• 专利附录
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    • 专利摘要:
    there is disclosed in the present invention a compound as shown in formula (ii), a tautomer or a pharmaceutically acceptable salt thereof and the use of them in the preparation of a drug to treat a disease associated with ask1 is also disclosed.
    公开号:BR112019014756A2
    申请号:R112019014756-0
    申请日:2018-01-22
    公开日:2020-03-03
    发明作者:Wu Chengde；Yu Tao；Li Ning；Chen Shuhui
    申请人:Fujian Cosunter Pharmaceutical Co., Ltd.；
    IPC主号:
    专利说明:

    PYRIDINE DERIVATIVE AS ASK1 INHIBITOR AND METHOD OF PREPARATION AND USE OF THE SAME
    CROSS REFERENCE TO RELATED APPLICATION [001] This application claims the priority of Chinese Patent Application N 2 CN201710054224.4 filed on January 22, 2017, the contents of which are incorporated here in this application.
    FIELD OF THE INVENTION [002] The present invention relates to a compound as shown in formula (II), a tautomer thereof or a pharmaceutically acceptable salt thereof and a use thereof in the manufacture of a medicament to treat diseases related to ASK1 .
    PREVIOUS [003] Apoptosis signal regulator kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family. ASK1 can be activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF-ot, FasL, endoplasmic reticulum stress, increased intracellular calcium concentration and the like. ASK1 responds to the variety of stimuli by activating JNK (c-Jun Nterminal kinase) and protein kinases activated by mitogen p38 and induces a variety of apoptosis through signals involving the mitochondrial cell death pathway. ASK1 activation and signaling play an important role in a wide range of diseases, including neurodegenerative diseases,
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    2/105 cardiovascular, inflammatory diseases, autoimmune diseases and metabolic disorders. Therefore, when the patient suffers from neurodegenerative disease, cardiovascular disease, inflammation, autoimmune disease and metabolic disease, the patient's life can be improved by using ASK1 inhibitors as therapeutic agents.
    CONTENTS OF THE PRESENT INVENTION [004] The present invention provides a compound as shown in formula (II), a pharmaceutically acceptable salt thereof and a tautomer thereof,
    N * X.
    x 3 - *, 'n
    R 2
    R.
    at least one of Xi, X2 and X3 is N, the remainder of which is CH;
    n is selected from 0 or 1;
    Rié selected from H, F, Cl, Br, I, OH, NH2, or selected from the group consisting of C1-4 alkyl, C1-4 heteroalkyl, 3 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl , each of which is optionally substituted with R;
    R2 is selected from H, F, Cl, Br, I;
    Rs is selected from H, F, Cl, Br, I, OH, NH2;
    R is selected from F, Cl, Br, I, OH, NH2, or selected from the group consisting of C1-3 alkyl, C1-3 alkoxy and 3 to 6 heterocycloalkyl
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    3/105 members, each of which is optionally substituted with 1, 2 or 3 R ';
    R 'is selected from the group consisting of F, Cl, Br, I, OH, NH2 and C1-3 alkyl;
    each hetero on C1-4 heteroalkyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl is independently selected from the group consisting of -NH-, N, -O- and -S-;
    in any of the above cases, the number of the heteroatom or heteroatomic group is independently selected from 1, 2 or 3.
    [005] In some embodiments of the present invention, the above R is selected from F, Cl, Br, I, OH, NH2, or selected from the group consisting of Me, and each of which is optionally substituted with 1, 2 or 3 R ';
    [006] In some embodiments of the present invention, the above R is selected from the group consisting of F, Cl, Br, I, OH, NH2, Me, oZZ ^ and oC / [007] In some embodiments of the present invention, the above Ri is selected from H, F, Cl, Br, I, OH, NH2, or selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, C1-3 alkylamino, morpholinyl and pyridyl, each one of which is optionally substituted with 1, 2 or 3 R and other variables are as defined in the present invention.
    [008] In some embodiments of the present invention, the above Ri is selected from H, F, Cl, Br, I, OH, NH2, or selected from the group
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    4/105 consisting of Me,,, ° '', H ,

    , each of which is optionally substituted with 1, 2 or 3 R and other variables are as defined in the present invention.
    [009] In some embodiments of the present invention, the above Ri is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, Me,
    in the present invention.
    [010] In some embodiments of the present invention, the portion
    above is selected from the group consisting of


    and other variables are as defined in the present invention.
    [011]
    In some embodiments of the present invention, the portion
    above is selected from the group consisting of
    variables are as defined in the present invention.
    [012] Other embodiments of the present invention can be obtained by arbitrarily combining the above variables.
    [013] In some embodiments of the present invention, the above compound,
    Petition 870190067738, of 7/17/2019, p. 117/336
    5/105 the pharmaceutically acceptable salt thereof and the tautomer thereof are selected from the group consisting of
    wherein, Χι, Χζ, Xs, Ri, R2 and R3 are as defined in the present invention.
    [014] In some embodiments of the present invention, the above compound, the pharmaceutically acceptable salt thereof and the tautomer thereof are selected from the group consisting of
    on what,
    Ri, R2 and R3 are as defined in the present invention.
    [015] The present invention also provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof and a tautomer thereof:
    at least one of Xi, X2 and X3 is N, the remainder of which is CH;
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    6/105
    n is 0 or 1;
    [016] In some embodiments of the present invention, the portion above is selected from the group consisting of


    [017]
    In some embodiments of the present invention, the portion
    above is selected from the group consisting of

    [018] In some embodiments of the present invention, the portion
    above is selected from the group consisting of


    and other variables are as defined in the present invention.
    [019]
    In some embodiments of the present invention, the portion
    above is selected from the group consisting of

    and other variables are as defined in the present invention.
    [020] Other embodiments of the present invention can be obtained by arbitrarily combining the above variables.
    [021] In some embodiments of the present invention, the above compound,
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    7/105 the pharmaceutically acceptable salt thereof and the tautomer thereof are selected from the group consisting of
    wherein, Χι, Χζ and X3 are as defined in the present invention.
    [022] In some embodiments of the present invention, the above compound, its pharmaceutically acceptable salt and its tautomer are selected from the group consisting of
    wherein, n is as defined in the present invention.
    [023] The present invention also provides a compound, a pharmaceutically acceptable salt thereof and a tautomer thereof which are selected from the group consisting of
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    8/105



    [024] The present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt thereof as the active principle and a pharmaceutically acceptable carrier.
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    9/105 [025] The present invention also provides a use of the above compound or the pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat ASK1-related diseases.
    [026] The present invention also provides a use of the above composition in the manufacture of a medicament to treat ASK1-related diseases.
    TECHNICAL EFFECT [027] As a new inhibitor of ASK1, the compound of the present invention has a significant inhibitory effect against ASK1. However, the compound of the present invention has good drugability due to its good solubility, permeability and the like, specific targeting and metabolic stability.
    DEFINITION AND DESCRIPTION [028] Unless otherwise indicated, the following terms when used in the descriptions and claims of the present invention have the following meanings. A specific term or phrase should not be considered indefinite or uncertain in the absence of a particular definition, but it should be understood in the usual sense. When a trade name appears in the present invention, it is intended to refer to its corresponding commodity or active ingredient therein. The term pharmaceutically acceptable is used in the present invention in terms of those compounds, materials, compositions, and / or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of medical judgment.
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    10/105 reliable, without any excessive toxicity, irritation, allergic reaction or other problems or complications, proportional to a reasonable risk / benefit ratio.
    [029] The term pharmaceutically acceptable salt refers to a salt of the compound of the present invention that is prepared by reacting the compound having a specific substituent of the present invention with a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by bringing the neutral form of the compound into contact with a sufficient amount of base in a pure solution or a suitable inert solvent. The pharmaceutically acceptable base addition salt includes a sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by bringing the neutral form of the compound into contact with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salt include an inorganic acid salt, wherein the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, phosphate dihydrogen, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid and the like; and an organic acid salt, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, submeric acid,
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    11/105 fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; and an amino acid salt (such as arginine and the like) and a salt of an organic acid such as glycuronic acid and the like (refer to Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Science 66: 1 - 19 (1977 )). Certain specific compounds of the present invention that contain both basic and acidic functional groups can be converted to any base or acid addition salt.
