 8.01 (d, J = 2.3Hz, 1H), 7.71(d,J=5.0Hz,1H),7.66(d,J=8.5Hz,1H),7.54(dd,J=8.5,2.3Hz,1H),7.44-7.32(m,2H),7.06(d,J=5. 0Hz,1H),6.07(s,2H),3.51(s,2H),2.80(d,J=10.9Hz,2H),2.33-2.24(m,1H),2.15(s,6H),2.07-2.02(m ,1H),2.00-1.91(m,2H),1.71(d,J=12.2Hz,2H),1.42-1.35(m,2H),1.07-1.04(m,2H),1.02-0.94(m,2H).

[0520] 19 F NMR(376MHz,DMSO-d6)δ-58.07,-129.46.

[0521] Example 51: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0522] Step A: tert-Butyl 3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

[0523] To a solution of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (2.0 g, 9.6 mmol) in N,N-dimethylformamide (20 mL) were added tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (2.4 g, 10.6 mmol) and anhydrous potassium carbonate (2.0 g, 14.3 mmol) at room temperature. The atmosphere was protected and replaced with nitrogen three times. The temperature was raised to 100°C and stirred overnight. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction system 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 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: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain the product as a yellow oily liquid (2.6 g, yield 66%).

[0524] LC-MS (ESI), m / z: [M+23] + =431.

[0525] Step B: 3-Fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine

[0526] To a solution of tert-butyl 3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (2.6 g, 6.4 mmol) in dichloromethane (30 mL) was slowly added trifluoroacetic acid (30 mL) at 0°C. The ice bath was removed, the mixture was warmed to room temperature and stirred for 1 hour. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid and dichloromethane, diluted with water, and adjusted to weak alkalinity by dropwise addition of saturated aqueous sodium carbonate solution. The mixture was 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 to give a crude yellow solid product (1.8 g), which was used directly in the next step without purification.

[0527] LC-MS (ESI), m / z: [M+1] +=309.

[0528] Step C: 3-Fluoro-1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine

[0529] To a solution of 3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (1.6 g, 5.2 mmol) in methanol (30 mL) were added formalin (2.6 g, 26.0 mmol) and sodium triacetoxyborohydride (1.7 g, 7.8 mmol) at 0°C. The ice bath was removed, the mixture was warmed to room temperature and stirred overnight. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was concentrated under reduced pressure to remove methanol, 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 to give a crude yellow liquid product (1.6 g), which was used directly in the next step without purification.

[0530] LC-MS (ESI), m / z: [M+1] + =323.

[0531] Step D: 4-((3-Fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline

[0532] To a mixed solution of 3-fluoro-1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (1.6 g, 5.0 mmol) in ethanol / water (15 mL, 2 / 1) at room temperature, zinc powder (1.6 g, 24.8 mmol) and ammonium chloride (1.3 g, 24.7 mmol) were slowly added in batches. The temperature was raised to 60°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was cooled to room temperature, concentrated under reduced pressure, filtered, washed with ethanol (15 mL), and the mother liquors were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to obtain a yellow solid product (1.3 g, yield 89%).

[0533] LC-MS (ESI), m / z: [M+1] + =293.

[0534] Step E: 1-(4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0535] At room temperature, triphosgene (534 mg, 1.8 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.4 mmol) in anhydrous tetrahydrofuran (10 mL), and the mixture was heated to 60 ° C and stirred for 1 hour; the reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, diluted with anhydrous tetrahydrofuran (20 mL), and placed in a constant pressure dropping funnel; 4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline (1.3 g, 4.4 mmol) was added to the mixture. l) in anhydrous tetrahydrofuran (20 mL) was added triethylamine (1.4 g, 13.4 mmol), and the atmosphere was replaced with nitrogen three times. The freshly prepared tetrahydrofuran solution of isocyanate was slowly added dropwise using a constant pressure dropping funnel. After the addition was completed, the temperature was raised to 60°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was directly concentrated under reduced pressure to dryness to obtain a crude product, which was purified by preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 50%-100% B, 55 minutes; flow rate: 70 mL / min) to obtain a white solid (1.2 g, yield 49%).

[0536] LC-MS (ESI), m / z: [M+1] + =556.

[0537] Step F: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

[0538] To a mixed solution of (1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) and 1-(4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (265 mg, 0.5 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) were added potassium carbonate (166 mg, 1.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]diol at room temperature. Palladium chloride (73 mg, 0.1 mmol) was replaced with nitrogen three times, and the temperature was raised to 100°C and stirred for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction system was cooled to room temperature, diluted with saturated sodium chloride aqueous 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% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid product (110 mg, yield 46%).

[0539] LC-MS (ESI), m / z: [M+1] + =602.

[0540] 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.66 (d, J = 2.7Hz, 1H), 8.24 (t, J = 8.5Hz, 1H), 7.88 (d, J =2.7Hz,1H),7.72(d,J=5.0Hz,1H),7.53(dd,J=9.0,2.7Hz,1H),7.47-7.28(m,3H),7.07(d,J =5.0Hz,1H),6.07(s,2H),5.03-4.66(m,2H),2.73(s,1H),2.59(d,J=10.4Hz,1H),2.45(s,1 H),2.38-2.29(m,2H),2.22(s,3H),1.97-1.82(m,1H),1.80-1.75(m,1H),1.14-0.92(m,4H).

[0541] 19 F NMR(376MHz,DMSO-d6)δ-60.67,-129.57.

[0542] Example 52: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0543] Step A: 1-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperazine

[0544] To a solution of 2-(piperazin-1-yl)ethane-1-ol (2.0 g, 15.4 mmol), pyridine (1.8 g, 23.1 mmol) and 4-(dimethylamino)pyridine (183 mg, 1.5 mmol) in dichloromethane (20 mL) was slowly added tert-butylchlorodiphenylsilane (5.1 g, 18.5 mmol) at 0°C under nitrogen. After the addition, the reaction was allowed to warm to room temperature and stirred overnight at room temperature. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. 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. The residue was purified by preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 30%-100% B, 55 min; flow rate: 60 mL / min) to give the product as a light yellow oily liquid (3.5 g, yield 62%).

[0545] LC-MS (ESI), m / z: [M+1] + =369.

[0546] Step B: 1-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine

[0547] To a solution of 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperazine (3.3 g, 8.9 mmol) and 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (3.3 g, 11.6 mmol) in dichloromethane (30 mL) was added potassium carbonate (2.5 g, 18.1 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was quenched with water and diluted, and extracted three times with dichloromethane. 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 the crude product (4.3 g, 85% yield) as a yellow oily liquid, which was used directly in the next reaction without purification.

[0548] LC-MS (ESI), m / z: [M+1] + =572.

[0549] Step C: 4-((4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)aniline

[0550] To a mixed solution of 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (4.4 g, 7.7 mmol) in ethanol / water (45 mL, 2 / 1) were slowly added zinc powder (2.5 g, 38.5 mmol) and ammonium chloride (2.0 g, 38.5 mmol) at room temperature. The reaction was allowed to proceed at room temperature for 1 hour, then heated to 60°C for 2 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction mixture was cooled to room temperature and filtered under reduced pressure. The filter cake was washed with ethanol (15 mL). The mother liquors were combined and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 20 / 1) to give a light yellow solid product (2.5 g, yield 60%).

[0551] LC-MS (ESI), m / z: [M+1] + =542.

[0552] Step D: 1-(4-((4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0553] At room temperature, triphosgene (445 mg, 1.5 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.2 mmol) in anhydrous tetrahydrofuran (20 mL), and the mixture was heated to 60 ° C and stirred for 1 hour; the reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, diluted with anhydrous tetrahydrofuran (20 mL), and placed in a constant pressure dropping funnel; 4-((4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (2.3 g) was added to the mixture. , 4.2mmol) in anhydrous tetrahydrofuran (20mL) was added triethylamine (2.5g, 24.7mmol), the atmosphere was replaced with nitrogen three times, and the freshly prepared isocyanate tetrahydrofuran solution was slowly added dropwise through a constant pressure dropping funnel. After the addition was completed, the temperature was raised to 60°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was directly concentrated under reduced pressure to dryness to obtain a crude product, which was purified by preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 30%-100% B, 55 minutes; flow rate: 60mL / min) to obtain a pale white solid product (2.6g, yield 77%).

[0554] LC-MS (ESI), m / z: [M+1] + =805.

[0555] Step E: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0556] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) and 1-(4-((4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (402 mg, 0.5 mmol) in 1,4-dioxane (10 mL) was added anhydrous potassium carbonate (166 mg, 1.2 mL) at room temperature. mol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) and water (2 mL), the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and the reaction was carried out for 3 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, 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 crude product, which was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain a brown solid product (330 mg, yield 97%).

[0557] LC-MS (ESI), m / z: [M+1] + =851.

[0558] Step F: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0559] To a solution of 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (255 mg 0.3 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 mL, 1 M) at 0°C. The mixture was slowly warmed to room temperature and stirred 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 preparative chromatography (mobile phase A: 0.1% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) to give the product as a white solid (100 mg, 54% yield).

[0560] LC-MS (ESI), m / z: [M+1] + =613.

[0561] 1 H NMR (400MHz, DMSO-d6) δ9.41 (s, 1H), 8.74 (d, J = 2.7Hz, 1H), 8.24 (t, J = 8.0Hz, 1H), 8.0 0(d,J=4.0Hz,1H),7.71(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.54(dd,J=8.0,4.0H z,1H),7.45-7.32(m,2H),7.06(d,J=4.0Hz,1H),6.06(s,2H),4.37(t,J=5.4Hz,1H),3 .53(s,2H),3.47(q,J=6.1Hz,2H),2.51(s,2H),2.49-2.26(m,9H),1.11-0.93(m,4H).

[0562] 19 F NMR(376MHz,DMSO-d6)δ-58.03,-129.45.

[0563] Example 53: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0564] Step A: 1-(2-fluoroethyl)-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine

[0565] To a solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (2.0 g, 7.0 mmol) in N,N-dimethylformamide (10 mL) were added 1-(2-fluoroethyl)-piperazine hydrochloride (1.4 g, 8.4 mmol) and potassium carbonate (2.9 g, 21.0 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC and LC-MS until 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 to give a crude yellow oily liquid (2.2 g, 94% yield), which was used directly in the next step.

[0566] LC-MS (ESI), m / z: [M+1] + =336.

[0567] Step B: 4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)aniline

[0568] To a mixed solution of 1-(2-fluoroethyl)-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (2.2 g, 6.6 mmol) in ethanol / water (21 mL, 2 / 1) were added zinc powder (2.1 g, 33.0 mmol) and ammonium chloride (1.8 g, 33.0 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The reaction mixture was cooled to room temperature and filtered under reduced pressure. The filter cake was washed with ethanol (15 mL). The mother liquor was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to obtain a light yellow solid product (1.3 g, yield 65%).

[0569] LC-MS (ESI), m / z: [M+1] + =306.

[0570] Step C: (3-Fluoro-4-(3-(4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)boronic acid

[0571] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (925 mg, 3.9 mmol) in anhydrous tetrahydrofuran (10 mL) was added triphosgene (445 mg, 1.5 mmol) at room temperature. 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 solution was cooled to room temperature, concentrated under reduced pressure, diluted with tetrahydrofuran (10 mL), and placed in a constant pressure dropping funnel. To a solution of 4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (1.2 g, 3.9 mmol) in anhydrous tetrahydrofuran (10 mL) were added triethylamine (1.2 g, 11.7 mmol) and a freshly prepared tetrahydrofuran solution of isocyanate. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°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 concentrated under reduced pressure, and the crude product was purified by preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 60 mL / min) to give a pale white solid (1.1 g, 58% yield).

[0572] LC-MS (ESI), m / z: [M+1] + =487.

[0573] Step D: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0574] At room temperature, 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) and (3-fluoro-4-(3-(4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)boronic acid (292 mg, 0.6 To a solution of 1,4-dioxane (2,4-dioxane, 1,2-dioxane, 1,1'-bis(diphenylphosphino)ferrocene) in 1,4-dioxane / water (10 mL, 4 / 1) were added anhydrous potassium carbonate (166 mg, 1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol). The atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and stirred for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The product was concentrated under reduced pressure, and the residue was purified by preparative chromatography (mobile phase A: 0.1% ammonium bicarbonate: mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid product (135 mg, 55% yield).

[0575] LC-MS (ESI), m / z: [M+1] + =615.

[0576] 1 H NMR (400MHz, DMSO-d6) δ9.41(d,J=4.6Hz,1H),8.73(d,J=2.7Hz,1H),8.24(t,J=8.5Hz,1H ),8.01(d,J=2.3Hz,1H),7.71(d,J=5.0Hz,1H),7.65(d,J=8.5Hz,1H),7.55(dd,J=8.5,2. 3Hz,1H),7.44-7.34(m,2H),7.06(d,J=4.9Hz,1H),6.09(s,2H),4.61-4.47(m,2H),3.54( s,2H),2.66(t,J=4.9Hz,1H),2.59(t,J=4.9Hz,1H),2.53-2.28(m,9H),1.09-0.95(m,4H).

[0577] 19 F NMR(376MHz,DMSO-d6)δ-58.04,-129.47,-217.21.

[0578] Example 54: 1-(4-(8-amino-3-(2-hydroxypropan-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0579] Step A: N-((3-chloropyrazin-2-yl)methyl)-2-hydroxy-2-methylpropionamide

[0580] To a solution of 2-hydroxy-2-methylpropionic acid (1.0 g, 9.6 mmol) and (3-chloropyrazin-2-yl)methanamine hydrochloride (2.1 g, 11.5 mmol) in anhydrous tetrahydrofuran (60 mL) were added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.7 g, 12.5 mmol) and N,N-diisopropylethylamine (5.0 g, 38.4 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 4 hours. 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 30 / 1) to give the product as a light yellow solid (1.6 g, yield 73%).

[0581] LC-MS (ESI), m / z: [M+1] +=230.