    [030] Preferably, by bringing the salt into contact with a base or an acid in a conventional manner, then separating the parent compound, the neutral form of the compound is thereby regenerated. The difference between the precursor form of the compound and its varied salt forms is found in specific physical properties, such as different solubility in a polar solvent.
    [031] Pharmaceutically acceptable salt used here belongs to a derivative of the compound of the present invention, wherein the parent compound is modified to form a salt with an acid or a base. Examples of the pharmaceutically acceptable salt include, but are not limited to, a basic portion inorganic acid or organic acid salt such as amine, an alkali metal salt or an acidic organic salt such as carboxylic acid and the like. The pharmaceutically acceptable salt includes conventional non-toxic salt or quaternary ammonium salt of the precursor compound, such as a
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    12/105 salt formed by a non-toxic inorganic acid or an organic acid. The conventional non-toxic salt includes, but is not limited to, the salt derived from an inorganic acid and an organic acid, in which the inorganic acid or organic acid is selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glycoeptosis, glyconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyl, hydroxyl, hydroxyl hydroxinaphthalene, isethionic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacthanic acid, propionic acid, salicylic acid, stearic acid, acid subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid and ptoluenesulfonic acid.
    [032] The pharmaceutically acceptable salt of the present invention can be prepared from the precursor compound which contains an acidic or basic portion by conventional chemical method. Generally, such a salt can be prepared by reacting the acid or free base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
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    13/105 [033] In addition to the salt form, the compound provided by the present invention also exists in the form of prodrug. The prodrug of the compound described in the present invention is the compound that easily undergoes chemical change under physiological condition to be converted into the compound of the present invention. In addition, the prodrug can be converted to the compound of the present invention by a chemical or biochemical method in an in vivo environment.
    [034] Certain compounds of the present invention can exist in an unsolvated form or a solvated form, including hydrated form. Generally, the solvated form is equivalent to the unsolvated form and both fall within the scope of the present invention.
    [035] Certain compounds of the present invention may have an asymmetric carbon atom (optical center) or a double bond. The racemate, diastereomer, geometric isomer and single isomer are all within the scope of the present invention.
    [036] Unless otherwise specified, the absolute configuration of a stereogenic center is represented by a solid wedge-shaped bond (> *) and a dashed wedge-shaped bond ('), a wavy line (- ^ ) represents a solid wedge-shaped bond (> **) or a dashed wedge-shaped bond (- '') and the relative configuration of a stereogenic center is represented by a straight solid bond (****) and a dashed straight connection ('' Λ ). When the compound described in the present invention contains an olefinic double bond or additional geometric asymmetric centers,
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    14/105 geometric isomers E and Z are included unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present invention.
    [037] The compound of the present invention can have a specific geometric or stereoisomeric shape. The present invention considers all such compounds, including cis and trans isomer, (-) - and (+) - enantiomer, (/ ) - and (5) enantiomer, diastereoisomer, (D) -isomer, (L) -isomer and racemic mixture and other mixtures, for example, a mixture enriched with enantiomer or diastereoisomer, all of which are within the scope of the present invention. The substituent such as alkyl may have an additional asymmetric carbon atom. All of these isomers and mixtures thereof are within the scope of the present invention.
    [038] (/ ) - and (S) -optically active isomer, or D and L isomer can be prepared using chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer type of a certain compound of the present invention is to be obtained, the desired pure enantiomer can be obtained by asymmetric synthesis or chiral auxiliary derivative action followed by separation of the resulting diastereomeric mixture and dividing of the auxiliary group. Alternatively, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), the compound reacts with an appropriate optically active acid or base to form a salt of the diastereomeric isomer which is then subjected to resolution
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    15/105 diastereomeric using the conventional method in the art to provide the pure enantiomer. In addition, the enantiomer and diastereoisomer are generally isolated by chromatography using a chiral stationary phase and optionally combining with a chemical derivative method (such as carbamate generated from amine).
    [039] The compound of the present invention may contain an unnatural proportion of atomic isotope in one or more than one atom that constitutes the compound. For example, the compound can be radiolabeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 l) or C-14 ( 14 C). All isotopic variations of the compound of the present invention, whether radioactive or not, are within the scope of the present invention.
    [040] The term pharmaceutically acceptable carrier refers to any carrier or carrier medium that is capable of releasing an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance and has no toxic side effect on the host or patient. The representative carrier includes water, oil, vegetable and mineral, base cream, base lotion, ointment base and the like. The base includes a suspending agent, a thickener, a penetration enhancer and the like. Its formulations are well known to the person skilled in the art in the cosmetic or topical pharmaceutical fields. Additional carrier information can be referred to Remington: The Science and Practice of Pharmacy, 21- Ed., Lippincott, Williams & Wilkins (2005), the contents of which
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    16/105 are incorporated into the present invention by reference.
    [041] The term excipient generally refers to the carrier, diluent and / or vehicle needed to formulate an effective pharmaceutical composition.
    [042] For a drug or pharmacologically active agent, the term effective amount or therapeutically effective amount refers to a non-toxic but sufficient amount to achieve a desired effect of the drug or agent. For the oral dosage form of the present invention, an effective amount of the active substance in the composition refers to an amount necessary to obtain a desired effect when combined with another active substance in the composition. The effective amount varies from person to person and is determined depending on the age and general condition of the recipient as well as the specific active substance. The appropriate effective amount in an individual case can be determined by the person skilled in the art based on the routine experiment.
    [043] The term active ingredient, therapeutic agent, active substance or active agent refers to a chemical entity that can effectively treat the target disorder, disease or condition.
    [044] Optionally or optionally means that the subsequent event or condition may occur but is not necessary, so that the term includes the example in which the event or condition occurs and the example in which the event or condition does not occur.
    [045] The term substituted means that one or more than one atom
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    17/105 of hydrogen in a specific atom is replaced with the substituent, including variants of deuterium and hydrogen, as long as the valence of the specific atom is normal and the substituted compound is stable. When the substituent is an oxygen (ie, = 0), this means that two hydrogen atoms are replaced. Positions in an aromatic ring cannot be replaced with a ketone. The term optionally substituted means that an atom can be substituted with a substituent or not, unless otherwise specified, the type and number of the substituent can be arbitrary as long as they are chemically obtainable.
    [046] When any variable (such as R) occurs in the constitution or structure of the compound more than once, the definition of the variable at each occurrence is independent. Thus, for example, if a group is replaced with 0 to 2 R, the group can optionally be replaced with up to two R's, where the definition of R in each occurrence is independent. In addition, a combination of the substituent and / or its variant is permitted only when the combination results in a stable compound.
    [047] When the number of a link group is 0, such as - (CRR) o-, this means that the link group is a single link.
    [048] When one of the variables is selected from a single link, this means that the two groups linked by the single link are directly connected. For example, when L in A-L-Z represents a single bond, the structure of A-L-Z is actually A-Z.
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    18/105 [049] When a substituent is vacant, this means that the substituent does not exist. For example, when X is vague in A-X, the structure of A-X is actually A. When a bond of a substituent can be cross-linked to more than one atom in a ring, such a substituent can be attached to any atom in the ring.
    For example, the structural unit means that the substituent R can be located at any position in cyclohexyl or cyclohexadiene. When an enumerable substituent does not indicate by which atom it is attached to a compound included in the general chemical formula but not specifically mentioned, that substituent can be attached by any of its atoms. For example, pyridinyl as a substituent can be attached to the substituted group with any carbon atoms in the pyridine ring. When the enumerable link group does not indicate the link direction, the link direction is arbitrary, for example, the link group L contained in is -MW-, then -MW- can link to ring A and ring B to form m —W— (b in the same direction as reading order from left to right and forming wm
    B in the opposite direction to the reading order from left to right. A combination of the linking group, substituents and / or variants thereof is permitted only when such a combination may result in a stable compound.
    [050] Unless otherwise specified, the term hetero
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    19/105 represents a heteroatom or a heteroatomic group (for example, an atomic group containing a heteroatom), including the atom except carbon (C) and hydrogen (H), and the atomic group containing the above heteroatom, for example, including oxygen ( O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, = 0, = S, -C ( = O) O-, -C (= O) -, -C (= S) -, -S (= O), S (= O) 2- and the group consisting of -C (= O) N (H ) -, -N (H) -, -C (= NH) -, -S (= 0) 2N (H) - and S (= O) N (H) -, each of which is optionally substituted.
    [051] Unless otherwise specified, the term ring refers to a substituted or unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkyl, aryl or heteroaryl. The so-called ring includes a single ring, a connecting ring, a spiral ring, a cast ring or a bridged ring. The number of the atom in the ring is usually defined as the number of members of the ring, for example, a 5- to 7-membered ring means that 5-7 atoms are arranged in a ring. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Therefore, a 5- to 7-membered ring includes, for example, phenyl, pyridinyl and piperidinyl; on the other hand, the term 5- to 7-membered heterocycloalkyl ring includes pyridyl and piperidinyl, but excluding phenyl. The term ring also includes a ring system containing at least one ring, each ring independently meeting the above definition.
    [052] Unless otherwise specified, the term heterocycle or heterocycle refers to a stable monocyclic, bicyclic or tricyclic ring
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    20/105 containing a heteroatom or a heteroatomic group, which can be saturated, partially unsaturated or unsaturated (aromatic) and can contain carbon atoms and 1, 2, 3 or 4 ring hetero atoms independently selected from the group consisting of N, O and S, wherein any of the above heterocycle can be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p, p is 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined in the present invention). The heterocycle can be attached to the pendant group of any heteroatom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycle described in the present invention can be substituted on a portion of carbon or nitrogen. The nitrogen atom in the heterocycle is optionally quaternized. In a preferred embodiment, when the total number of S and O atoms of the heterocycle is more than 1, the heteroatom is not adjacent to each other. In another preferred embodiment, the total number of S and O atom of the heterocycle is not more than 1. As used in the present invention, the term aromatic or heteroaryl heterocyclic group refers to a stable monocyclic or bicyclic aromatic ring of 5 , 6 or 7 members or 7, 8, 9 or 10 membered bicyclic heterocyclic containing carbon atoms and 1, 2, 3 or 4 ring hetero atoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (ie, N or NR, where R is H or other
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    21/105 substituents already defined here). Nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) P , p is 1 or 2). It is worth noting that the total number of S and O atoms of an aromatic heterocycle is not more than one. The bridged ring is also included in the definition of the heterocycle. A bridged ring is formed when one or more than one atom (ie, C, O, N or S) bonds two non-adjacent carbon or nitrogen atoms. A preferred bridged ring includes, but is not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and a carbon-nitrogen group. It is worth noting that a bridge always converts a monocyclic ring to a tricyclic ring. In a bridged ring, the substituent on the ring may also be present on the bridge.
    [053] Examples of the heterocyclic compound include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptophuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetraoxazol, benzotazazole, benzotazazole, carbazolyl, carbolinyl, chromanyl, chromene, cinolinyl decahydroquinolinyl, 2 / - /, 6 / - / - 1,5,2-dithiazinyl, dihydrofuro [2,3b] tetrahydrofuranyl, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, l / - / -indazole ila, indolenila, indolinyl, indolizinyl, indolyl, 3 / - / - indole ila, isobenzofuranyl, isoindolyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naftiridinyl, 1,2- -oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
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    22/105 oxazolidinyl, oxazolyl, hydroxindolyl, pyrimidinyl, phenantridinyl, phenanthrolinyl, phenazin, phenothiazine, benzoxanthinyl, phenoloxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, piperinyl, pyridinyl, pyridinyl, pyridinyl, piperinyl, pyridinyl, piperinyl, pyridine , pyridazinyl, pyrido-oxazolyl, pyrido-imidazolyl, pyrido-thiazolyl, pyridinyl, pyrrolidinyl, pyrrolinyl, 2 / - / - pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4 / - / - quinolizinyl, quinoxalinyl, tetrahydroquinoline, tetrahydroquinoline , tetrazolyl, 6 / - / 1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 thiadiazolyl, tiantrenyl, thiazolyl, isothiazoliltienil , thieno-oxazolyl, thieno-thiazolyl, thieno-imidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl . Also included are fused ring compounds and spiro compounds.
    [054] Unless otherwise specified, the term hydrocarbyl or its hyponyms (for example, alkyl, alkenyl, alkynyl and aryl, etc.), alone or as part of another substituent, refers to a radical linear, branched or cyclic hydrocarbon or any combination thereof. They can be completely saturated (for example, alkyl), mono- or polyunsaturated (for example, alkenyl, alkynyl and aryl), they can be mono- or polysubstituted, they can be monovalent (for example, methyl), bivalent (for example, methylene ) or multivalent (for example, methylenyl), can also include a bivalent or multivalent group, have a specific number of carbon atoms (for example, C1-C12 indicates 1 to 12 atoms of
    Petition 870190067738, of 7/17/2019, p. 135/336
    23/105 carbon, Ci-iz is selected from Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, Cio, C11 and C12; C3-12 is selected from C3, C4, C5, Ce, C7, Cs, C9, Cio, C11 and C12). The term hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl and aromatic hydrocarbyl. Aliphatic hydrocarbyl includes linear and cyclic hydrocarbyl, specifically includes, but is not limited to, alkyl, alkenyl and alkynyl. Aromatic hydrocarbyl includes, but is not limited to, 6 to 12-membered aromatic hydrocarbyl such as phenyl, naphthyl and the like. In some embodiments, the term hydrocarbyl refers to a linear or branched group or a combination thereof that can be completely saturated, mono- or polyunsaturated and can include a divalent or multivalent group. Examples of the saturated hydrocarbyl group include, but are not limited to, methyl, ethyl, npropyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl and the homologous or isomer of n -amyl, n-hexyl, n-heptyl, n-octyl and other atom groups. Unsaturated hydrocarbyl has one or more than one double or triple bond. Examples of unsaturated alkyl include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and more homologues and higher isomers.
    [055] Unless otherwise specified, the term heterohydrocarbyl or its hyponyms (such as heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl, etc.), alone or as part of another substituent, refers to a hydrocarbon group linear, branched or stable
    Petition 870190067738, of 7/17/2019, p. 136/336
    24/105 cyclic or any combination thereof, which has a specific number of carbon atoms and at least one heteroatom. In some embodiments, the term heteroalkyl alone or in combination with another term refers to a stable, straight chain, branched hydrocarbon radical or a combination thereof that has a specific number of carbon atoms and at least one heteroatom. In a specific embodiment, a heteroatom is selected from the group consisting of B, O, N and S, in which nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroatom or heteroatomic group can be located in any interior position of a heterohydrocarbyl, including the position where the hydrocarbyl attaches to the remainder of the molecule. But the terms alkoxy, alkylamino and alkylthio (or thioalkoxy) are used by conventional meaning and refer to an alkyl group connected to the remainder of the molecule via an oxygen atom, an amino or a sulfur atom respectively. Examples include, but are not limited to, -CH2-CH2O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH 3 ) -CH 3 , -CH2-S-CH2-CH3, -CH2 -CH2, -S (O) CH 3 , -CH2-CH2-S (O) 2 -CH 3 , -CH = CH-O-CH 3 , -CH2-CH = N-OCH 3 and -CH = CH- N (CH 3 ) -CH 3 . Up to two consecutive heteroatoms can be present, such as, -CH2-NHOCH3.