[0582] Step B: 8-chloro-3-(prop-1-en-2-yl)imidazo[1,5-a]pyrazine

[0583] To a solution of N-((3-chloropyrazin-2-yl)methyl)-2-hydroxy-2-methylpropionamide (2.5 g 10.9 mmol) in anhydrous 1,4-dioxane (20 mL) was added phosphorus oxychloride (2.5 g, 16.3 mmol) at room temperature, the temperature was raised to 80°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was directly concentrated under reduced pressure to remove phosphorus oxychloride, quenched and diluted with ice water, and adjusted to weak alkalinity with saturated aqueous sodium carbonate solution. The mixture was 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 column chromatography (mobile phase: petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give an off-white solid product (220 mg, yield 10%).

[0584] LC-MS (ESI), m / z: [M+1] + =194.

[0585] Step C: 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)propan-2-ol

[0586] To a solution of 8-chloro-3-(prop-1-en-2-yl)imidazo[1,5-a]pyrazine (200 mg, 1.0 mmol) in isopropanol / dichloromethane (8 mL, 3 / 1) at 0°C were added tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese (38 mg, 0.06 mmol) and phenylsilane (224 mg, 2.1 mmol). The atmosphere was purged with oxygen three times and stirred at room temperature for 2 hours. The reaction was monitored by TLC and LC-MS to reveal 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: petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give a white solid product (70 mg, yield 33%).

[0587] LC-MS (ESI), m / z: [M+1] + =212.

[0588] Step D: 2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)propan-2-ol

[0589] To a solution of 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)propan-2-ol (70 mg, 0.3 mmol) in N,N-dimethylformamide (6 mL) was added N-bromosuccinimide (71 mg 0.4 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The mixture 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 15 / 1) to give the product as a white solid (30 mg, yield 34%).

[0590] LC-MS (ESI), m / z: [M+1] + =290.

[0591] Step E: 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)propan-2-ol

[0592] To a solution of 2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)propan-2-ol (30 mg 0.1 mmol) in isopropanol (5 mL) was added aqueous ammonia (7 mL, 50.0 mmol, 25%) at room temperature. The temperature was raised to 95°C and stirred overnight. 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 = 50 / 1 to 10 / 1) to give the product as a white solid (10 mg, yield 37%).

[0593] LC-MS (ESI), m / z: [M+1] + =271.

[0594] Step F: 1-(4-(8-amino-3-(2-hydroxypropan-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0595] To a solution of 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)propan-2-ol (10 mg, 0.04 mmol) and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (20 mg, 0.04 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) was added anhydrous potassium carbonate at room temperature. (17 mg, 0.12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7 mg, 0.01 mmol), the atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C and stirred for 3 hours, the reaction was monitored by TLC and LC-MS, and the starting material disappeared; the product was concentrated under reduced pressure, and 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 product (7 mg, yield 29%).

[0596] LC-MS (ESI), m / z: [M+1] + =601.

[0597] 1 H NMR(400MHz, DMSO-d6)δ9.42(s,1H),8.76(d,J=4.0Hz,1H),8.27(t,J=8.0Hz,1H),8.02-7.97(m,2H),7.66(d,J=8.0Hz,1H),7.56(dd,J=8.0 ,4.0Hz,1H),7.45-7.37(m,2H),7.02(d,J=4.0Hz,1H),6.05(s,2H),5.67(s,1H),3.54(s,2H),2.39-2.34(m,8H),2.16(s,3H),1.63(s,6H).

[0598] 19 F NMR(376MHz,DMSO-d6)δ-58.03,-129.42.

[0599] Example 55: 1-(4-(8-amino-3-(2-methoxyethyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0600] Step A: N-((3-chloropyrazin-2-yl)methyl)-3-methoxypropionamide

[0601] To a solution of 3-methoxypropionic acid (2.0 g, 19.2 mmol) and (3-chloropyrazin-2-yl)methylamine hydrochloride (4.5 g, 25.0 mmol) in anhydrous tetrahydrofuran (80 mL) were added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.5 g, 25.0 mmol) and N,N-diisopropylethylamine (7.4 g, 57.6 mmol) in sequence at 0°C. The mixture was warmed to room temperature and stirred for 4 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. 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 80 / 1) to give the product as a light yellow oil (3.0 g, yield 68%).

[0602] LC-MS (ESI), m / z: [M+1] + =230.

[0603] Step B: 8-chloro-3-(2-methoxyethyl)imidazo[1,5-a]pyrazine

[0604] To a solution of N-((3-chloropyrazin-2-yl)methyl)-3-methoxypropionamide (6.0 g, 26.1 mmol) in 1,4-dioxane (30 mL) was added phosphorus oxychloride (6.0 g, 39.2 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and stirred for 2 hours, and the reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The product was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution. The organic phase was separated, 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 = 50 / 1 to 1 / 1) to give a light yellow solid product (4.0 g, yield 72%).

[0605] LC-MS (ESI), m / z: [M+1] + =212.

[0606] Step C: 1-Bromo-8-chloro-3-(2-methoxyethyl)imidazo[1,5-a]pyrazine

[0607] To a solution of 8-chloro-3-(2-methoxyethyl)imidazo[1,5-a]pyrazine (2.50 g, 11.8 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N-bromosuccinimide (2.5 g, 14.2 mmol) at 0°C. The atmosphere was replaced with nitrogen three times, the mixture was warmed to room temperature and stirred for 2 hours. 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 60 / 1) to give a light yellow solid product (2.0 g, yield 58%).

[0608] LC-MS (ESI), m / z: [M+1] + =290.

[0609] Step D: 1-Bromo-3-(2-methoxyethyl)imidazo[1,5-a]pyrazin-8-amine

[0610] To a solution of 1-bromo-8-chloro-3-(2-methoxyethyl)imidazo[1,5-a]pyrazine (407 mg, 1.4 mmol) in isopropanol (15 mL) was added aqueous ammonia (12 mL, 68.8 mmol, 25% mw) at room temperature, and the temperature was raised to 95°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The product was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to give the product as a pale yellow solid (300 mg, yield 79%).

[0611] LC-MS (ESI), m / z: [M+1] + =271.

[0612] Step E: 1-(4-(8-amino-3-(2-methoxyethyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0613] To a mixed solution of 1-bromo-3-(2-methoxyethyl)imidazo[1,5-a]pyrazin-8-amine (163 mg, 0.6 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (376 mg, 0.7 mmol), potassium carbonate (332 mg, 2.4 mmol) and 1,1'-bis(difluoromethane)-1-ol at room temperature. The mixture was added with [(4-(phenylphosphine)ferrocene)]palladium dichloride (73 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100° C. and stirred for 3 hours. 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 preparative chromatography (mobile phase A: 0.1% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid product (40 mg, yield 11%).

[0614] LC-MS (ESI), m / z: [M+1] + =601.

[0615] 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 8.76 (d, J = 2.8Hz 1H),8.27(t,J=8.0Hz,1H),8.02(d,J=2.4Hz,1H),7.66(d,J=8.4Hz,1H),7.60(d,J=4.8Hz,1H),7.55(dd,J=8.4,2.0Hz,1H),7.45(dd,J=12.4, 2.0Hz,1H),7.40(dd,J=8.4,2.0Hz,1H),7.04(d,J=5.2Hz,1H),6.10(s,2H),3.76(t,J=6.4Hz,2H),3.54(s,2H),3.26(s,3H),3.21(t,J=6.8Hz, 2H),2.37-2.33(m,8H),2.16(s,3H).

[0616] 19 F NMR(376MHz,DMSO-d6)δ-58.03,-129.42.

[0617] Example 56: 1-(4-(8-amino-3-(3-methoxypropyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

[0618] Step A: N-((3-chloropyrazin-2-yl)methyl)-4-methoxybutyramide

[0619] To a solution of 4-methoxybutyric acid (250 mg, 2.1 mmol) and (3-chloropyrazin-2-yl)methylamine hydrochloride (486 mg, 2.7 mmol) in anhydrous tetrahydrofuran (20 mL) were added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.0 g, 2.7 mmol) and N,N-diisopropylethylamine (820 mg, 6.3 mmol) in sequence at 0°C. The mixture was warmed to room temperature and stirred for 4 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. 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 80 / 1) to give the product as a light yellow oil (400 mg, yield 78%).

[0620] LC-MS (ESI), m / z: [M+1] + =244.

[0621] Step B: 8-chloro-3-(3-methoxypropyl)imidazo[1,5-a]pyrazine

[0622] To a solution of N-((3-chloropyrazin-2-yl)methyl)-4-methoxybutyramide (439 mg, 1.8 mmol) in 1,4-dioxane (10 mL) was added phosphorus oxychloride (414 mg, 2.7 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The product was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution. The organic phase was separated, 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 = 50 / 1 to 2 / 1) to give a light yellow solid product (360 mg, yield 89%).

[0623] LC-MS (ESI), m / z: [M+1] + =226.

[0624] Step C: 1-Bromo-8-chloro-3-(3-methoxypropyl)imidazo[1,5-a]pyrazine

[0625] To a solution of 8-chloro-3-(3-methoxypropyl)imidazo[1,5-a]pyrazine (1.2 g, 5.3 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N-bromosuccinimide (1.1 g, 6.4 mmol) at 0°C. The atmosphere was replaced with nitrogen three times, the temperature was raised to room temperature and stirred for 2 hours. 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 50 / 1) to give a light yellow solid product (1.0 g, yield 62%).

[0626] LC-MS (ESI), m / z: [M+1] + =304.

[0627] Step D: 1-Bromo-3-(3-methoxypropyl)imidazo[1,5-a]pyrazin-8-amine

[0628] To a solution of 1-bromo-8-chloro-3-(3-methoxypropyl)imidazo[1,5-a]pyrazine (396 mg, 1.3 mmol) in isopropanol (10 mL) was added aqueous ammonia (10 mL, 68.8 mmol, 25% mw) at room temperature. The temperature was raised to 95°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, indicating the disappearance of the starting material. The product was concentrated under reduced pressure and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to give the product as a pale yellow solid (350 mg, 94% yield).

[0629] LC-MS (ESI), m / z: [M+1] + =285.

[0630] Step E: 1-(4-(8-amino-3-(3-methoxypropyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-ylmethyl)methyl)-3-(trifluoromethyl)phenyl)urea

[0631] To a mixed solution of 1-bromo-3-(3-methoxypropyl)imidazo[1,5-a]pyrazin-8-amine (143 mg, 0.5 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (322 mg, 0.6 mmol), potassium carbonate (207 mg, 400 mL), and ...trifluoromethyl)phenyl)urea (322 mg, 0.6 mmol), potassium carbonate (207 mg, 400 mL), and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3 mg, 1.5 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol), the atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C and stirred for 3 hours. 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 preparative chromatography (mobile phase A: 0.1% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid product (37 mg, yield 12%).

[0632] LC-MS (ESI), m / z: [M+1] + =615.

[0633] 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 8.76 (d, J = 2.8Hz, 1H), 8.26 (t, J = 8.0Hz, 1H) ,8.02(d,J=2.4Hz,1H),7.66(d,J=8.0Hz,1H),7.57-7.52(m,2H),7.47-7.39(m,2 H),7.05(d,J=4.8Hz,1H),6.10(s,2H),3.54(s,2H),3.41(t,J=6.0Hz,2H),3.25( s,3H),2.97(t,J=7.6Hz,2H),2.38-2.32(m,8H),2.16(s,3H),2.02-1.95(m,2H).

[0634] 19 F NMR(376MHz,DMSO-d6)δ-58.03,-129.40.

[0635] Example 57: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea

[0636] Step A: 1-(3-(tert-Butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0637] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (190 mg, 0.8 mmol) in anhydrous tetrahydrofuran (10 mL) was added triphosgene (89 mg, 0.3 mmol) at room temperature. 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 solution was cooled to room temperature, concentrated under reduced pressure, diluted with tetrahydrofuran (10 mL), and placed in a constant pressure dropping funnel. To a solution of 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine (172 mg, 0.8 mmol) in anhydrous tetrahydrofuran (10 mL) were added triethylamine (324 mg, 3.2 mmol) and a freshly prepared tetrahydrofuran solution of isocyanate. The atmosphere was replaced with nitrogen three times, the temperature was raised to 60°C, and the stirring was continued for 2 hours. 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 15 / 1) to give the product as a reddish-brown solid (120 mg, yield 31%).

[0638] LC-MS (ESI), m / z: [M+1] + =479.

[0639] Step B: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea

[0640] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (405 mg, 1.6 mmol) and 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (861 mg, 1.8 mmol) in 1,4-dioxane / water (20 mL, 4 / 1) was added anhydrous potassium carbonate (885 mg, 6.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] at room temperature. ] Palladium dichloride (145 mg, 0.2 mmol), nitrogen replacement three times, heated to 100 ° C and stirred for 3 hours, TLC and LC-MS monitored the reaction, the starting material disappeared; the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, washed 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 product (235 mg, yield 28%).

[0641] LC-MS (ESI), m / z: [M+1] + =525.

[0642] 1 H NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.92(s,1H),8.23(t,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.57-7.54(m,4H),7.46-7.42(m,1H),7. 40-7.33(m,2H),7.06(d,J=8.0Hz,1H),6.43(s,1H),6.06(s,2H),2.36-2.29(m,1H),1.29(s,9H),1.08-1.03(m,2H),1.00-0.96(m,2H).

[0643] 19 F NMR(376MHz,DMSO-d6)δ-129.24

[0644] Example 58: 1-(4-(4-amino-7-cyclopropylimidazo[5,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea

[0645] To a solution of 5-bromo-7-cyclopropylimidazo[5,1-f][1,2,4]triazin-4-amine (179 mg, 0.7 mmol) and 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (383 mg, 0.8 mmol) in 1,4-dioxane / water (20 mL, 4 / 1) was added anhydrous potassium carbonate (290 mg, 2.1 mmol) and [1,1'-bis(diphenylphosphine)]-1-[ ... )ferrocene]palladium dichloride (73 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100°C and stirred for 3 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, 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 product (44 mg, yield 12%).

[0646] LC-MS (ESI), m / z: [M+1] + =526.

[0647] 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.91(s,1H),8.25(t,J=8.0Hz,1H),7.91(s,1H),7.58-7.52(m,4H) ,7.46-7.42(m,1H),7.40-7.34(m,2H),6.43(s,1H),2.49-2.44(m,1H),1.30(s,9H),1.09-1.06(m,4H).