    [056] Unless otherwise specified, the term cyclohydrocarbyl, heterocyclohydrocarbyl or their hyponyms (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,
    Petition 870190067738, of 7/17/2019, p. 137/336
    25/105 cycloalkynyl, heterocycloalkyl, etc.) alone or in combination with another term refers to cyclized hydrocarbyl or heterohydrocarbyl. In addition, for heterohydrocarbyl or heterocyclohydrocarbyl (for example, heteroalkyl and heterocycloalkyl), a heteroatom can occupy the position where the heterocycle attaches to the remaining position of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3cyclohexenyl, cycloheptyl and the like. Non-limiting examples of heterocycloalkyl include 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2piperazinyl.
    [057] Unless otherwise specified, the term alkyl refers to a branched or straight chain saturated hydrocarbon group, may be monosubstituted (for example, -CH2F) or polysubstituted (for example, -CF3), may be monovalent ( for example, methyl), bivalent (for example, methylene) or multivalent (for example, methylenyl). Examples of alkyl include methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, s-butyl, t-butyl), pentyl (such as n- pentila, isopentila, neopentila) and the like.
    [058] Unless otherwise specified, the term alkenyl refers to an alkyl group having one or more than one carbon-carbon double bond at any position in the chain, it may be monosubstituted or
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    26/105 polysubstituted and can be monovalent, bivalent or multivalent. Examples of alkenyl include ethylene, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl and the like.
    [059] Unless otherwise specified, the term alkynyl refers to an alkyl group having one or more than one carbon-carbon triple bond at any position in the chain, may be monosubstituted or polysubstituted and may be monovalent, bivalent or multivalent. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like.
    [060] Unless otherwise specified, cycloalkyl includes any stable cyclic or polycyclic hydrocarbyl and any carbon atom is saturated, can be monosubstituted or polysubstituted and can be monovalent, bivalent or multivalent. Examples of cycloalkyl include, but are not limited to, cyclopropyl, norbornanil, [2,2,2] bicyclooctane, [4,4,0] bicyclodecanyl and the like.
    [061] Unless otherwise specified, cycloalkenyl includes any stable cyclic or polycyclic hydrocarbyl having one or more unsaturated carbon-carbon single bonds at any position in the ring, may be monosubstituted or polysubstituted and may be monovalent, bivalent or multivalent. Examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl and the like.
    [062] Unless otherwise specified, cycloalkynyl includes any stable cyclic or polycyclic hydrocarbyl having one or more bonds
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    27/105 carbon-carbon triples in any position in the ring, can be monosubstituted or polysubstituted and can be monovalent, bivalent or multivalent.
    [063] Unless otherwise specified, the term halo or halogen alone or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom. In addition, the term haloalkyl is intended to include monoaloalkyl and polyaloalkyl. For example, the term haloalkyl (C1-C4) is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4chlorobutyl, 3-bromopropyl and the like. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl.
    [064] The term alkoxy represents any alkyl defined above having a specific number of carbon atoms linked by an oxygen bridge. Unless otherwise specified, Ci-e alkoxy includes Ci, C2, C3, C4, C5 and Ce alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentoxy.
    [065] Unless otherwise specified, the term aryl refers to a polyunsaturated aromatic substituent, may be mono-, di- or polysubstituted, may be monovalent, bivalent or multivalent, may be a single ring or a multiple ring (for example, one to three rings; at least one ring is aromatic), which are fused together or covalently connected. The term heteroaryl refers to an aryl (or ring) containing
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    28/105 one to four heteroatoms. In an illustrative example, the heteroatom is selected from the group consisting of B, O, N and S, where nitrogen and sulfur atoms are optionally oxidized and nitrogen atom is optionally quaternized. A heteroaryl can attach to the remaining part of a molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyloxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl benzothiazyl, benzyl, benzyl, benzyl, benzyl, benzine , 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4oxazolyl, 2-phenyl-4-oxazolyl , 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3pyridyl , 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5quinoxalinyl, 3-quinolyl and 6-quinolyl. The substituent for any of the above aryl and heteroaryl ring system is selected from the acceptable substituent described below.
    [066] Unless otherwise specified, when aryl combines with other terms (such as aryloxy, arylthio, arylalkyl), aryl includes the aryl and heteroaryl ring as defined above. Thus, the term aralkyl is intended to include the group (for example, benzyl, phenethyl, pyridylmethyl, etc.) where an aryl is attached to an alkyl, including an alkyl where the carbon atom (for example,
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    29/105 methylene) was replaced with an atom such as oxygen, for example, phenoxymethyl, 2-pyridyloxy, 3- (1-naphthyloxy) propyl and the like.
    [067] The term leaving group refers to a functional group or atom that can be replaced with another functional group or atom through a substitution reaction (such as a nucleophilic substitution reaction). For example, representative starting groups include triflate; chlorine, bromine and iodine; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, ptoluenesulfonates and the like; acyloxy, such as acetoxy, trifluoroacetoxy and the like.
    [068] The term protection group includes, but is not limited to, amino protection group, hydroxy protection group or uncle protection group. The term amino protecting group refers to a protecting group suitable for blocking the side reaction in nitrogen of an amino. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (for example, acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-bis- (4'-methoxyphenyl) methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term hydroxy protection group refers to a protection group suitable for blocking the side reaction in hydroxy. Representative hydroxy protecting groups include, but are not limited to: alkyl such as methyl, ethyl
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    30/105 and tert-butyl; acyl such as alkanoyl (e.g., acetyl); arylmethyl such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl such as trimethylsilyl (TMS) and tert-butyl dimethyl silyl (TBS) and the like.
    [069] The compound of the present invention can be prepared by a variety of synthetic methods well known to the person skilled in the art, including the following enumerable modality, the modality formed by the following enumerable modality in combination with other chemical synthesis methods and the equivalent substitution known to the technician on the subject. The preferred embodiment includes, but is not limited to, the embodiment of the present invention.
    [070] All solvents used in the present invention are commercially available. This present invention adopts the abbreviated words as follows: Aq refers to water; HATU refers to O-p-azabenzotriazol-1-ylJ-A / '/ V' / V '/ V'-tetramethyluronium hexafluorophosphate; EDC refers to / V- (3-dimethylaminopropyl) - / / '- ethylcarbodiimide hydrochloride; m-CPBA refers to 3-chloroperoxybenzoic acid; eq refers to an equivalent; CDI refers to carbonyldiimidazole; DCM refers to dichloromethane; PE refers to petroleum ether; DIAD refers to diisopropyl azodicarboxylate; DMF refers to / V, / / - dimethylformamide; DMSO refers to dimethyl sulfoxide; EtOAc refers to ethyl acetate; EtOH refers to ethanol; MeOH refers to methanol; CBz refers to benzyloxycarbonyl, which is a protection group for
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    31/105 amines; BOC refers to t-butylcarbonyl which is a protecting group for amines; HOAc refers to acetic acid; NaCNBFH refers to sodium cyanoborohydride; r.t. refers to room temperature; O / N refers to overnight; THF refers to tetrahydrofuran; BOC2O refers to di-tert-butyldicarbonate; TFA refers to trifluoroacetic acid; DIPEA refers to diisopropylethylamine; SOCb refers to thionyl chloride; CS2 refers to carbon disulfide; TsOH refers to p-toluenesulfonic acid; NFSI refers to / V-fluoro- / V- (phenylsulfonyl) benzenesulfonamide; NCS refers to 1chloropyrrolidine-2,5-dione; n-Bu4NF refers to tetrabutylammonium fluoride; iPrOH refers to 2-propyl; mp refers to the melting point; LDA refers to diisopropylamino lithium; DMP refers to dimethyl phthalate; Xantphos refers to 4,5-bisdiphenylphosphine-9,9-dimethyloxaxime; Pd2 (dba) s refers to tris (dibenzylidenoacetone) dipaladium; Xant-Phos refers to 4,5bisdiphenylphosphine-9,9-dimethyloxaxane; EGTA refers to ethylene glycol tetracetic acid; DIEA refers to Λ /, / V-diisopropylethylamine; Xantphos refers to 4,5-bisdiphenylphosphine-9,9-dimethyloxaxan; AIBN refers to 2,2'-azobis (2methylpropionitrile); Pd2 (dba) s refers to tris (dibenzylidenoacetone) dipaladium; Pd (dppf) Cb refers to palladium [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride; BnBr refers to benzyl bromide; DMAP refers to 4dimethylaminopyridine; EGTA refers to ethylene glycol tetracetic acid; TMSN3 refers to azidotrimethylsilane; (Bpin ^ refers to bis (pinacolate) diboro; BnBr refers to benzyl bromide; 'ΊΤ2Ο refers to
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    32/105 trifluoromethanesulfonic anhydride; trifluoromethanesulfonic anhydride; Hepes refers to 4-hydroxyethylpiperazinoethanesulfonic acid; EGTA refers to ethylene glycol tetracetic acid.
    [071] Compounds are named manually or by ChemDraw® software, commercially available compounds use their supplier directory names.
    DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [072] The following examples further illustrate the present invention, but by all means the invention is not limited to them. Although the present invention has been described in detail and with reference to its specific modalities, it will be apparent to those skilled in the art that various changes and modifications can be made to it without departing from its spirit and scope.
    WXBB-1 fragment:
    COOH
    Synthetic route:
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    WXBB-1-5
    WXBB-1-1 WXBB-1-3


    WXBB-1-4a WXBB-1-4
    Step 1: Synthesis of Compound WXBB-1-3 [073] WXBB-1-1 (50.00 g, 127.48 mmol, 1.00 eq) was dissolved in acetonitrile (500.00 mL) followed by addition of WXBB -1-2 (12.87 g, 152.98 mmol, 15.14 mL, 1.20 eq). The reaction was carried out at 70 ° C for 2 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature, rotary evaporated to dryness by water pump under reduced pressure at 40 ° C and then dissolved in dichloromethane (150 ml). After washing with water (75 ml * 2), the organic phase was concentrated to about 90 ml and then 75 ml * 3 of n-hexane (removing residual dichloromethane) was added and rotary evaporated to provide a white solid in the organic phase . The white solid was filtered and the filter cake was washed with 180 ml of n-hexane and the filter cake was rotary evaporated until dry under reduced pressure to provide WXBB-1-3 (27.00 g, 106.17 mmol, 83.29% yield) as a white solid. 1 H NMR (400 MHz, DMSO-ck) δ ppm 0.79 - 0.86 (m,
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    10/34
    Η) 0.88 - 0.97 (m, 2 Η) 1.99 - 2.10 (m, 1 Η) 2.42 (s, 3 Η) 4.98 (s, 2 Η) 7.49 ( d, J = 8.16 Hz, 2 H) 7.82 (d, J = 8.28 Hz, 2 H), m / z = 255.1 (M + 1).
    Step 2: Synthesis of Compound WXBB-1-4 [074] WXBB-l-4a (20.00 g, 98.02 mmol, 1.00 eq) was dissolved in Nmethylpyrrolidone (100.00 mL), followed by addition of cuprous cyanide (17.56 g, 196.04 mmol, 42.83 mL, 2.00 eq). The reaction was carried out at 180 ° C for 3 hours. The reaction solution was cooled to room temperature, followed by the addition of water (300 ml) and ammonia (300 ml), stirred at room temperature for 30 minutes and extracted with ethyl acetate (200 ml * 3). The organic phase was washed with saturated brine (200 ml) and water (200 ml), dried over anhydrous sodium sulfate, suction filtered and rotary evaporated until dry under reduced pressure to provide a crude product as a brown-black solid. The crude product was isolated by silica gel column chromatography (PE: EA = 20: 1 - 3: 1) to provide WXBB-1-4 (12.00 g, 79.92 mmol, 81.53% yield) like a yellow solid. 1 H NMR (400 MHz, D-CHLOROPHORM) δ ppm 2.21 (s, 3 H) 3.68 (br s, 2 H) 6.80 (d, J = 5.40 Hz, 1 H) 6 , 91 (d, J = 9.29 Hz, 1 H).
    Step 3: Synthesis of Compound WXBB-1-5 [075] WXBB-1-3 (6.00 g, 39.96 mmol, 1.00 eq), WXBB-1-4 were added in a single-mouthed flask, followed by addition of diisopropylethylamine (10.85 g, 83.92 mmol, 14.66 ml, 2.10 eq). The reaction was carried out at 100 ° C for 18 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature, followed by
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    35/105 by adding 50 mL of water. After phase separation, the organic phase was sequentially washed with 50 ml of ammonium chloride solution (27%), 50 ml of sodium hydrogen carbonate solution (9%) and 45 ml of saturated brine, dried over sulfate anhydrous sodium and rotary evaporated until dry with a water pump under reduced pressure at 45 ° C to about 30 ml of remaining toluene. 60 ml of n-hexane was added to the organic phase, followed by filtration. The filter cake was washed with 60 ml of isopropanol (10 minutes in an ice bath) and rotary evaporated until dry with a water pump under reduced pressure at 40 ° C (white solid). The crude product was purified by column chromatography (S1O2, 100 to 200 mesh, PE: EA = 10: 1 - 3: 1) to provide WXBB-1-5 (1.80 g, 7.75 mmol, 19.39 % yield) as a yellow solid. Ã H NMR (400 MHz, DMSO-cfc) δ ppm 0.81 - 0.86 (m, 2 H) 0.87 - 0.90 (m, 2 H) 2.42 (s, 3 H) 4 , 98 (s, 2 H) 5.20 - 5.28 (m, 1 H) 5.23 (s, 1 H) 6.67 (d, J = 5.52 Hz, 2 H) 6.87 ( d, J = 5.77 Hz, 1 H).
    Step 4: Synthesis of Compound WXBB-1-6 [076] WXBB-1-5 (1.25 g, 5.38 mmol, 1.00 eq) was placed in a 100 ml single-mouthed bottle containing acetic acid ( 20.00 mL). Solid potassium thiocyanate (1.05 g, 10.76 mmol, 1.05 mL, 2.00 eq) was added to the reaction solution and charged with nitrogen three times. The reaction was carried out at 110 ° C for 5 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature, rotary evaporated until dry with an oil pump under reduced pressure at 60 ° C and
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    36/105 dissolved in 10 mL of dichloromethane. The organic phase was washed with water (5 ml * 2) and the aqueous phase was extracted with 10 ml * 2 of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and rotary evaporated until dry under reduced pressure to provide a brown solid. The brown solid obtained was dissolved with 5 ml of ethyl acetate, followed by the addition of 15 ml of n-hexane. The solution was layered with a brown top layer and stirred by magnetizer without any precipitation of solids. The mixture is rotary evaporated until dry under reduced pressure to provide a brown oil. The crude product was purified by column chromatography (S1O2, 100 to 200 mesh, PE: EA = 10: 1 - 3: 1) to provide WXBB-1-6 (390.00 mg, 756.23 pmol, 14.06 % yield, 53% purity) as a yellow solid, m / z = 274.0 (M + 1).
    Step 5: Synthesis of Compound WXBB-1-7 [077] Acetic acid (8.00 mL), water (1.60 mL) and hydrogen peroxide (487.96 mg, 4.30 mmol, 413.53 pL, 30% purity, 3.01 eq) were added in a pre-dried 100 ml three-mouthed flask and the mixture was heated to 45 ° C (internal temperature) under a nitrogen atmosphere. After the addition of WXBB1-6 (390.00 mg, 1.43 mmol, 1.00 eq) as a solid (the internal temperature was kept below 55 ° C) and the reaction solution was reacted at 45 ° C by 30 minutes. After completion of the reaction, the reaction solution was cooled to room temperature, followed by the addition of 4 ml of a 20% sodium sulfite solution, stirred at room temperature for 0.5 hour and evaporated
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    37/105 rotating until dry with an oil pump to provide a white solid. 4 ml of water was added to the white solid and the pH was adjusted to about 10 with 4N ammonium hydroxide. The aqueous phase was extracted with dichloromethane (6 ml * 3). The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to dryness under reduced pressure to provide WXBB-1-7 (200.00 mg, 828.98 pmol, 57.97% yield) as a yellow solid, m / z = 242.2 (M + 1).