[0648] 19 F NMR(376MHz,DMSO-d6)δ-129.08.

[0649] Example 59: 1-(4-(4-amino-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea

[0650] To a solution of 5-bromo-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (202 mg, 0.8 mmol) and 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (431 mg, 0.9 mmol) in 1,4-dioxane / water (20 mL, 4 / 1) was added anhydrous potassium carbonate (332 mg, 2.4 mmol) and [1,1'-bis(diphenylphosphine)]-1-[ ... )ferrocene]palladium dichloride (73 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100°C and stirred for 3 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, 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 product (80 mg, yield 19%).

[0651] LC-MS (ESI), m / z: [M+1] + =525.

[0652] 1 H NMR (400MHz, DMSO-d6) δ9.02(s,1H),8.88(s,1H),8.20(t,J=8.0Hz,1H),7.91(s,1H),7.58-7.52(m,4H),7.46-7.42(m,1H),7.27(dd,J=12. 0,4.0Hz,1H),7.19(dd,J=8.0,4.0Hz,1H),6.42(s,1H),6.39(s,1H),2.32-2.26(m,1H),1.29(s,9H),1.03-0.98(m,2H),0.81-0.77(m,2H).

[0653] 19 F NMR(376MHz,DMSO-d6)δ-128.91.

[0654] Example 60: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)urea

[0655] Step A: 3-(tert-Butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-amine

[0656] 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.

[0657] LC-MS (ESI), m / z: [M+1] + =234.

[0658] Step B: 1-(3-(tert-Butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0659] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.4 g, 5.9 mmol) in anhydrous tetrahydrofuran (20 mL) was added triphosgene (714 mg, 2.4 mmol) at room temperature. 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 solution was cooled to room temperature, concentrated under reduced pressure, diluted with tetrahydrofuran (20 mL), and placed in a constant pressure dropping funnel. To a solution of 3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-amine (1.4 g, 6.0 mmol) in anhydrous tetrahydrofuran (15 mL) were added triethylamine (1.8 g, 17.7 mmol) and a freshly prepared tetrahydrofuran solution of isocyanate. The atmosphere was replaced with nitrogen three times, the temperature was raised to 60°C, and the stirring was continued for 2 hours. 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 15 / 1) to give an off-white solid product (1.6 g, yield 55%).

[0660] LC-MS (ESI), m / z: [M+1] + =497.

[0661] Step C: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)urea

[0662] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (150 mg, 0.6 mmol) and 1-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (295 mg, 0.6 mmol) in 1,4-dioxane / water (20 mL, 4 / 1) was added anhydrous potassium carbonate (248 mg, 1.8 mmol) and tetrakistriphenylphosphine palladium at room temperature. (116 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100 ° C and stirred for 3 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, the organic phases were combined, washed once with water, washed 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 product (58 mg, yield 18%).

[0663] LC-MS (ESI), m / z: [M+1] + =543.

[0664] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.88(s,1H),8.22(t,J=8.0Hz,1H),7.71(d,J=4.0Hz,1H),7.59-7.56(m,2H),7.42-7.33( m,4H),7.06(d,J=4.0Hz,1H),6.42(s,1H),6.06(s,2H),2.36-2.30(m,1H),1.29(s,9H),1.08-1.03(m,2H),1.00-0.96(m,2H).

[0665] 19 F NMR(376MHz,DMSO-d6)δ-114.46,-129.24.

[0666] Example 61: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(2,6-difluorophenyl)-1H-pyrazol-5-yl)urea

[0667] Step A: 3-(tert-Butyl)-1-(2,6-difluorophenyl)-1H-pyrazol-5-amine

[0668] To a solution of 4,4-dimethyl-3-oxopentanonitrile (700 mg, 5.6 mmol) and 2,6-difluorophenylhydrazine hydrochloride (1.0 g, 5.6 mmol) in ethanol (15 mL) was added concentrated hydrochloric acid (4.6 mL, 55.2 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 product 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 (1.2 g), which was used directly in the next step without purification.

[0669] LC-MS (ESI), m / z: [M+1] + =252.

[0670] Step B: (4-(3-(3-(tert-Butyl)-1-(2,6-difluorophenyl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)boronic acid

[0671] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.1 mmol) in anhydrous tetrahydrofuran (15 mL) was added triphosgene (237 mg, 0.8 mmol) at room temperature. 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 solution was cooled to room temperature, concentrated under reduced pressure, diluted with tetrahydrofuran (20 mL), and placed in a constant pressure dropping funnel. To a solution of 3-(tert-butyl)-1-(2,6-difluorophenyl)-1H-pyrazol-5-amine (528 mg, 2.1 mmol) in anhydrous tetrahydrofuran (15 mL) were added triethylamine (640 mg, 6.3 mmol) and a freshly prepared tetrahydrofuran solution of isocyanate. The atmosphere was replaced with nitrogen three times, the temperature was raised to 60°C, and the stirring was continued for 2 hours. 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 = 50 / 1 to 10 / 1) to give an off-white solid product (260 mg, yield 29%).

[0672] LC-MS (ESI), m / z: [M+1] +=433.

[0673] Step C: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(2,6-difluorophenyl)-1H-pyrazol-5-yl)urea

[0674] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (127 mg, 0.5 mmol) and (4-(3-(3-(tert-butyl)-1-(2,6-difluorophenyl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)boronic acid (216 mg, 0.5 mmol) in 1,4-dioxane / water (20 mL, 4 / 1) was added anhydrous potassium carbonate (207 mg, 1.5 mmol) and tetrakistriphenylphosphine palladium (116 mg, 0.1 mmole) at room temperature. ol), replaced with nitrogen three times, heated to 100 ° C and stirred 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, the organic phases were combined, washed once with water, washed 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 product (32 mg, yield 11%).

[0675] LC-MS (ESI), m / z: [M+1] + =561.

[0676] 1 H NMR(400MHz, DMSO-d6)δ8.97(s,1H),8.88(s,1H),8.23(t,J=8.0Hz,1H),7.76-7.67(m,2H),7.49-7.40(m,2H),7.41-7.31(m ,2H),7.06(d,J=4.0Hz,1H),6.45(s,1H),6.11(s,2H),2.38-2.29(m,1H),1.27(s,9H),1.09-1.02(m,2H),1.01-0.94(m,2H).

[0677] 19 F NMR(376MHz,DMSO-d6)δ-118.43,-129.35.

[0678] Example 62: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea

[0679] Step A: 4-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)benzonitrile

[0680] To a solution of 4,4-dimethyl-3-oxopentanonitrile (738 mg, 5.9 mmol) and 4-hydrazinobenzonitrile hydrochloride (1.0 g, 5.9 mmol) in ethanol (15 mL) was added concentrated hydrochloric acid (3 mL, 36.0 mmol, 12 N) at room temperature. The temperature was raised to 80°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 (1.4 g), which was used directly in the next step without purification.

[0681] LC-MS (ESI), m / z: [M+1] + =241.

[0682] Step B: 1-(3-(tert-Butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0683] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (506 mg, 2.1 mmol) in anhydrous tetrahydrofuran (15 mL) was added triphosgene (237 mg, 0.8 mmol) at room temperature. 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 solution was cooled to room temperature, concentrated under reduced pressure, diluted with tetrahydrofuran (20 mL), and placed in a constant pressure dropping funnel. To a solution of 4-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)benzonitrile (500 mg, 2.1 mmol) in anhydrous tetrahydrofuran (15 mL) were added triethylamine (640 mg, 6.3 mmol) and a freshly prepared tetrahydrofuran solution of isocyanate. The atmosphere was replaced with nitrogen three times, the temperature was raised to 60°C and stirred for 2 hours. 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 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 the product as a pale yellow solid (400 mg, 38% yield).

[0684] LC-MS (ESI), m / z: [M+1] + =504.

[0685] Step C: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea

[0686] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (100 mg, 0.4 mmol) and 1-(3-(tert-butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (300 mg, 0.6 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) was added anhydrous potassium carbonate (221 mg, 1.6 mmol) and tetrakistriphenylmethane (100 mg, 0.4 mmol) at room temperature. Phosphate palladium (116 mg, 0.1 mmol), nitrogen replacement three times, heated to 90 ° C and stirred for 4 hours, TLC and LC-MS monitoring of the reaction, the starting material disappeared; the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, washed 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% ammonia water: mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid product (5 mg, yield 2%).

[0687] LC-MS (ESI), m / z: [M+1] + =550.

[0688] 1 H NMR (400MHz, CDCl3) δ8.35(t,J=8.0Hz,1H),8.00(s,1H),7.76-7.66(m,4H),7.40(d,J=5.4Hz,1H),7.36(dd,J=8.5,2 .0Hz,1H),7.33-7.28(m,2H),6.95(d,J=5.4Hz,1H),6.44(s,1H),2.02-1.98(m,1H),1.34(s,9H),1.19-1.15(m,4H).

[0689] 19 F NMR(376MHz,DMSO-d6)δ-129.60.

[0690] Example 63: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)urea

[0691] Step A: 1-(3-(tert-Butyl)-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0692] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.5 g, 6.3 mmol) in anhydrous tetrahydrofuran (15 mL) was added triphosgene (653 mg, 2.2 mmol) at room temperature. 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 solution was cooled to room temperature, concentrated under reduced pressure, diluted with tetrahydrofuran (20 mL), and placed in a constant pressure dropping funnel. To a solution of 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine (965 mg, 6.3 mmol) in anhydrous tetrahydrofuran (15 mL) were added triethylamine (1.9 g, 18.9 mmol) and a freshly prepared tetrahydrofuran solution of isocyanate. The atmosphere was replaced with nitrogen three times, the temperature was raised to 60°C, and the stirring was continued 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 15 / 1) to give an off-white solid product (2.0 g, yield 76%).

[0693] LC-MS (ESI), m / z: [M+1] + =417.

[0694] Step B: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)urea

[0695] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (200 mg, 0.8 mmol) and 1-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (333 mg, 0.8 mmol) in 1,4-dioxane / water (10 mL, 4 / 1) was added anhydrous potassium carbonate (332 mg, 2.4 mmol) and tetrakistriphenylphosphine palladium (11 The mixture was added with 1% ethyl acetate (6 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100 ° C and stirred for 3 hours, and 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 product (180 mg, yield 49%).

[0696] LC-MS (ESI), m / z: [M+1] + =463.

[0697] 1 H NMR (400MHz, CDCl3) δ8.96(s,1H),8.92(d,J=2.8Hz,1H),8.25(t,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.44-7.34(m,2H),7 .07(d,J=4.0Hz,1H),6.18-6.05(m,3H),3.63(s,3H),2.37-2.30(m,1H),1.22(s,9H),1.08-1.04(m,2H),1.00-0.97(m,2H).

[0698] 19 F NMR(376MHz,DMSO-d6)δ-129.71.

[0699] Example 64: 1-(4-(8-amino-3-(1-methylpyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0700] Step A: Benzyl 3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

[0701] To a solution of 1-(benzyloxycarbonyl)pyrrolidine-3-carboxylic acid (2.3 g, 9.2 mmol) and (3-chloropyrazin-2-yl)methylamine hydrochloride (1.4 g, 7.8 mmol) in anhydrous N,N-dimethylformamide (20 mL) were added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.9 g, 10.3 mmol) and N,N-diisopropylethylamine in sequence at 0°C. (3.0 g, 23.2 mmol), warmed to room temperature and stirred for 4 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 column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 80 / 1) to obtain a light yellow oily product (2.8 g, yield 96%).

[0702] LC-MS (ESI), m / z: [M+1] + =375.

[0703] Step B: Benzyl 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate

[0704] To a solution of benzyl 3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (2.8 g, 7.5 mmol) in 1,4-dioxane (30 mL) was added phosphorus oxychloride (1.7 g, 11.1 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The product was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution. The organic phase was separated, 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 = 50 / 1 to 1 / 1) to give a light yellow solid product (2.0 g, yield 75%).

[0705] LC-MS (ESI), m / z: [M+1] + =357.

[0706] Step C: Benzyl 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate

[0707] To a solution of benzyl 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (1.9 g, 5.3 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added N-bromosuccinimide (1.4 g, 7.9 mmol) at 0°C. The atmosphere was replaced with nitrogen three times, the mixture was warmed to room temperature and stirred for 2 hours. 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 preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 20%-100% B, 55 minutes; flow rate: 70 mL / min) to give a light yellow solid product (1.3 g, yield 56%).

[0708] LC-MS (ESI), m / z: [M+1] + =435.

[0709] Step D: Benzyl 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate

[0710] To a solution of benzyl 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (1.3 g, 3.0 mmol) in isopropanol (10 mL) was added aqueous ammonia (10 mL, 25% mw) at room temperature, and the temperature was raised to 95°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The product was concentrated under reduced pressure, and the residue was purified by preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 20%-100% B, 55 min; flow rate: 70 mL / min) to give a white solid (1.1 g, yield 88%).

[0711] LC-MS (ESI), m / z: [M+1] + =416.

[0712] Step E: Benzyl 3-(8-amino-1-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate

[0713] To a solution of benzyl 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (1.1 g, 2.6 mmol) in 1,4-dioxane / water (24 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (2.8 g, 5.2 mmol), potassium carbonate (1.1 g, The reaction mixture was diluted with water and extracted with ethyl acetate three times. 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: petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give a yellow solid (820 mg, yield 42%).

[0714] LC-MS (ESI), m / z: [M+1] + =746.

[0715] Step F: 1-(4-(8-amino-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0716] To a solution of benzyl 3-(8-amino-1-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (100 mg, 0.1 mmol) in methanol (8 mL) was added palladium on carbon (10 mg, 10%) at room temperature. The mixture was evacuated and replaced with hydrogen three times, and then stirred under a hydrogen balloon at 25°C for 16.0 hours. LCMS confirmed the complete reaction of the starting material. The reaction solution was filtered under reduced pressure, and the filter cake was rinsed with a small amount of methanol. The mother liquor was concentrated to dryness under reduced pressure to give a crude yellow solid (80 mg), which was used directly in the next reaction without further purification.

[0717] LC-MS (ESI), m / z: [M+1] + =612.