    Step 6: Synthesis of Compound WXBB-1 [078] A reaction solution of WXBB-1-7 (200.00 mg, 828.98 pmol, 1.00 eq) and hydrochloric acid (6.00 mL, 38% purity) was added to a dry 100 mL single-mouthed flask and reacted at 100 ° C for 18 hours. After completion of the reaction, the reaction solution was cooled to room temperature and rotary evaporated until dry. 5 ml * 2 of toluene was added to it and rotary evaporated to dryness under reduced pressure to provide WXBB-1 (200.00 mg, 768.46 pmol, 92.70% yield) as a brown solid. X H NMR (400 MHz, DMSO-d6) δ ppm 0.81 - 0.89 (m, 2 H) 0.98 - 1.06 (m, 2 H) 1.96 - 2.05 (m, 1 H) 2.24 (s, 3 H) 7.54 (d, J = 11.29 Hz, 1 H) 7.74 (s, 1 H) 8.00 (d, J = 6.78 Hz, 1 H) 9.28 (s, 1 H), m / z = 261.1 (M + 1).
    WXBB-2 fragment:
    Synthetic route:
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    WXBB-2-1 WXBB-2-2
    WXBB-2
    Step 1: Synthesis of Compound WXBB-2-2 [079] Phosphorus pentasulfide (52.24 g, 235.02 mmol, 24.99 mL, 2.00 eq) was dissolved in tetrahydrofuran (300.00 mL), followed by slow addition of sodium carbonate (12.45 g, 117.51 mmol, 1.00 eq). The system was stirred at 20 ° C for 1 hour. Compound WXBB-2-1 was added to the system and the system was heated to 60 ° C and stirred for 48 hours. The reaction solution was cooled to room temperature, followed by filtration. The filtrate was concentrated to dryness under reduced pressure to provide a crude product. The crude product was purified by column chromatography (0 to 60% EA / PE) to provide Compound WXBB-2-2 (6.20 g, 61.28 mmol, 52.15% yield) as a white solid. X H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.166 - 2.249 (m, 2 H) 2.896 - 2.936 (m, 2 H) 3.664 - 3.699 (m, 2 H) 8.676 (s, 1 H).
    Step 2: Synthesis of Compound WXBB-2 [080] Compound WXBB-2-2 (200.00 mg, 1.98 mmol, 1.00 eq) and Compound WXBB-4 (360.00 mg, 2.37 mmol, 1.19 eq) were dissolved in cyclohexanol (4.00 ml). The system was stirred at 170 ° C for 24 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with water (80 ml) and extracted with ethyl acetate (30 ml * 6). The organic phase was dried over anhydrous sodium sulfate, followed by filtration. The filtrate was
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    39/105 concentrated under reduced pressure to provide a crude product. The crude product was purified by column chromatography (0 to 10% MeOH / DCM) to provide Compound WXBB-2 (180.00 mg, 831.88 pmol, 42.01% yield, 93% purity) as a yellow solid. X H NMR (400 MHz, DMSO-d6) δ ppm 2.71 - 2.64 (m, 2H) 2.86 (d, J = 7.2 Hz, 2 H) 4.32 (t, J = 7.2 Hz, 2 H) 6.13 (br.s, 2H) 6.48 (d, J = 8.4 Hz, 1 H) 7.22 (d, J = 7.2 Hz, 1 H) 7.52 - 7.47 (m, 1H). m / z = 202.0 [M + H] +.
    WXBB-3 fragment:
    Synthetic route:
    Step 1: Synthesis of Compound WXBB-3-2 [081] Phosphorus pentasulfide (56.06 g, 252.19 mmol, 26.82 mL, 1.00 eq) was added to acetonitrile (500.00 mL) to form a suspension, followed by slow addition of triethylamine (25.52 g, 252.19 mmol, 34.96 ml, 1.00 eq). The system was stirred at room temperature for 1 hour, followed by the addition of WXBB-3-1 (25.00 g, 252.19 mmol, 1.00 eq) and the system was stirred at 60 ° C for 19
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    40/105 hours. The reaction solution was poured into sodium hypochlorite (200 ml) and concentrated under reduced pressure to remove acetonitrile and extracted with dichloromethane (200mL * 3). The organic phases were combined, sequentially washed with water (400 ml) and brine (400 ml) and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to provide a crude product. The crude product was purified by column chromatography (0 to 10% MeOH / DCM) to provide Compound WXBB-3-2 (10.00 g, 86.81 mmol, 34.42% yield) as a yellow solid . H NMR (400 MHz, DMSO-d6) δ ppm 1.53 -1.71 (m, 4 H) 2.57 to 2.67 (m, 2 H) 3.13 (br s, 1H) 3.18 (td, J = 5.77, 2.51 Hz, 1 H).
    Step 2: Synthesis of Compound WXBB-3 [082] Compound WXBB-3-2 (6.00 g, 52.08 mmol, 1.00 eq) and Compound WXBB-4 (8.72 g, 57.29 mmol, 1.10 eq) were dissolved in cyclohexanol (100.00 ml). The system was stirred at 170 ° C for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with water (200 ml), adjusted to pH 5 with hydrochloric acid (2N, 100 ml) and extracted with ethyl acetate (200 ml). The aqueous phase was adjusted to pH 9 with sodium hydroxide (2N, 100 ml) and extracted with ethyl acetate (200 ml * 2). The organic phases were combined, sequentially washed with water (200 ml) and brine (200 ml) and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to provide a crude product. The crude product was purified by column chromatography (0 to 10% DCM / MeOH) to
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    41/105 provide Compound WXBB-3 (5.00 g, 17.50 mmol, 33.60% yield,
    75.32% purity) as a brown solid, m / z = 216.0 [M + H] +.
    WXBB-4 fragment:
    h 2 n
    H
    N x
    NH 2
    Synthetic route:
    h 2 n
    WXBB-4-1 h 2 n
    WXBB-4
    H
    N.
    NH 2
    Step 1: Synthesis of Compound WXBB-4 [083] Compound WXBB-4-1 (20.00 g, 131.45 mmol, 1.00 eq) was dissolved in methanol (200.00 mL) to provide a yellow solution clear, followed by slow addition of hydrazine hydrate (19.74 g, 394.35 mmol, 19.17 mL, 3.00 eq). The reaction system was stirred at 75 ° C for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by filtration. The filter cake was washed with ethyl acetate (50mL * 2) and the filter cake was rotary evaporated until dry under reduced pressure to provide Compound WXBB-4 (20.00 g, 131.45 mmol, 100.00% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm
    4.48 (br s, 2 H) 6.09 (s, 2 H) 6.60 (d, J = 8.28 Hz, 1 H) 7.11 (d, J = 7.03 Hz, 1 H ) 7.51 (t, J = 7.78 Hz, 1 H) 9.19 (br s, 1 H).
    Example 001: WX001
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    Synthetic route:

    WXBB-l
    WX001
    Step 1: Synthesis of Compound WX001 [084] WXBB-1 (100.00 mg, 337.02 pmol, 1.00 eq, HCI) and WXBB-2 (80.00 mg, 369.73 pmol, 1.10 eq ) (93% pure) were dissolved in pyridine (5.00 mL), followed by a slow addition of phosphorus oxychloride (50.00 mg, 326.09 μηηοΙ, 30.30 μί, 0.97 eq). The reaction system was stirred at 50 ° C for 1 hour. The reaction solution was cooled with water and concentrated under reduced pressure to provide a crude product. The crude product was isolated and purified by prep HPLC. (neutral system) to provide WX001. X H NMR: 0.63 - 0.71 (m, 2 H) 0.74 - 0.83 (m, 2 H) 1.76 - 1.89 (m, 1 H) 2.23 (s, 3 H) 2.67 (quin, J = 7.34 Hz, 2 H) 2.81 - 2.92 (m, 2 H) 4.38 (t, J = 7.03 Hz, 2 H) 7, 17 (d, J = 0.75 Hz, 1 H) 7.47 (d, J = 10.79 Hz, 1 H) 7.56 - 7.64 (m, 1 H) 7.68 (d, J = 1.00 Hz, 1 H) 7.85 (d, J = 7.53 Hz, 1 H) 7.98 (t, J = 7.91 Hz, 1 H) 8.15 (d, J = 8 , 28 Hz, 1 H) 10.90 (s, 1 H). m / z = 444.2 (M + 1).