[0718] Step G: 1-(4-(8-amino-3-(1-methylpyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0719] At room temperature, 1-(4-(8-amino-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea (80 mg, 0.1 mmol) was dissolved in methanol (6 mL), and formaldehyde aqueous solution (53 mg, 0.7 mmol, 37% wt) was added. Sodium triacetoxyborohydride (41 mg, 0.2 mmol) and stirred at room temperature for 1.0 hour. LCMS confirmed complete conversion of the starting material. The reaction solution was dropwise dissolved in aqueous sodium carbonate to adjust the pH to >8. Water was added and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative chromatography (mobile phase A: 0.1% aqueous ammonia; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) to afford a white solid (7 mg, 8% yield).

[0720] LC-MS (ESI), m / z: [M+1] + =626.

[0721] 1 H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.78(d,J=2.7Hz,1H),8.26(s,1H),8.01(d,J=2.2Hz,1H), 7.65(d,J=5.1Hz,2H),7.55(dd,J=8.4,2.3Hz,1H),7.48-7.35(m,2H),7.04(d,J=4.9Hz,1H),6. 08(s,2H),3.82-3.73(m,1H),3.54(s,2H),2.99(t,J=8.6Hz,1H),2.72(dd,J=9.1,6.9Hz,1H),2 .69-2.63(m,1H),2.62-2.52(m,2H),2.46-2.23(m,10H),2.19-2.14(m,4H),1.99-1.93(m,1H).

[0722] 19 F NMR(376MHz,DMSO-d6)δ-58.02,-129.38.

[0723] Example 65: 1-(4-(8-amino-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0724] Step A: N-((3-chloropyrazin-2-yl)methyl)-3-hydroxy-3-methylbutanamide

[0725] To a solution of (3-chloropyrazin-2-yl)methanamine hydrochloride (5.0 g, 27.8 mmol) and β-hydroxyvaleric acid (3.9 g, 33.3 mmol) in tetrahydrofuran (20 mL) were added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (10.1 g, 36.1 mmol) and triethylamine (8.4 g, 83.3 mmol) at 0°C. The temperature was raised to 25°C and stirred for 16 hours. 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: petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give a white solid (5.3 g, yield 78%).

[0726] LC-MS (ESI), m / z: [M+1] + =244.

[0727] Step B: 8-chloro-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazine

[0728] To a solution of N-((3-chloropyrazin-2-yl)methyl)-3-hydroxy-3-methylbutanamide (5.3 g, 21.7 mmol) in 1,4-dioxane (50 mL) was slowly added phosphorus oxychloride (6.7 g, 43.5 mmol) at room temperature. The atmosphere was protected and replaced three times with nitrogen and stirred at 80°C for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was cooled to room temperature and quenched by pouring into ice water. A saturated aqueous sodium carbonate solution was added dropwise to adjust the solution to a weak base. 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. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give a light yellow solid (1.0 g, yield 22%).

[0729] LC-MS (ESI), m / z: [M+1] + =208.

[0730] Step C: 1-Bromo-8-chloro-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazine

[0731] To a solution of 8-chloro-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazine (750 mg, 3.6 mmol) in N,N-dimethylformamide (8 mL) was added N-bromosuccinimide (836 mg, 4.7 mmol) at 0°C and stirred 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 A: water; mobile phase B: acetonitrile; gradient: 20%-100% B, 55 minutes, flow rate: 70 mL / min) to give a light yellow solid (160 mg, yield 15%).

[0732] LC-MS (ESI), m / z: [M+1] + =286.

[0733] Step D: 1-Bromo-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine

[0734] To a solution of 1-bromo-8-chloro-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazine (160 mg, 0.6 mmol) in isopropanol (2 mL) was added aqueous ammonia (4 mL) at room temperature, and the temperature was raised to 90°C and stirred for 16 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 20%-100% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (95 mg, yield 64%).

[0735] LC-MS (ESI), m / z: [M+1] + =267.

[0736] Step E: 1-(4-(8-amino-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl]methyl)-3-(trifluoromethyl)phenyl)urea

[0737] To a mixed solution of 1-bromo-3-(2-methylprop-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine (100 mg, 0.4 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea (301 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (82 mg, 0.1 mmol) and potassium carbonate (155 mg, 1.1 mmol) at room temperature. , replaced with nitrogen three times, heated to 90°C and stirred for 2 hours, the reaction was monitored by TLC and LC-MS, and the starting material disappeared; the reaction solution was cooled to room temperature, the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, washed 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% ammonia water; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (31 mg, yield 14%).

[0738] LC-MS (ESI), m / z: [M+1] + =597.

[0739] 1 H NMR (400MHz, DMSO-d6) δ9.42(s,1H),8.76(d,J=2.7Hz,1H),8.26(t,J=8.5Hz,1H),8.00(d,J =2.2Hz,1H),7.69(d,J=5.1Hz,1H),7.65(d,J=8.5Hz,1H),7.55(dd,J=8.5,2.3Hz,1H),7.48( dd,J=12.2,2.0Hz,1H),7.42(dd,J=8.4,1.9Hz,1H),7.06(d,J=4.9Hz,1H),6.53(t,J=1.6Hz, 1H),6.10(s,2H),3.53(s,2H),2.38(s,8H),2.26(s,3H),2.17(s,3H),2.01(d,J=1.4Hz,3H).

[0740] 19 F NMR(376MHz,DMSO-d6)δ-58.02,-129.31.

[0741] Example 66: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)urea

[0742] Step A: 3-Cyclopropyl-1-phenyl-1H-pyrazol-5-amine

[0743] To a solution of phenylhydrazine (1.0 g, 9.3 mmol) in ethanol (20 mL) was added 3-cyclopropyl-3-oxopropionitrile (1.0 g, 9.3 mmol) and concentrated hydrochloric acid (4.6 mL, 55.2 mmol) at room temperature under nitrogen. The temperature was raised to 90°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction was quenched with saturated aqueous sodium carbonate solution and adjusted to weak alkalinity. The product 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 give a crude product as a pale yellow solid (1.3 g, yield 71%).

[0744] LC-MS (ESI), m / z: [M+1] + =200.

[0745] Step B: (4-(3-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)boronic acid

[0746] At room temperature, triphosgene (237 mg, 0.8 mmol) was added to anhydrous tetrahydrofuran (10 mL) of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g, 2.1 mmol) and the mixture was stirred at 60°C for 1 hour. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction system was concentrated to dryness and dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another 5-nitropropane-1-phenyl-1H-pyrazol-5-amine (420 mg, 2.1 mmol) solution. ) and triethylamine (427 mg, 4.2 mmol) in tetrahydrofuran (10 mL) were added to a round-bottom flask, and the temperature was raised to 60° C. under a nitrogen atmosphere, and the reaction was stirred 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 inorganic salts were filtered off, and the organic phase was concentrated to dryness. The concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to obtain an off-white solid (337 mg, yield 42%).

[0747] LC-MS (ESI), m / z: [M+1]+ =381.

[0748] Step C: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)urea

[0749] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (177 mg, 0.7 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added (4-(3-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)boronic acid (280 mg, 0.7 mmol), potassium carbonate (204 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) at room temperature. l), replaced with nitrogen three times, raised to 100 ° C and stirred for 3 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, the organic phases were combined, washed once with water, washed 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 (80 mg, yield 21%).

[0750] LC-MS (ESI), m / z: [M+1] + =509.

[0751] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.92 (s, 1H), 8.22 (t, J = 8.5Hz, 1H), 7.72 ( d,J=4.9Hz,1H),7.59-7.50(m,4H),7.46-7.41(m,1H),7.41-7.31(m,2H),7.06 (d,J=4.9Hz,1H),6.23(s,1H),6.11(s,2H),2.37-2.29(m,1H),1.94-1.85(m,1 H),1.09-1.02(m,2H),1.01-0.94(m,2H),0.94-0.86(m,2H),0.74-0.67(m,2H).

[0752] 19 F NMR(376MHz,DMSO-d6)δ-129.24.

[0753] Example 67: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0754] Step A: 3-Oxo-3-(1-(trifluoromethyl)cyclopropyl)propionitrile

[0755] 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.

[0756] LC-MS (ESI), m / z: [M+1] + =178.

[0757] Step B: 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine

[0758] 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%).

[0759] LC-MS (ESI), m / z: [M+1] + =268.

[0760] Step C: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0761] At room temperature, triphosgene (500 mg, 1.7 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.2 mmol) in anhydrous tetrahydrofuran (16 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (1.1 g, 4.1 mmol). A solution of triethylamine (1.3 g, 12.8 mmol) in tetrahydrofuran (16 mL) was placed in a round-bottom flask, heated to 60° C. under a nitrogen atmosphere, and stirred 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 inorganic salts were filtered off, and the organic phase was concentrated to dryness. The concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to give an off-white solid (1.9 g, yield 87%).

[0762] LC-MS (ESI), m / z: [M+1] + =531.

[0763] Step D: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0764] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (212 mg, 0.4 mmol), potassium carbonate (166 mg, 1.2 mmol) and tetra(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (212 mg, 0.4 mmol) in sequence at room temperature. The mixture was added with 1,2-diphenylphosphine)palladium (116 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100 ° C and stirred for 3 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, 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 (40 mg, yield 17%).

[0765] LC-MS (ESI), m / z: [M+1] + =577.

[0766] 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),9.05(s,1H),8.23(t,J=8.0Hz,1H),7 .71(d,J=4.0Hz,1H),7.61-7.54(m,4H),7.52-7.48(m,1H),7.41-7.34(m, 2H),7.06(d,J=4.0Hz,1H),6.62(s,1H),6.05(s,2H),2.36-2.29(m,1H),1 .38-1.35(m,2H),1.32-1.29(m,2H),1.08-1.02(m,2H),1.00-0.96(m,2H).

[0767] 19 F NMR(376MHz,DMSO-d6)δ-67.47,-129.16.

[0768] Example 68: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

[0769] Step A: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

[0770] At room temperature, triphosgene (682 mg, 2.3 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.4 g, 5.9 mmol) in anhydrous tetrahydrofuran (16 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another flask containing 3-methyl-1-phenyl-1H-pyrazol-5-amine (1.0 g, 5.8 mmol), triethylamine (1. A solution of 1,8 g, 17.8 mmol) in tetrahydrofuran (16 mL) was placed in a round-bottom flask, and the temperature was raised to 60° C. under a nitrogen atmosphere, and the reaction was stirred for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. The mixture was quenched by adding water and diluted, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The inorganic salts were filtered off, and the organic phase was concentrated to dryness. The concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 15 / 1) to obtain an off-white solid (1.8 g, yield 71%).

[0771] LC-MS (ESI), m / z: [M+1] + =437.

[0772] Step B: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

[0773] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (150 mg, 0.6 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea (259 mg, 0.6 mmol), potassium carbonate (378 mg, 1.8 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C and stirred for 3 hours. 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 and washed once with water. The product was washed 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 (40 mg, yield 14%).

[0774] LC-MS (ESI), m / z: [M+1] + =483.

[0775] 1 H NMR (400MHz, DMSO-d6) δ9.06(d,J=4.0Hz,1H),8.93(s,1H),8.22(t,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.58-7.51(m,4H),7.47-7.42(m,1H ),7.40-7.33(m,2H),7.06(d,J=4.0Hz,1H),6.34(s,1H),6.06(s,2H), 2.36-2.29(m,1H),2.21(s,3H),1.08-1.03(m,2H),1.00-0.96(m,2H).

[0776] 19 F NMR(376MHz,DMSO-d6)δ-129.25.

[0777] Example 69: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

[0778] Step A: 4,4,4-Trifluoro-3-oxobutyronitrile

[0779] To anhydrous tetrahydrofuran of ethyl 2,2,2-trifluoroacetate (2.4 g, 16.9 mmol) were added sodium hydride (1.5 g, 35.5 mmol, 57%) and acetonitrile (1.0 g, 24.4 mmol) at 0°C. The temperature was raised to 70°C under a nitrogen atmosphere and stirred for 2 hours. The reaction was monitored by TLC and LCMS. The starting material disappeared. Water was added to the mixture to quench the mixture and the mixture was diluted. The mixture was 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 light yellow liquid (1.8 g, yield 78%).

[0780] LC-MS (ESI), m / z: [M+1] + =138.

[0781] Step B: 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine

[0782] To a solution of 4,4,4-trifluoro-3-oxobutanenitrile (1.6 g, 11.9 mmol) in anhydrous ethanol (18 mL) were added phenylhydrazine (1.4 g, 13.1 mmol) and concentrated hydrochloric acid (10 mL, 120.0 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, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 1 to 5 / 1) to obtain a yellow solid (1.8 g, yield 67%).

[0783] LC-MS (ESI), m / z: [M+1] + =228.

[0784] Step C: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

[0785] At room temperature, triphosgene (504 mg, 1.7 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.2 mmol) in anhydrous tetrahydrofuran (15 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-amine (954 mg, 4.2 mmol), triphosgene (504 mg, 1.7 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.2 mmol) in anhydrous tetrahydrofuran (15 mL). A solution of ethylamine (1.3 g, 12.6 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask and heated to 60°C under nitrogen atmosphere with stirring for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. The mixture was quenched by adding water and diluted, 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 concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to give an off-white solid (1.8 g, yield 87%).

[0786] LC-MS (ESI), m / z: [M+1] + =491.

[0787] Step D: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

[0788] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (76 mg, 0.3 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (147 mg, 0.3 mmol), potassium carbonate (166 mg, 1.2 mmol) and tetrakis(triphenylphosphine) in sequence at room temperature. Palladium (116 mg, 0.1 mmol), nitrogen replacement three times, raised to 100 ° C and stirred for 3 hours, TLC and LC-MS monitoring of the reaction, the starting material disappeared; the reaction solution was diluted with water, 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 (26 mg, yield 16%).

[0789] LC-MS (ESI), m / z: [M+1]+ =537.

[0790] 1 H NMR (400MHz, DMSO-d6) δ9.21(d,J=8.0Hz,2H),8.22(t,J=8.0Hz,1H),7.71(d,J=4.0Hz,1H),7.68-7.58(m,5H),7.42-7 .35(m,2H),7.07(d,J=4.0Hz,1H),6.92(s,1H),6.05(s,2H),2.36-2.30(m,1H),1.08-1.02(m,2H),1.00-0.96(m,2H).

[0791] 19 F NMR(376MHz,DMSO-d6)δ-61.34,-128.96.

[0792] Example 70: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)urea

[0793] Step A: tert-Butyl 2-(1-methylpiperidin-4-ylidene)hydrazine-1-carboxylate

[0794] To a solution of 1-methylpiperidin-4-one (5.0 g, 44.2 mmol) in n-hexane (50 mL) was added tert-butyloxycarbonylhydrazine (6.4 g, 48.4 mmol) at room temperature under nitrogen. The temperature was raised to 70°C and stirred for 1 hour. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was cooled to 0-5°C to precipitate a large amount of white solid, which was filtered, washed three times with n-hexane, and dried to obtain a white solid (3.6 g, 36% yield).

[0795] LC-MS (ESI), m / z: [M+1] + =228.

[0796] Step B: 4-Hydrazino-1-methylpiperidine hydrochloride

[0797] To a solution of tert-butyl 2-(1-methylpiperidin-4-ylidene)hydrazine-1-carboxylate (3.6 g, 15.8 mmol) in anhydrous tetrahydrofuran (30 mL) was added a solution of borane in tetrahydrofuran (15.8 mL, 31.6 mmol, 2 N) at 0°C. The mixture was warmed to room temperature and stirred overnight. The reaction was monitored by TLC and LC-MS for the disappearance of the starting material. The reaction solution was cooled to 0°C and quenched by the slow addition of methanol dropwise with stirring for 2 hours to ensure complete quenching of the excess borane. A solution of hydrochloric acid in methanol (39.6 mL, 79.2 mmol, 2 N) was then added to the reaction system. The mixture was warmed to 40°C and stirred for 4 hours. The reaction was monitored by TLC and LC-MS for the disappearance of the starting material. The reaction system was concentrated to dryness to obtain the product (1.7 g, 65% yield), which was used directly in the next step without further purification.

[0798] LC-MS (ESI), m / z: [M+1] + =130.

[0799] Step C: 3-(tert-Butyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-amine

[0800] To a solution of 4-hydrazino-1-methylpiperidine hydrochloride (1.7 g, 10.3 mmol) in anhydrous ethanol (30 mL) was added 4,4-dimethyl-3-oxopentanonitrile (1.3 g, 10.4 mmol) and concentrated hydrochloric acid (5.2 mL, 62.4 mmol, 12 N) at room temperature under nitrogen. The temperature was raised to 90°C and stirred overnight. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a light yellow solid (1.1 g, yield 45%).

[0801] LC-MS (ESI), m / z: [M+1] + =237.

[0802] Step D: (4-(3-(tert-Butyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)boronic acid

[0803] At room temperature, triphosgene (534 mg, 1.8 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.1 g, 4.6 mmol) in anhydrous tetrahydrofuran (15 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-amine (1.1 g, 4.6 mmol), triethylamine, and 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-amine. A solution of amine (931 mg, 9.2 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask and heated to 60°C under nitrogen atmosphere with stirring for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. The mixture was quenched by adding water and diluted, 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 concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 to 10 / 1) to give an off-white solid (867 mg, yield 45%).

[0804] LC-MS (ESI), m / z: [M+1] + =418.

[0805] Step E: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)urea

[0806] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (177 mg, 0.7 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added (4-(3-(tert-butyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)ureido)-3-fluorophenyl)boronic acid (292 mg, 0.7 mmol), potassium carbonate (194 mg, 1.4 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.7 mmol) at room temperature. 1mmol), replaced with nitrogen three times, raised to 100°C and stirred for 3 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, 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 (47 mg, yield 12%).

[0807] LC-MS (ESI), m / z: [M+1] +=546.

[0808] 1 H NMR (400MHz, DMSO-d6) δ8.88(d,J=2.6Hz,1H),8.80(s,1H),8.23(t,J=8.5Hz,1H),7.72(d,J=5.0H z,1H),7.67-7.53(m,1H),7.42(dd,J=12.3,2.0Hz,1H),7.35(dd,J=8.4,2.0Hz,1H),7.07(d,J=5. 0Hz,1H),6.10(s,1H),6.06(s,1H),4.05-3.88(m,1H),2.98-2.79(m,2H),2.39-2.28(m,1H),2.21 (s,3H),2.12-1.94(m,4H),1.85-1.68(m,2H),1.23(s,9H),1.11-1.01(m,2H),1.00-0.92(m,2H).

[0809] 19 F NMR(376MHz,DMSO-d6)δ-129.43.

[0810] Example 71: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl)urea

[0811] Step A: 2-(2-oxo-2-phenylethyl)isoindole-1,3-dione

[0812] To a solution of 2-chloro-1-phenylethyl-1-one (6.0 g, 38.8 mmol) in anhydrous N,N-dimethylformamide (30 mL) was added potassium phthalimide (7.2 g, 38.8 mmol) at room temperature under nitrogen. The temperature was raised to 70°C and stirred for 3 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction system was cooled to room temperature and poured into ice water to precipitate a large amount of solid. The solid was filtered and rinsed with water three times. The filter cake was dried in vacuo to obtain a white solid (9.8 g, 95% yield).

[0813] LC-MS (ESI), m / z: [M+1] + =266.

[0814] Step B: (E)-2-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)isoindole-1,3-dione

[0815] To a solution of 2-(2-oxo-2-phenylethyl)isoindole-1,3-dione (2.0 g, 7.5 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (2.2 g, 18.5 mmol) at room temperature under nitrogen. The temperature was raised to 105°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The product 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 dryness. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 1 to 5 / 1) to give a white solid (2.0 g, yield 83%).

[0816] LC-MS (ESI), m / z: [M+1] + =321.

[0817] Step C: 2-(1-(tert-Butyl)-3-phenyl-1H-pyrazol-4-yl)isoindole-1,3-dione

[0818] To a solution of (E)-2-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)isoindole-1,3-dione (2.0 g, 6.2 mmol) in anhydrous ethanol (20 mL) was added tert-butylhydrazine hydrochloride (1.9 g, 15.5 mmol) at room temperature under nitrogen. The temperature was raised to 90°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The product 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 dryness. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 1 to 5 / 1) to give a white solid (1.9 g, yield 89%).

[0819] LC-MS (ESI), m / z: [M+1] + =346.

[0820] Step D: 1-(tert-Butyl)-3-phenyl-1H-pyrazol-4-amine

[0821] To a solution of 2-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl)isoindole-1,3-dione (2.0 g, 5.8 mmol) in ethanol (20 mL) was added hydrazine hydrate (1.8 g, 29.0 mmol, 80% wt) at room temperature under nitrogen protection. The temperature was raised to 90°C and stirred for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The product 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 dryness. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 20 / 1) to give a light yellow solid (800 mg, yield 64%).

[0822] LC-MS (ESI), m / z: [M+1] + =216.

[0823] Step E: 1-(1-(tert-Butyl)-3-phenyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0824] At room temperature, triphosgene (415 mg, 1.4 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (806 mg, 3.4 mmol) in anhydrous tetrahydrofuran (15 mL), and the mixture was heated to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another round-bottom flask containing 1-(tert-butyl)-3-phenyl-1H-pyrazol-4-amine (732 mg, 3.4 mmol) and triethylamine (1.0 g, 10.1 mmol) in tetrahydrofuran (15 mL). The temperature was raised to 60° C. under a nitrogen atmosphere, and the reaction was stirred for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. The mixture was quenched and diluted with water, extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 15 / 1) to give an off-white solid (1.1 g, yield 68%).

[0825] LC-MS (ESI), m / z: [M+1] + =479.

[0826] Step F: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl)urea

[0827] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (177 mg, 0.7 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (335 mg, 0.7 mmol), potassium carbonate (304 mg, 2.2 mmol) and tetrakis(triphenylphosphine) in sequence at room temperature. Palladium (116 mg, 0.1 mmol), nitrogen replacement three times, raised to 100 ° C and stirred for 3 hours, TLC and LC-MS monitoring of the reaction, the starting material disappeared; the reaction solution was diluted with water, 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 (140 mg, yield 38%).

[0828] LC-MS (ESI), m / z: [M+1] + =525.

[0829] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.27(t,J=8.0Hz,1H),7.83(s,1H),7.79(s,1H),7.70(d,J=4.0Hz,1H),7.57-7.53(m,3H),7.42-7. 40(m,2H),7.35-7.29(m,2H),7.05(d,J=8.0Hz,1H),6.03(s,2H),2.35-2.28(m,1H),1.36(s,9H),1.07-1.02(m,2H),1.01-0.95(m,2H).

[0830] 19 F NMR(376MHz,DMSO-d6)δ-129.80.

[0831] Example 72: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0832] Step A: 3,3-Dimethyl-1-(anilino)butan-2-one

[0833] To a solution of aniline (2.6 g, 27.9 mmol) in anhydrous N,N-dimethylformamide (30 mL) was added sodium bicarbonate (4.7 g, 56.0 mmol) and 1-bromopinacolone (5.0 g, 28.0 mmol) in sequence at room temperature under nitrogen protection. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Saturated brine was added, 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 inorganic salts were filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 1 to 20 / 1) to give a light yellow liquid (4.6 g, yield 86%).

[0834] LC-MS (ESI), m / z: [M+1] + =192.

[0835] Step B: 4-(tert-Butyl)-1-phenyl-1H-imidazol-2-amine

[0836] To a solution of 3,3-dimethyl-1-(anilino)butan-2-one (4.2 g, 22.0 mmol) in anhydrous ethanol (30 mL) at room temperature under nitrogen was added cyanamide (1.7 g, 44.0 mmol) and concentrated hydrochloric acid (6.7 mL, 80.4 mmol) in sequence. The temperature was raised to 50°C and stirred for 4 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to 8-9. The product was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 80 / 1 to 3 / 1) to give an off-white solid (2.8 g, yield 59%).

[0837] LC-MS (ESI), m / z: [M+1] + =216.

[0838] Step C: 1-(4-(tert-Butyl)-1-phenyl-1H-imidazol-2-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0839] At room temperature, triphosgene (445 mg, 1.5 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (877 mg, 3.7 mmol) in anhydrous tetrahydrofuran (15 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another 4-(tert-butyl)-1-phenyl-1H-imidazole-2-amine (797 mg, 3.7 mmol), triethylamine, 1,2-dimethylthiazolinone ... A solution of amine (1.1 g, 11.1 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask and heated to 60°C with stirring under a nitrogen atmosphere for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. The mixture was quenched by adding water and diluted, 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 concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to give an off-white solid (500 mg, yield 28%).

[0840] LC-MS (ESI), m / z: [M+1] + =479.

[0841] Step D: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0842] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (253 mg, 1.0 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(4-(tert-butyl)-1-phenyl-1H-imidazol-2-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (480 mg, 1.0 mmol), potassium carbonate (415 mg, 3.0 mmol) and tetrakis(triphenylphosphine) in sequence at room temperature. ) palladium (116 mg, 0.1 mmol), nitrogen replaced three times, raised to 100 ° C and stirred for 3 hours, TLC and LC-MS monitored the reaction, the starting material disappeared; the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, washed 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 (20 mg, yield 4%).

[0843] LC-MS (ESI), m / z: [M+1] + =525.

[0844] 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 8.28 (t, J = 8.4Hz, 1H), 7.71 (d, J = 5.0Hz, 1H), 7.57-7.40 (m, 6H), 7.35 (dd, J = 8.5, 2.0Hz, 1H), 7.07 (d, J = 4 .9Hz,1H),6.92(s,1H),6.05(s,2H),2.33(ddd,J=13.1,8.4,4.9Hz,1H),1.30(s,9H),1.05(dt,J=8.1,2.8Hz,2H),0.99(dt,J=5.1,2.8Hz,2H).

[0845] 19 F NMR(376MHz,DMSO-d6)δ-129.64.

[0846] Example 73: 1-(5-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)pyridin-2-yl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea

[0847] Step A: 1-(3-(tert-Butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea

[0848] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (500 mg, 2.3 mmol) in anhydrous tetrahydrofuran (15 mL) was added a solution of phenyl p-nitrochloroformate (685 mg, 3.4 mmol) in tetrahydrofuran (10 mL) and pyridine (546 mg, 6.9 mmol) under nitrogen at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The reaction system was concentrated to dryness and dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another flask containing 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine. (495 mg, 2.3 mmol), N,N-diisopropylethylamine (1.2 g, 9.2 mmol) in tetrahydrofuran (15 mL) were placed in a round-bottom flask, heated to 60 ° C. and stirred for 2 hours under a nitrogen atmosphere. 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, filtered, and concentrated to dryness. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 10 / 1) to give an off-white solid (290 mg, yield 27%).

[0849] LC-MS (ESI), m / z: [M+1] + =462.

[0850] Step B: 1-(5-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)pyridin-2-yl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea

[0851] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (185 mg, 0.4 mmol) and potassium carbonate (166 mg, 1.2 mmol) at room temperature. and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol), nitrogen was replaced three times, the temperature was raised to 100°C and stirred for 3 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, 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 (48 mg, yield 24%).

[0852] LC-MS (ESI), m / z: [M+1] + =508.

[0853] 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.10(s,1H),7.97(d,J=4.0Hz,1H),7 .91(dd,J=8.0,4.0Hz,1H),7.73(d,J=4.0Hz,1H),7.62-7.57(m,4H),7.49-7 .45(m,1H),7.22(d,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.50(s,1H),6.12( s,2H),2.37-2.31(m,1H),1.30(s,9H),1.09-1.05(m,2H),1.00-0.96(m,2H).

[0854] Example 74: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea

[0855] Step A: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0856] At room temperature, triphosgene (475 mg, 1.6 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (972 mg, 4.1 mmol) in anhydrous tetrahydrofuran (15 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another 5-well plate containing 3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.0 g, 4.1 mmol). ), a solution of triethylamine (1.2 g, 12.2 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask, and the temperature was raised to 60° C. under a nitrogen atmosphere, and the reaction was stirred 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, filtered, and concentrated to dryness. The concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain a white solid (1.0 g, yield 48%).

[0857] LC-MS (ESI), m / z: [M+1] + =509.