    Example 002: WX002
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    Synthetic route:
    WXBB-3 WX002
    Step 1: Synthesis of Compound WX002 [085] WXBB-1 (100.00 mg, 337.02 pmol, 1.21 eq, HCI) was dissolved in dichloromethane (5.00 ml), followed by the addition of oxalyl chloride ( 70.76 mg, 557.49 pmol, 48.80 pL, 2.00 eq) and / V, / / - dimethylformamide (20.37 mg, 278.75 pmol, 21.45 pL, 1.00 eq) under nitrogen atmosphere. The system was stirred at 0 ° C for 1 hour. The reaction solution was rotary evaporated to dry under reduced pressure, followed by sequential addition of dichloromethane (5.00 mL), WXBB-3 (60.00 mg, 278.75 pmol, 1.00 eq) and DMAP (136, 22 mg, 1.12 mmol, 4.00 eq). The system was stirred at 0 ° C for 3 hours. The reaction solution was rotary evaporated under reduced pressure to provide a crude product. The crude product was isolated by a prep TLC plate. (DCM: MeOH = 20: 1) to provide WX002. H NMR (400 MHz, METHANOL-d4) ppm 9.17 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.16 to 8.08 (m, 1H) , 8.06 - 7.96 (m, 2H), 7.63 (s, 1H), 7.50 (d, J = 10.8 Hz, 1H), 4.82 (br. S., 2H) , 3.27 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 2.20 (br. S., 2H), 2.15 - 2.04 (m, 3H) , 1.22 -1.12 (m, 2H), 0.98 - 0.89 (m, 2H).
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    Example 003: WX003
    Synthetic route:

    WX003-3
    WX003-4
    WX003-1
    Step 1: Synthesis of Compound WX003-3 [086] WX003-1 (1.50 g, 9.99 mmol, 1.00 eq) was dissolved in acetonitrile (60.00 mL) and cooled to 0 ° C, followed by addition of isoamyl nitrite (1.76 g, 14.99 mmol, 2.02 mL, 1.50 eq), then TMSN3 (1.73 g, 14.99 mmol, 1.96 mL, 1.50 eq) was added dropwise to the reaction solution. The ice bath was removed after 25 minutes. The reaction solution was warmed to room temperature 25 ° C and reacted for 2 hours. WX003-2 (1.98 g, 29.97 mmol, 2.48 mL, 3.00 eq) and CU2O (142.95 mg, 999.00 pmol, 102.11 pL, 0.10 eq) were then added to the reaction solution and the reaction was carried out at 50 ° C for 18 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature and rotary evaporated to
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    45/105 dry, diluted with 50 ml of dichloromethane, sequentially washed with 30 ml of saturated ammonium chloride and 30 ml of saturated brine and dried over anhydrous sodium sulfate, rotary evaporated until dry. The crude product was purified by column chromatography (S1O2, PE: EA = 10: 1 to 4: 1) to provide WX003-3. m / z = 242.9 [M + l],
    Step 2: Synthesis of Compound WX003-4 [087] WX003-3 (380.00 mg, 1.57 mmol, 1.00 eq) was added in 38% hydrochloric acid (15.00 mL) and refluxed at 100 ° C for 18 hours. The reaction solution was adjusted to pH 9 with solid sodium carbonate and extracted with 10 mL * 3 of ethyl acetate. The aqueous phase was retained, adjusted to pH 2 with 2N HCI and extracted with 30 ml * 3 of ethyl acetate. The organic phase was retained and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness to provide WX003-4. m / z = 261.9 [M + 1].
    Step 3: Synthesis of Compound WX003-5 [088] WX003-4 (300.00 mg, 1.15 mmol, 1.00 eq) was dissolved in anhydrous dichloromethane (10.00 mL) and charged with nitrogen gas, followed by addition of oxalyl chloride (248.15 mg, 1.95 mmol, 171.14 pL, 1.70 eq) to form an emulsion. Subsequently, / V, / / - anhydrous dimethylformamide (8.41 mg, 115.00 pmol, 8.85 pL, 0.10 eq) was added to it and the reaction was carried out at 25 ° C for 2 hours under atmosphere nitrogen. 5 ml of anhydrous dichloromethane was added to the reaction solution and concentrated under reduced pressure at 35 ° C to 5 ml of remaining anhydrous dichloromethane. Such procedures were repeated
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    46/105 four times and the resulting product in anhydrous DCM was used directly in the next step. The resulting WX003-5 was dissolved in 5 ml of dichloromethane. m / z = 276.1 [MS methyl ester].
    Step 4: Synthesis of Compound WX003 [089] Diisopropylethylamine (131.82 mg, 1.02 mmol, 178.14 pL, 1.00 eq) was added to a solution of WX003-5 (285.29 mg, 1.02 mmol, 1.00 eq) in anhydrous dichloromethane (6.00 mL) under a nitrogen atmosphere, followed by the addition of WXBB-3 (220.00 mg, 1.02 mmol, 1.00 eq). The reaction was carried out at 25 ° C for 18 hours under a nitrogen atmosphere. After completion of the reaction, 5 ml of saturated brine was added to the reaction solution. The organic phase was separated and rotary evaporated (rotary evaporation by water pump at 40 ° C) until it dried under reduced pressure to provide a crude product. The crude product was purified by prep HPLC. (column: waterXbridge 150 * 25 5u; mobile phase: [Water (NH4HCO310 mM) -ACN]; B%: 12% to 52%, 10.5 min) to provide Compound WX003. NMR of (400 MHz, CHLOROPHORM-d) δ ppm 0.95 - 1.00 (m, 2 H) 1.03 -1.10 (m, 2 H) 1.95 - 2.02 (m, 2 H ) 2.04 - 2.12 (m, 3 H) 2.35 (s, 3 H) 3.10 (t, J = 6.34 Hz, 2 H) 4.51 (t, J = 6.09 Hz, 2 H) 7.23 (s, 1 H) 7.50 (s, 1 H) 7.90 (t, J = 8.03 Hz, 1 H) 8.12 (dd, J = 15.37 , 7.34 Hz, 2 H) 8.36 (d, J = 8.28 Hz, 1 H) 9.02 (br d, J = 14.30 Hz, 1 H).
    Example 004: WX004 n H
    F
    I X N nn
    N, 'n
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    Synthetic route:
    [^ CN
    WX004-6a
    WX004-6
    WX004-1 WX004-2
    WX004-3


    Step 1: Synthesis of Compound WX004-2 [090] / V-bromosuccinimide (22.97 g, 129.75 mmol, 1.00 eq) was added to a mixture of WX004-1 (20.00 g, 129.75 mmol, 1.00 eq) and concentrated sulfuric acid (200.00 mL) and stirred at 20 ° C for 20 minutes. The reaction solution was poured into ice water (1000 mL) while stirring and a white solid was formed. After filtration, the filter cake was dissolved with 500 ml of dichloromethane, dried over magnesium sulfate, filtered and evaporated to dryness to provide WX004-2. H NMR (400 MHz, CHLOROFORM-d) δ ppm
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    2.45 (s, 3 Η) 7.07 (d, J = 11.17 Hz, 1 Η) 8.16 (d, J = 6.90 Hz, 1 Η).