[0858] Step B: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea

[0859] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (253 mg, 1.0 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (508 mg, 1.0 mmol), potassium carbonate (415 mg, 3.0 mmol) and tetra(trimethylol)pyrazol-8-amine in sequence at room temperature. The mixture was added with 1,2-diphenylphosphine)palladium (116 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100 ° C and stirred for 3 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, 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 (50 mg, yield 9%).

[0860] LC-MS (ESI), m / z: [M+1] + =555.

[0861] 1 H NMR (400MHz, DMSO-d6) δ9.06(d,J=2.5Hz,1H),8.81(s,1H),8.25(t,J=8.5Hz,1H),7.71(d,J=5.0Hz,1H),7.45-7.34( m,4H),7.15-7.03(m,3H),6.39(s,1H),6.05(s,2H),3.84(s,3H),2.37-2.28(m,1H),1.28(s,9H),1.10-0.94(m,4H).

[0862] 19 F NMR(376MHz,DMSO-d6)δ-129.29.

[0863] Example 75: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

[0864] Step A: 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0865] At room temperature, triphosgene (504 mg, 1.7 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.3 mmol) in anhydrous tetrahydrofuran (15 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another flask containing 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (986 mg, 4.3 mmol). , a solution of triethylamine (1.3 g, 12.9 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask, heated to 60°C under a nitrogen atmosphere, stirred and reacted for 1 hour, and 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 concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain a white solid (1.7 g, yield 80%).

[0866] LC-MS (ESI), m / z: [M+1] + =493.

[0867] Step B: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

[0868] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (253 mg, 1.0 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (493 mg, 1.0 mmol), potassium carbonate (385 mg, 3.0 mmol) and tetrakis(triphenylmethane)-1-[ ... The mixture was added with 1% phosphine) palladium (116 mg, 0.1 mmol), replaced with nitrogen three times, heated to 100 ° C and stirred for 3 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, 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 (72 mg, yield 13%).

[0869] LC-MS (ESI), m / z: [M+1] + =539.

[0870] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.85 (s, 1H), 8.24 (t, J = 8.5Hz, 1H), 7.71 (d, J = 5.0Hz, 1H), 7.48-7.32 (m, 6H), 7.06 (d, J = 5.0Hz, 1H),6.41(s,1H),6.05(s,2H),2.39(s,3H),2.36-2.30(m,1H),1.28(s,9H),1.05(dt,J=8.1,2.9Hz,2H),0.98(dt,J=5.2,2.9Hz,2H).

[0871] 19 F NMR(376MHz,DMSO-d6)δ-129.30.

[0872] Example 76: 1-(5-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)pyridin-2-yl)-3-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)urea

[0873] Step A: 1-(3-(tert-Butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea

[0874] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (600 mg, 2.7 mmol) in anhydrous tetrahydrofuran (15 mL) was added p-nitrophenyl chloroformate (685 mg, 3.4 mmol) and pyridine (427 mg, 5.4 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 3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-amine (677 mg, 2.9 mmol), N , a solution of N-diisopropylethylamine (1.1 g, 8.2 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask, heated to 60°C under a nitrogen atmosphere, and stirred 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 it 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 obtain a white solid (500 mg, yield 39%).

[0875] LC-MS (ESI), m / z: [M+1] + =480.

[0876] Step B: 1-(5-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)pyridin-2-yl)-3-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)urea

[0877] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (152 mg, 0.6 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (288 mg, 0.6 mmol), potassium carbonate (249 mg, 1.8 mmol) and 1,1'-bis(diphenylmethane)-1-[ ... The reaction mixture 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 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 (66 mg, yield 21%).

[0878] LC-MS (ESI), m / z: [M+1] + =526.

[0879] 1 H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.08(s,1H),8.01(d,J=2.4Hz,1H),7 .91(dd,J=8.0,4.0Hz,1H),7.73(d,J=4.0Hz,1H),7.64-7.61(m,2H),7.4-7. 41(m,2H),7.25(d,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.48(s,1H),6.12(s ,2H),2.38-2.31(m,1H),1.30(s,9H),1.09-1.05(m,2H),1.01-0.97(m,2H).

[0880] 19 F NMR(376MHz,DMSO-d6)δ-113.85

[0881] Example 77: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)urea

[0882] Step A: 3-(tert-Butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-amine

[0883] To a solution of 4,4-dimethyl-3-oxopentanonitrile (780 mg, 6.2 mmol) in anhydrous ethanol (16 mL) was added (3-fluoro-4-methylphenyl)hydrazine hydrochloride (1.0 g, 5.7 mmol) and concentrated hydrochloric acid (5 mL, 60.0 mmol) at room temperature under nitrogen. The temperature was raised to 85°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was diluted with water, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The product 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 give a yellow solid (1.2 g, yield 85%).

[0884] LC-MS (ESI), m / z: [M+1] + =248.

[0885] Step B: 1-(3-(tert-Butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0886] To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (593 mg, 2.5 mmol) in anhydrous tetrahydrofuran (15 mL) was added triphosgene (297 mg, 1.0 mmol) at room temperature, and the mixture was heated to 60°C with stirring for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another round-bottom flask containing a solution of 3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-amine (668 mg, 2.7 mmol) and triethylamine (769 mg, 7.6 mmol) in tetrahydrofuran (15 mL). The mixture was heated to 60°C with stirring under a nitrogen atmosphere for 1 hour. TLC The reaction was monitored by 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 concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to give a white solid (900 mg, yield 71%).

[0887] LC-MS (ESI), m / z: [M+1] + =511.

[0888] Step C: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)urea

[0889] To a solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (177 mg, 0.7 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (357 mg, 0.7 mmol), potassium carbonate (290 mg, 2.1 mmol) and 1,1'-bis( [diphenylphosphine) ferrocene] palladium dichloride (73 mg, 0.1 mmol), nitrogen replacement three times, raised to 100 ° C and stirred for 3 hours, TLC and LC-MS monitoring of the reaction, the starting material disappeared; the reaction solution was diluted with water, 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 (20 mg, yield 5%).

[0890] LC-MS (ESI), m / z: [M+1] + =557.

[0891] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.91(s,1H),8.22(t,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),7.41-7.31(m,4H ),7.06(d,J=4.0Hz,1H),6.42(s,1H),6.05(s,2H),2.36-2.33(m,1H),2.31(s,3H),1.29(s,9H),1.08-1.03(m,2H),1.00-0.97(m,2H).

[0892] 19 F NMR(376MHz,DMSO-d6)δ-115.38,-129.16.

[0893] Example 78: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-yl)urea

[0894] Step A: 3-(tert-Butyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-amine

[0895] To a solution of 4,4-dimethyl-3-oxopentanonitrile (740 mg, 5.9 mmol) in anhydrous ethanol (16 mL) was added (4-isopropylphenyl)hydrazine hydrochloride (1.0 g, 5.4 mmol) and concentrated hydrochloric acid (5 mL, 60.0 mmol) at room temperature under nitrogen. The temperature was raised to 85°C and stirred for 18 hours. The reaction was monitored by TLC and LC-MS, and the starting material disappeared. The reaction solution was diluted with water, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The product 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 give a yellow solid (1.1 g, yield 79%).

[0896] LC-MS (ESI), m / z: [M+1] + =258.

[0897] Step B: 1-(3-(tert-Butyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[0898] At room temperature, triphosgene (297 mg, 1.0 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (600 mg, 2.5 mmol) in anhydrous tetrahydrofuran (15 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another flask containing 3-(tert-butyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-amine (695 mg, 2.7 mmol). ol), triethylamine (769 mg, 7.6 mmol) in tetrahydrofuran (15 mL) was placed in a round-bottom flask, and the temperature was raised to 60° C. under a nitrogen atmosphere, and the reaction was stirred for 1 hour. The reaction was monitored by TLC and LCMS, and the starting material disappeared. The mixture was quenched by adding water and diluted, and 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 column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain a white solid (1.0 g, yield 77%).

[0899] LC-MS (ESI), m / z: [M+1] + =521.

[0900] Step C: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-yl)urea

[0901] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (177 mg, 0.7 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(3-(tert-butyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (364 mg, 0.7 mmol), potassium carbonate (290 mg, 2.1 mmol) and 1,1'-bis(diphenyl)-1,4-dioxane were added in sequence at room temperature. The mixture was added with [(4-amino-2-( ...2

[0902] LC-MS (ESI), m / z: [M+1] + =567.

[0903] 1 H NMR(400MHz,DMSO-d6)δ9.08(d,J=4.0Hz,1H),8.93(s,1H),8.25(t,J=8.0H z,1H),7.71(d,J=8.0Hz,1H),7.46-7.40(m,4H),7.40-7.34(m,2H),7.06(d, J=4.0Hz,1H),6.42(s,1H),6.05(s,2H),3.02-2.95(m,1H),2.36-2.30(m,1H) ),1.28(s,9H),1.26(d,J=4.0Hz,6H),1.08-1.03(m,2H),1.00-0.96(m,2H).

[0904] 19 F NMR(376MHz,DMSO-d6)δ-129.31.

[0905] Example 79: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0906] Step A: 1-(4-Fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine

[0907] 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%).

[0908] LC-MS (ESI), m / z: [M+1] + =286.

[0909] Step B: 1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0910] At room temperature, triphosgene (118 mg, 0.5 mmol) was added to a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (308 mg, 1.3 mmol) in anhydrous tetrahydrofuran (16 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction system was concentrated to dryness and then dissolved in tetrahydrofuran (16 mL). The dissolved liquid was added dropwise to another 1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (371 mg, 1.3 mmol) solution. .), a solution of triethylamine (410 mg, 4.1 mmol) in tetrahydrofuran (16 mL) was placed in a round-bottom flask, and the temperature was raised to 60°C under a nitrogen atmosphere, and the reaction was stirred 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 inorganic salts were filtered off, and the organic phase was concentrated to dryness. The concentrated residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 30 / 1) to give an off-white solid (220 mg, yield 31%).

[0911] LC-MS (ESI), m / z: [M+1] + =549.

[0912] Step C: 1-(4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

[0913] To a mixed solution of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8-amine (101 mg, 0.4 mmol) in 1,4-dioxane / water (12 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(1-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (219 mg, 0.4 mmol), potassium carbonate (166 mg, 1.2 mmol) and 1,1'-bis ...) in sequence at room temperature. (Diphenylphosphino) ferrocene] palladium dichloride (73 mg, 0.1 mmol), nitrogen replacement three times, raised to 100 ° C and stirred for 3 hours, TLC and LC-MS monitoring of the reaction, the starting material disappeared; the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with water, washed 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 (30 mg, yield 13%).

[0914] LC-MS (ESI), m / z: [M+1] + =595.

[0915] 1 H NMR(400MHz, DMSO-d6)δ9.08(s,1H),9.00(s,1H),8.22(t,J=8.0Hz,1H),7.71(d,J=4.0Hz,1H),7.62-7.58(m,2H),7.45-7.34(m,4H),7.06 (d,J=4.0Hz,1H),6.61(s,1H),6.05(s,2H),2.36-2.29(m,1H),1.37-1.34(m,2H),1.32-1.29(m,2H),1.08-1.03(m,2H),1.00-0.96(m,2H).

[0916] 19 F NMR(376MHz,DMSO-d6)δ-67.47,113.38,-129.11.

[0917] Example 80: 1-(4-(4-amino-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0918] To a solution of 5-bromo-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (76 mg, 0.3 mmol) in 1,4-dioxane / water (8 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea (137 mg, 0.3 mmol), potassium carbonate (124 mg, 0.9 mmol) and 1,1'-bis(diphenyl)-1-[ ...)] The mixture was added with [(4-amino-2-( ...2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-

[0919] LC-MS (ESI), m / z: [M+1] + =502.

[0920] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),8.87(d,J=2.6Hz,1H),8.18(t,J=8.5Hz,1H),7.92(s,1H),7.32(dd,J=12.1,2.0Hz,1H),7. 23(dd,J=8.4,2.2Hz,1H),6.90(s,1H),6.42(s,1H),2.33-2.26(m,1H),1.60-1.46(m,4H),1.06-0.94(m,2H),0.81-0.78(m,2H).

[0921] 19 F NMR(376MHz,DMSO-d6)δ-67.62,-128.92.

[0922] Example 81: 1-(4-(4-amino-7-cyclopropylimidazo[5,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

[0923] To a mixed solution of 5-bromo-7-cyclopropylimidazo[5,1-f][1,2,4]triazin-4-amine (76 mg, 0.3 mmol) in 1,4-dioxane / water (8 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea (137 mg, 0.3 mmol), potassium carbonate (124 mg, 0.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) at room temperature. The atmosphere was replaced with nitrogen three times and the temperature was raised to 90°C. The mixture was stirred 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 min; flow rate: 70 mL / min) to give a white solid (42 mg, yield 28%).

[0924] LC-MS (ESI), m / z: [M+1] + =503.

[0925] 1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.86(s,1H),8.20-8.14(m,1H),7.36-7.24(m,3H),6.90( s,1H),6.15(s,2H),3.61-3.55(m,1H),1.57-1.54(m,2H),1.51-1.48(m,2H),1.06-1.02(m,4H).

[0926] 19 F NMR(376MHz,DMSO-d6)δ-67.62,-128.80.

[0927] Example 82: 1-(4-(4-amino-7-cyclopropylimidazo[5,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea

[0928] To a solution of 5-bromo-7-cyclopropylimidazo[5,1-f][1,2,4]triazin-4-amine (76 mg, 0.3 mmol) in 1,4-dioxane / water (8 mL, 3 / 1) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)urea (137 mg, 0.3 mmol), potassium carbonate (124 mg, 0.9 mmol) and 1,1'-bis(diphenyl)-1-[[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ... The mixture was added with [(4-amino-2-( ...2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-(2-2-2-

[0929] LC-MS (ESI), m / z: [M+1] + =503.

[0930] 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.83(s,1H),8.20-8.07(m,2H),7.39-7.21( m,3H),6.20-6.16(m,2H),3.61-3.56(m,1H),1.50-1.35(m,4H),1.08-0.96(m,4H).

[0931] 19 F NMR(376MHz,DMSO-d6)δ-67.20,-128.40.

[0932] Referring to the above examples and the synthesis methods of the intermediates, the examples in the table below were synthesized as follows:

[0933] Effect evaluation

[0934] 1. NEK7 enzyme inhibitory activity (IC 50 ) detection

[0935] The compound was diluted with DMSO (manufacturer: Sigma, catalog number: D4540). SYSTEM) Transfer 40 nL of compound to a 384-well plate (Manufacturer: Greiiner, 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 .

[0936] Data Analysis:

[0937] Where: %Inhibition represents the percentage inhibition rate; Conversion%_sample is the conversion rate reading of the sample; Conversion%_min is the mean of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; Conversion%_max is the mean of the ratio of the positive control wells, representing the conversion rate reading of the wells without compound inhibition.

[0938] Fitting the dose-effect curve: The Log value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The Log (inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 8.0 was used to fit the dose-effect curve to obtain the IC value of each compound for enzyme inhibition. 50 value.

[0939] Table 1: Inhibitory activity of compounds against NEK7 kinase Note: 10nM <A<100nM;100nM<B<1000nM;1000nM<C;

[0940] The example compounds of the present invention have a relatively suitable inhibitory effect on NEK7 kinase activity.

[0941] Among them, WO2022216680A_Cmp I-28 has the following structural formula:

[0942] Ofirnoflast (HT-6184) has the following structural formula:

[0943] 2. Experimental operation of IL-1β secretion by THP-1 cells

[0944] 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 a working concentration of 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 an 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 .

[0945] Table 2: Inhibitory activity of compounds on IL-1β release Note: 1nM <A<10nM;10nM<B<100nM;100nM<C<1000nM;D> 1000nM;

[0946] The example compounds of the present invention prevent the formation of NLRP3 inflammasome by inhibiting NEK7-NLRP3 signaling, thereby inhibiting the production of IL-1β and IL-18 and the cleavage of pore-forming gasdermin D; some compounds have more suitable kinase inhibition effects, but have stronger specific inhibition of IL-1β release, and have more unique molecular action characteristics.

[0947] 3. Activity of compounds on hPBMC cells (CGT test, cells do not proliferate)

[0948] Experimental methods and results:

[0949] (1) Cell recovery and culture: PBMC cells were cultured in RPMI 1640 medium supplemented with 1% double antibody and 10% FBS at 37°C and 5% CO2;

[0950] (2) Cell plating (Day 1)

[0951] a) Cells are routinely cultured until the cell saturation reaches 80-90%. When the cell number reaches the required level, the cells are harvested;

[0952] b) Resuspend the cells in the corresponding complete medium and count them. When the cell viability is above 95%, prepare a cell suspension of appropriate density in the complete medium. The cell density is shown in Table 3:

[0953] Table 3 Cells and cell density

[0954] c) Add the cell suspension to a 96-well plate, 100 μL per well, in duplicate;

[0955] d) The cells were cultured in a 37°C, 5% CO2 incubator overnight.

[0956] (3) Preparation of compounds (Day 0):

[0957] a) Staurosporine was diluted 3-fold in DMSO starting from 10 mM to 9 concentrations;

[0958] b) The four test compounds were diluted 3-fold with DMSO to a total of nine concentrations starting from 10 mM;

[0959] c) The high-reading control wells contained 0.1% DMSO, and the low-reading control wells contained no cell culture medium.

[0960] (4) Compound-treated cells (Day 0):

[0961] a) 24 hours after cell plating, the compound prepared in step (3) was diluted 333.3-fold with complete culture medium, and 50 μL was pipetted into the corresponding cell plate. The cell plate was then incubated in a 37° C., 5% CO 2 incubator for 3 days.

[0962] b) Final concentration of test compound: Staurosporine (10000, 3333, 1111, 370, 123, 41, 13.72, 4.57, 1.52, 0 nM); test compound (10000, 3333, 1111, 370, 123, 41, 13.72, 4.57, 1.52, 0 nM);

[0963] (5)CTG method detection (Day 3)

[0964] a) Add 60 μL of CTG reagent (CelltiterGlo kit) to each well, shake on a high-speed shaker for 3 minutes, and incubate at room temperature in the dark for 30 minutes;

[0965] b) Read the chemiluminescent signal using an Envision instrument.

[0966] (6) Data Analysis

[0967] EC was calculated using GraphPad Prism 8 software. 50 , using the nonlinear fitting formula to obtain the EC of the compound 50 (50% effective concentration):

[0968] X: Log value of compound concentration, Y: Viability

[0969] Y: %Viability=RLU treatment / RLU Avg(High control)*100

[0970] %Viability: viability;

[0971] RLU treatment: compound well reading;

[0972] RLU Avg (High control): Average reading of the high read value control wells.

[0973] (7) Experimental results

[0974] Follow the above steps to perform the experiment and calculate the viability based on the readings. Apply the calculated cell viability to obtain EC 50 The fitting curve is shown in Table 4 below.

[0975] Table 4: Inhibitory activity of compounds on hPBMC cells

[0976] Conclusion: At low concentrations, Examples 10 and 33 of the present invention had no effect on hPBMC cell viability; at high concentrations, Examples 10 and 33 had certain cytotoxicity, but were comparable to the toxicity of the known patented positive reference molecule Cmp I-28 (WO2022216680A).

[0977] Among them, Staurosporine has the following structural formula:

[0978] 4. Inhibitory activity of compounds on HepG2 cell proliferation (CGT test)

[0979] Experimental methods and results:

[0980] (1) Cell recovery and culture: HepG2 cells were cultured in MEM medium supplemented with 1% double antibody and 10% FBS at 37°C and 5% CO2.

[0981] (2) Cell plating (Day 1):

[0982] a) Cells are routinely cultured until the cell saturation reaches 80-90%. When the cell number reaches the required level, the cells are harvested;

[0983] b) Resuspend the cells with corresponding complete culture medium and count the cells. When the cell viability is above 95%, prepare a cell suspension with appropriate density using complete culture medium. The cell density is shown in 5.

[0984] Table 5 Cells and cell density

[0985] c) Add the cell suspension to a 384-well plate, 35 μL per well, in duplicate;

[0986] d) The cells were cultured in a 37°C, 5% CO2 incubator overnight.

[0987] (3) Compound-treated cells (Day 0):

[0988] a) Staurosporine was diluted 3-fold in DMSO to 9 concentrations starting from 1 mM;

[0989] b) 4 test compounds were diluted 4-fold with DMSO to 9 concentrations starting from 10 mM;

[0990] c) The high-reading control wells contained 0.1% DMSO, and the low-reading control wells contained no cell culture medium.

[0991] (4) Compound-treated cells (Day 0):

[0992] a) 24 hours after cell plating, 35 nL of the compound prepared in step (3) was added to the corresponding cell plate using Echo, and the cell plate was then incubated in a 37° C., 5% CO 2 incubator for 3 days.

[0993] b) Final concentration of test compound: Staurosporine (1000, 333, 111, 37.0, 12.3, 4.12, 1.37, 0.46, 0.15, 0 nM); test compound (10000, 2500, 625, 156, 39.06, 9.77, 2.44, 0.61, 0.15, 0 nM);

[0994] (5)CTG method detection (Day 3)

[0995] a) Add 20 μL of CTG reagent (CelltiterGlo kit) to each well, shake on a high-speed shaker for 3 minutes, and incubate at room temperature in the dark for 30 minutes;

[0996] b) Read the chemiluminescent signal using an Envision instrument.

[0997] (6) Data Analysis

[0998] IC was calculated using GraphPad Prism 8 software. 50 , using the nonlinear fitting formula to obtain the IC of the compound 50 (50% effective concentration):

[0999] X: Log value of compound concentration, Y: inhibition rate (%inhibition)

[1000] Inhibition rate (% inhibition) = 100-(compound well reading-low reading control well average reading) / (high reading control well average reading-low reading control well average reading)*100

[1001] (7) Experimental results

[1002] Follow the above steps to perform the experiment and calculate the inhibition rate based on the reading. Apply the calculated cell viability inhibition rate to obtain IC 50 The fitting curve is shown in Table 6.

[1003] Table 6: Inhibitory activity of compounds on HepG2 cells

[1004] Conclusion: Examples 10 and 33 of the present invention have strong inhibitory activity against HepG2 cells, which is comparable to the inhibitory activity of the known patented positive reference molecule Cmp I-28 (WO2022216680A).

[1005] 5. Pharmacokinetic evaluation

[1006] 5.1 Pharmacokinetic evaluation in rats

[1007] Male SD rats were divided into groups of 3 per group and were administered the example compound (10 mg / kg) orally ...

[1008] Table 7: Pharmacokinetic parameters of the compound after intravenous administration of 2 mg / kg in rats

[1009] Table 8: Pharmacokinetic parameters of different compounds after oral administration to rats at 10 mg / kg

[1010] Conclusion: In rat tests, the intravenous PK of Example 10 of the present invention is superior to that of the patented positive reference molecule Cmp I-28 (WO2022216680A), and the intravenous and oral pharmacokinetic parameters of Examples 33, 57 and 60 are significantly superior to those of the known patented positive reference molecule Cmp I-28 (WO2022216680A).

[1011] 5.2 Pharmacokinetic evaluation in mice

[1012] 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.

[1013] Table 9: Pharmacokinetic parameters of different compounds after oral administration to mice at 10 mg / kg

[1014] Conclusion: The compounds of the present invention have good pharmacokinetic properties when tested in mice. In particular, the oral pharmacokinetic parameters of Example 79 are significantly better than those of the known compound Ofirnoflast (HT-6184).

[1015] 6. Safety evaluation of hERG cardiotoxicity

[1016] The test substance and positive control concentrations were prepared by diluting the example stock solution (10 mM) 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 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 sonicated for 20 minutes. The Cisapride (positive control) stock solution (10 mM) was diluted 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%.

[1017] Experimental equipment: HEKA EPC 10 patch clamp amplifier.

[1018] 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.

[1019] 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.

[1020] 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;

[1021] Among them, Peak tail current compound Peak tail current control It represents the peak-to-tail current of blank control.

[1022] Table 10: Inhibitory effect of compounds on cardiac hERG potassium channels

[1023] Conclusion: Examples 22, 57, 58, 59, 60, 80 and 82 of the present invention have weaker inhibitory effects on cardiac hERG potassium channels than Ofirnoflast (HT-6184) and are safer.

[1024] 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 as shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled form, isomer or prodrug thereof, in, 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 in, L is a direct key, O or CR 21 R 22 ; R L To replace 0-4 R C C 6-10 Aryl, substituted with 0-4 R C C 3-10 Cycloalkyl, substituted with 0-4 R C 3-10 membered heterocyclic group or substituted with 0-4 R C A 5-6 membered heteroaryl group; X1 for CR 31 or N; X2 is C or N; X3 for CR 32 or N; X4 is C or N; Z1 is CH or N; Z2 is O or S; Z3 is C or N; Z4 is C or N; In ring 1 This indicates the presence of a conjugated double bond in ring 1; R1 is selected from 0-4 R 0 C 6-10 Aryl, substituted with 0-4 R 0 C 3-10 Cycloalkyl, 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 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 ; R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; R A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R B are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, substituted with 0-4 R B1 C 6-10 Aryl, substituted with 0-4 R B1 C 3-10 Cycloalkyl, substituted with 0-4 R B1 3-10 membered heterocyclic group or substituted with 0-4 R B1 A 5-6 membered heteroaryl group; 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 Haloalkyl; R C are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 31 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 32 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 , R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 , R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, substituted with 0-4 R 70 C 6-10 Aryl, substituted with 0-4 R 70 C 3-10 Cycloalkyl, substituted with 0-4 R 70 3-10 membered heterocyclic group or substituted with 0-4 R 70 A 5-6 membered heteroaryl group; R 70 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 1-membered heterocyclic group or NR 11 R 12 ; R 0 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group or NR 11 R 12 ; 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 Haloalkyl; 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 21 and R 22 Together with the connected carbon, it forms C 3-6 Cycloalkyl; n is 1 or 2.

2. The compound according to claim 1, wherein 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 monocyclic heteroaryl group.

3. The compound according to claim 2, wherein Ring A is substituted with 0 or 1 R A benzene ring.

4. The compound according to claim 2, wherein Ring A is substituted with 0 or 1 R A of the pyridine ring.

5. The compound according to claim 2, wherein Ring A is substituted with 0 or 1 R A pyrimidine ring.

6. The compound according to any one of claims 1 to 5, wherein R A For halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

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

8. The compound according to any one of claims 1 to 7, wherein R2 is hydrogen.

9. The compound according to any one of claims 1 to 7, wherein R1 is substituted with 0-4 R 0 C 3-10 Cycloalkyl, substituted with 0-4 R 0 3-10 membered heterocyclic group or substituted with 0-4 R 0 C 1-6 alkyl; R 0 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

10. The compound according to any one of claims 1 to 7, wherein R1 is C 3-10 Cycloalkyl is, for example, cyclopropyl.

11. The compound according to any one of claims 1 to 7, wherein R1 is substituted with 0-1 R 0 3-10 membered heterocyclic group, substituted with 0-1 R 0 C 2-6 Alkenyl or substituted with 0-1 R 0 C 1-6 alkyl; R 0 Each independently selected from halogen, hydroxyl, cyano or C 1-3 Alkoxy.

12. The compound according to claim 11, wherein R1 is one of the following groups:

13. A compound according to any one of claims 1 to 12, wherein R is isoxazolyl substituted with one R7, oxazolyl substituted with one R7, oxadiazolyl substituted with one R7, triazolyl substituted with one R7, thiazolyl substituted with one R7, isothiazolyl substituted with one R7, or thiadiazolyl substituted with one R7; Wherein R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, substituted with 0-1 R 70 C 6-10 Aryl, substituted with 0-1 R 70 C 3-10 Cycloalkyl, substituted with 0-1 R 70 3-10 membered heterocyclic group or substituted with 0-1 R 70 A 5-6 membered heteroaryl group; 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.

14. A compound according to any one of claims 1 to 12, wherein R has the following structure In the above structure It indicates the presence of conjugated double bonds within the ring structure; Wherein R7 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl 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 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3-8 membered heterocyclic group; Z2 is O or S; Z3 is C or N; Z4 is C or N.

15. The compound according to claim 14, wherein Z2 is O, Z3 is CH, and Z4 is N; or Z2 is N, Z3 is CH, and Z4 is O; or Z2 is S, Z3 is CH, and Z4 is N; or Z2 is S, Z3 is N, and Z4 is N.

16. The compound according to claim 14, wherein R has one of the following structural formulas or Among them, R Ba C 1-6 Alkyl, C 1-6 Haloalkyl or substituted with 1 R B1a C 3-6 Cycloalkyl, Where R B1a C 1-6 Alkyl or C 1-6 Halogenated alkyl.

17. A compound according to any one of claims 1 to 10, wherein R has the following structure 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 Haloalkyl; R4 has the following structure L is O, CH2, CF2, CD2 or R L For substitution there are 0-1 R C C 6-10 Aryl, substituted with 0-1 R C C 3-10 Cycloalkyl, substituted with 0-1 R C 3-10 membered heterocyclic group or substituted with 0-1 R C A 5-6 membered heteroaryl group; R C Halogen or C 1-6 alkyl.

18. The compound according to claim 17, wherein R B is hydrogen or C 1-6 haloalkyl, such as trifluoromethyl; L is O, CH2, CF2, CD2 or R L To replace there is 1 R C A 3-10 membered heterocyclic group; R C Halogen or C 1-3 alkyl.

19. A compound according to any one of claims 1 to 18, wherein R L Has one of the following structures or Among them, R Bb C 1-6 alkyl.

20. The compound according to claim 17, wherein R has one of the following structural formulas Wherein, L is O or CH2; R Bb C 1-3 Alkyl; R Bc is hydrogen or C 1-3 Haloalkyl is for example trifluoromethyl.

21. A compound according to any one of claims 1 to 12, wherein R has the following structure R4 has one of the following structures or Among them, R Bb C 1-6 alkyl; R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 , R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 , R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl; n is 1 or 2.

22. The compound according to claim 21, wherein R has the following structural formula or, in, R 51 and R 52 are each independently selected from hydrogen, halogen, deuterium or tritium, or R 51 , R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R 61 and R 62 are each independently selected from hydrogen, halogen, deuterium or tritium, or R 61 , R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R Bb C 1-6 alkyl; n=1 or 2.

23. A compound according to any one of claims 1 to 22, wherein X1 and X2 are both N, X3 is CH, and X4 is C.

24. A compound according to any one of claims 1 to 22, wherein X1, X2 and X3 are all N, and X4 is C.

25. A compound according to any one of claims 1 to 22, wherein X1 and X3 are both CH, X2 is C, and X4 is N.

26. A compound according to any one of claims 1 to 22, wherein X1 and X3 are both CH, X2 is N, and X4 is C.

27. A compound according to any one of claims 1 to 22, wherein X1 and X4 are both N, X2 is C, and X3 is CH.

28. A compound according to any one of claims 1 to 22, wherein X1 is CH, X2 and X3 are N, and X4 is C.

29. A compound according to any one of claims 1 to 22, wherein X1 is CH, X2 is C, and X3 and X4 are both N.

30. A compound according to any one of claims 1 to 20, wherein X1, X3 and X4 are all N, and X2 is C.

31. The compound according to claim 1, wherein The compound has the structure of Formula IA in, R is one of the following structural formulas or, R4 is the following group in, L is a direct key, O or CR 21 R 22 ; R L To replace 0-4 R C C 6-10 Aryl, substituted with 0-4 R C C 3-10 Cycloalkyl, substituted with 0-4 R C 3-10 membered heterocyclic group or substituted with 0-4 R C A 5-6 membered heteroaryl group; X1 for CR 31 or N; X2 is C or N; X3 for CR 32 or N; X4 is C or N; X5 for CR 33 or N; Z1 is CH or N; Z2 is O or S; Z3 is C or N; Z4 is C or N; In ring 1 This indicates the presence of a conjugated double bond in ring 1; R1 is selected from 0-4 R 0 C 6-10 Aryl, substituted with 0-4 R 0 C 3-10 Cycloalkyl, 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 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 ; R B are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, substituted with 0-4 R B1 C 6-10 Aryl, substituted with 0-4 R B1 C 3-10 Cycloalkyl, substituted with 0-4 R B1 3-10 membered heterocyclic group or substituted with 0-4 R B1 A 5-6 membered heteroaryl group; 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 Haloalkyl; R C are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 31 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 32 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 33 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 , R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 , R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, substituted with 0-4 R 70 C 6-10 Aryl, substituted with 0-4 R 70 C 3-10 Cycloalkyl, substituted with 0-4 R 70 3-10 membered heterocyclic group or substituted with 0-4 R 70 A 5-6 membered heteroaryl group; R 70 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group or NR 11 R 12 ; R 0 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group or NR 11 R 12 ; 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 Haloalkyl; 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 21 and R 22 Together with the connected carbon, it forms a C3-6 cycloalkyl group; n is 1 or 2.

32. The compound according to claim 31, wherein X5 for CR 33 , where R 33 is fluorine, hydrogen, methoxy or trifluoromethoxy.

33. The compound according to claim 31, wherein X5 is N.

34. The compound according to claim 31, wherein R1 is substituted with 0-1 R 0 C 3-10 Cycloalkyl, substituted with 0-1 R 0 3-10 membered heterocyclic group or substituted with 0-1 R 0 C 1-6 alkyl; R 0 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

35. The compound according to claim 31, wherein R1 is C 3-10 Cycloalkyl is, for example, cyclopropyl.

36. The compound according to claim 31, wherein R1 is substituted with 0-1 R 0 3-10 membered heterocyclic group, substituted with 0-1 R 0 C 2-6 Alkenyl or substituted with 0-1 R 0 C 1-6 alkyl; R 0 Each independently selected from halogen, hydroxyl, cyano or C 1-3 Alkoxy.

37. The compound according to claim 36, wherein R1 is one of the following groups:

38. The compound according to claim 31, wherein X1 and X2 are both N, X3 is CH, and X4 is C; or X1, X2 and X3 are all N, and X4 is C; or X1 and X3 are both CH, X2 is C, and X4 is N; or X1 and X3 are both CH, X2 is N, and X4 is C; or X1 and X4 are both N, X2 is C, and X3 is CH; or X1 is CH, X2 and X3 are N, and X4 is C; or X1 is CH, X2 is C, and X3 and X4 are both N; or X1, X3 and X4 are all N, and X2 is C.

39. The compound according to claim 31, wherein R has the following structure In the above structure It indicates the presence of conjugated double bonds within the ring structure; Wherein R7 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl 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 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3-8 membered heterocyclic group; Z2 is O or S; Z3 is C or N; Z4 is C or N.

40. The compound according to claim 39, wherein Z2 is O, Z3 is CH, and Z4 is N; or Z2 is N, Z3 is CH, and Z4 is O; or Z2 is S, Z3 is CH, and Z4 is N; or Z2 is S, Z3 is N, and Z4 is N.

41. The compound according to claim 39, wherein R has one of the following structural formulas or Among them, R Ba C 1-6 Alkyl, C 1-6 Haloalkyl or substituted with 1 R B1a C 3-6 Cycloalkyl, Where R B1a C 1-6 Alkyl or C 1-6 Halogenated alkyl.

42. The compound according to claim 31, wherein R has the following structure 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 Haloalkyl; R4 has the following structure L is O, CH2, CF2, CD2 or R L For substitution there are 0-1 R C C 6-10 Aryl, substituted with 0-1 R C C 3-10 Cycloalkyl, substituted with 0-1 R C 3-10 membered heterocyclic group or substituted with 0-1 R C A 5-6 membered heteroaryl group; R C Halogen or C 1-6 alkyl.

43. The compound according to claim 42, wherein R B is hydrogen or C 1-6 haloalkyl such as trifluoromethyl; L is O, CH2, CF2, CD2 or R L To replace there is 1 R C A 3-10 membered heterocyclic group; R C C 1-3 alkyl.

44. The compound according to claim 42, wherein R L Has one of the following structures or Among them, R Bb C 1-6 alkyl.

45. The compound according to claim 42, wherein R has one of the following structural formulas Wherein, L is O or CH2; R Bb C 1-3 alkyl.

46. ​​The compound according to claim 45, wherein R Bb is methyl; R Bc It is hydrogen or trifluoromethyl.

47. The compound according to claim 31, wherein R has the following structure R4 has one of the following structures or Among them, R Bb C 1-6 alkyl; R 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 51 , R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium or C 1-6 Alkyl, or R 61 , R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl; n is 1 or 2.

48. The compound according to claim 47, wherein R has the following structural formula or, in, R 51 and R 52 are each independently selected from hydrogen, halogen, deuterium or tritium, or R 51 , R 52 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R 61 and R 62 are each independently selected from hydrogen, halogen, deuterium or tritium, or R 61 , R 62 and the carbons to which they are connected together form C 3-6 Cycloalkyl; R Bb C 1-6 alkyl; n=1 or 2.

49. A compound according to any one of claims 41 to 48, wherein R Bb It is methyl.

50. The compound shown in formula II or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled form, isomer or prodrug thereof, in, X1 for CR 31 or N; X2 is C or N; X3 for CR 32 or N; X4 is C or N; X5 for CR 33 or N; In ring 1 This indicates the presence of a conjugated double bond in ring 1; R1 is selected from 0-4 R 0 C 6-10 Aryl, substituted with 0-4 R 0 C 3-10 Cycloalkyl, 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 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 ; R 31 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 32 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 33 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 Hydroxyalkyl or C 1-6 Haloalkyl; R 0 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group or NR 11 R 12 ; 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 Haloalkyl; Ring B is a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O or S, and the ring B is substituted with m R8; R8 are each independently selected from protium, deuterium, tritium, halogen, hydroxyl, cyano, optionally substituted with R 80 C 1-6 Alkyl, optionally substituted with R 80 C 1-6 Alkoxy, optionally substituted with R 80 C 3-6 Cycloalkyl, optionally substituted with R 80 C 6-10 Aryl, optionally substituted with R 80 3-10 membered heterocyclic group, -CONR 81 R 82 Or-COR 83 ; R 80 are each independently selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; R 81 and R 82 are each independently selected from hydrogen or C 1-6 alkyl; R 83 Selected from C 1-6 alkyl; m is 1, 2 or 3.

51. The compound according to claim 50, wherein Ring B is selected from one of the following structural formulas: in, Indicates the position where the B ring is connected to the NH in the structure of formula II; The B ring is substituted with two R8s.

52. The compound according to claim 50, wherein Ring B has the following structural formula: The B ring is substituted with 2 to 3 R8.

53. The compound according to claim 51 or 52, wherein Two R8 are optionally hydrogen, deuterium, tritium, halogen, substituted with R 80 C 1-6 alkyl, the other R8 is optionally substituted with R 80 The aromatic group.

54. The compound according to claim 50, wherein X5 for CR 33 , where R 33 is fluorine, hydrogen, methoxy or trifluoromethoxy.

55. The compound according to claim 50, wherein X1 and X2 are both N, X3 is CH, and X4 is C; or X1, X2 and X3 are all N, and X4 is C; or X1 and X3 are both CH, X2 is C, and X4 is N; or X1 and X3 are both CH, X2 is N, and X4 is C; or X1 and X4 are both N, X2 is C, and X3 is CH; or X1 is CH, X2 and X3 are N, and X4 is C; or X1 is CH, X2 is C, and X3 and X4 are both N; or X1, X3 and X4 are all N, and X2 is C.

56. The compound according to claim 50, wherein X1 and X2 are both N, X3 is CH, and X4 is C.

57. The compound according to claim 50, wherein The compound has the structural formula II-1 Wherein R1 is substituted with 0-1 R 0 C 3-10 Cycloalkyl, substituted with 0-1 R 0 3-10 membered heterocyclic group or substituted with 0-1 R 0 C 1-6 alkyl; R 0 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; R 33 Halogen or C 1-6 alkyl; R 91 is optionally substituted with R 90 C 1-6 Alkyl, optionally substituted with R 90 C 3-6 Cycloalkyl, optionally substituted with R 90 C 3-6 Cycloalkyl, optionally substituted with R 90 A 3-10 membered heterocyclic group; R 92 is optionally substituted with R 90 Phenyl or optionally substituted with R 90 A 3-10 membered heterocyclic group; R 93 For protium, deuterium, tritium, halogen or C 1-6 alkyl; R 90 Each independently selected from protium, deuterium, tritium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl.

58. The compound according to claim 57, wherein R1 is C 3-6 Cycloalkyl is, for example, cyclopropyl.

59. The compound according to claim 57, wherein R 91 C 1-6 Alkyl such as tert-butyl, R 92 is optionally substituted with R 90 Phenyl, R 90 are each independently selected from halogen such as fluorine, C 1-6 Alkyl such as methyl, ethyl or isopropyl, or C 1-6 Alkoxy groups such as methoxy; R 93 For hydrogen.

60. The compound according to claim 57, wherein R 91 is optionally substituted with R 90 C 3-6 Cycloalkyl, R 90 Each independently selected from C 1-6 Haloalkyl, such as R 91 for R 92 is optionally substituted with R 90 Phenyl, R 90 are each independently selected from halogen such as fluorine, C 1-6 Alkyl such as methyl, ethyl or isopropyl, or C 1-6 Alkoxy groups such as methoxy; R 93 For hydrogen.

61. The compound according to claim 59 or 60, wherein R 92 One of the following structures:

62. The compound according to claim 1 or 50, wherein The compound is selected from one of the following:

63. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 62 and a pharmaceutically acceptable carrier, diluent or excipient.

64. A method for treating or preventing a NEK7-NLRP3 interactively mediated disorder, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 62 or a pharmaceutical composition of claim 63.

65. The method of claim 64, wherein the disorder is selected from the group consisting of autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases, and ischemic conditions.

66. The method of claim 64 or 65, wherein the 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 Muller-Weiss syndrome.

67. The method of claim 64, 65, or 66, wherein the NEK7-NLRP3-interacting disorder is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndromes, cryptopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL 1 receptor antagonist), Alzheimer's disease, Parkinson's disease, and cancer.

68. Use of a compound as claimed in any one of claims 1 to 62 in the preparation of a medicament for treating or preventing a disorder mediated by the interaction of NEK7-NLRP3.

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