    Step 2: Synthesis of Compound WX004-3 [091] The crude material WX004-2 (27.00 g, 115.86 mmol, 1.00 eq) was dissolved in methanol (200.00 mL), followed by addition of acid concentrated sulfuric (11.36 g, 115.86 mmol, 6.18 mL, 1.00 eq). The reaction was carried out at 90 ° C for 18 hours. The reaction solution was evaporated to dryness and dissolved in 250 ml of dichloromethane, followed by the addition of 150 ml of saturated sodium bicarbonate solution, extraction and evaporation until dry to provide WX004-3. NMR of à H (400 MHz, CHLOROPHORMUM-d) δ ppm 2.42 (s, 3 H) 3.92 (s, 3 H) 7.04 (d, J = 11.04 Hz, 1 H) 8, 09 (d, J = 6.90 Hz, 1 H).
    Step 3: Synthesis of Compound WX004-4 [092] WX004-3 (5.00 g, 20.24 mmol, 1.00 eq) was dissolved in dioxane (60.00 mL) followed by the addition of (Bpin) 2 ( 7.71 g, 30.36 mmol, 1.50 eq), potassium acetate (5.96 g, 60.72 mmol, 3.00 eq) and Pd (dppf) Cb (2.96 g, 4.05 mmol, 0.20 eq) and charged with nitrogen gas. The reaction was carried out at 90 ° C for 18 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through diatomite and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (S1O2, PE: EA = 20: 1 - 7: 1) to provide WX004-4. H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 to 1.37 (m, 12 H) 2.53 to 2.58 (m, 3 H) 3.90 (s, 3 H) 6 , 92 (d, J = 12.17 Hz, 1 H) 8.32 (d, J = 8.53 Hz, 1 H)
    Step 4: Synthesis of Compound WX004-5
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    49/105 [093] WX004-4 was dissolved in tetrahydrofuran (35.00 mL), followed by the addition of sodium periodate (5.09 g, 23.80 mmol, 1.32 mL, 2.00 eq) and solution of IN hydrochloric acid (10.00 mL). The reaction solution was reacted at 25 ° C for 18 hours. After the completion of the reaction, the reaction solution was evaporated to dryness and diluted with 60 ml of ethyl acetate. The organic phase was washed with 40 ml of water and 40 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness to provide a crude product. The crude product was purified by column chromatography (SiCh, PE: EA ~ 5: 1 for EA) to provide WX004-5.
    Step 5: Synthesis of Compound WX004-6 [094] Sodium azide (9.69 g, 149.05 mmol, 2.50 eq) and tributyl stannous chloride (48.52 g, 149.05 mmol, 40.10 mL , 2.50 eq) were added to a solution of WX004-6a (4.00 g, 59.62 mmol, 4.40 ml, 1.00 eq) in o-xylene (50.00 ml). The reaction was carried out at 160 ° C for 6 hours under a nitrogen atmosphere. (The reaction mechanism was cooled with sodium hypochlorite). After the reaction solution was cooled to room temperature, the reaction solution was adjusted to pH 9 with 20% sodium hydroxide and stirred at room temperature for 1 hour, followed by separation. The aqueous phase was adjusted to pH = 2 with 2N hydrochloric acid, extracted with 100 mL * 3 of ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dry with the placement of the baffles to provide WX004-6. H NMR (400 MHz, METHANOL-c / 4) δ ppm 1.01 to 1.09 (m, 2 H) 1.19 -1.25 (m, 2 H) 2.17 to 2.25 ( m, 1 H).
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    Step 6: Synthesis of Compound WX004-7 [095] WX004-6 (800.00 mg, 7.26 mmol, 1.00 eq), WX004-5 (1.54 g, 7.26 mmol, 1.00 eq ) and C112O (51.98 mg, 363.00 pmol, 37.13 μΙ_, 0.05 eq) were added sequentially in dimethyl sulfoxide (24.00 ml). The solution was reacted at 110 ° C for 18 hours under an atmosphere of O2. After the completion of the reaction, the reaction solution was cooled to room temperature, diluted with 80 ml of dichloromethane and washed with 60 ml of 1M hydrochloric acid and 60 ml of saturated brine. After separation, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (S1O2, petroleum ether: ethyl acetate = 1: 0 to 50: 1 to 20: 1) to provide WX004-7. Å H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 1.1 (m, 2 H) 1.2 (m, 2 H) 2.2 (m, 1 H) 2.42 (s, 3 H) 3.94 (m, 3 H) 7.19 (d, J = 10.67 Hz, 1 H) 8.19 (d, J = 6.65 Hz, 1 H).
    Step 7: Synthesis of Compound WX004-8 [096] WX004-7 (500.00 mg, 1.81 mmol, 1.00 eq) was dissolved in tetrahydrofuran (5.00 mL) and water (5.00 mL), followed by addition of LiOH (130.04 mg, 5.43 mmol, 3.00 eq). The reaction solution was reacted at 25 ° C for 2 hours and extracted with 10 ml of methyl tert-butyl ether. The isolated aqueous phase was adjusted to pH 2 with 2N hydrochloric acid and extracted with 20 ml * 3 of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness to provide WX004-8. NMR of à H (400 MHz, CHLOROPHORMUM-d) δ ppm 1.18 (d, J = 6.78 Hz, 4 H) 2.26 - 2.36 (m, 1 H) 2.45 (s, 3 H) 7.23 (d, J = 10.79 Hz, 1 H) 8.27 (d, J
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    51/105 = 6.65 Hz, 1 Η).
    Step 8: Synthesis of Compound WX004-9 [097] WX004-8 (150.00 mg, 572.00 pmol, 1.00 eq) was added to a flask containing anhydrous dichloromethane (7.00 ml) and charged with nitrogen gas 3 times. Oxalyl chloride (123.43 mg, 972.40 pmol, 85.12 pL, 1.70 eq) was then added to form an emulsion, followed by the addition of N, Ndimethylformamide (4.18 mg, 57.20 pmol, 4.40 pL, 0.10 eq). The reaction was carried out at 25 ° C for 1 hour under a nitrogen atmosphere. 5 ml of anhydrous dichloromethane was added to the reaction solution and evaporated at room temperature under reduced pressure to 2 ml of remaining anhydrous dichloromethane. Such procedures were repeated four times to provide WX004-9 dissolved in 2 ml of anhydrous dichloromethane, m / z = 277.1 (M + 1) (MS methyl ester).
    Step 9: Synthesis of Compound WX004 [098] WX004-9 (130.40 mg, 464.58 pmol, 1.00 eq) was dissolved in anhydrous dichloromethane (3.00 ml) in a flask, followed by addition of WXBB- 3 (100.00 mg, 464.58 pmol, 1.00 eq) and diisopropylethylamine (60.04 mg, 464.58 pmol, 81.14 pL, 1.00 eq). The reaction was carried out at 25 ° C for 18 hours under a nitrogen atmosphere. The reaction solution was washed with 10 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to provide a crude product. The crude product was purified by prep HPLC. (column: WatersXbridge 150 * 25 mm 5 pm; mobile phase: [water (10 mM NHziHCOsJ-ACN]; B%: 25% to 60%, 10.5 min) to provide WX004. m / z = 460.2 [M + l]. H NMR (400 MHz, cHLOROFORM
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    d) δ ppm 1.19 (d, J = 6.65 Hz, 4 H) 1.94 - 2.13 (m, 4 H) 2.32 (t, J = 6.53 Hz, 1 H) 2 , 49 (s, 3 H) 3.11 (t, J = 6.15 Hz, 2 H) 4.52 (t, J = 5.96 Hz, 2 H) 7.26 (br s, 1 H) 7.91 (t, J = 8.03 Hz, 1 H) 8.11 (d, J = 7.28 Hz, 1 H) 8.35 - 8.40 (m, 1 H) 8.45 (d , J = 7.28 Hz, 1 H) 9.01 (br d, J = 15.06 Hz, 1 H)
    Example 005: WX005
    Synthetic route:

    WX005
    Step 1: Synthesis of Compound WX005-3 [099] WX005-3a (2.28 g, 33.91 mmol, 2.50 mL, 1.00 eq) was added in
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    53/105 a three-ml flask of 100 mL pre-dried and charged with nitrogen gas three times, followed by the addition of 10 mL of hydrochloric acid (4.87 N in dioxane). Subsequently, anhydrous ethanol (1.56 g, 33.91 mmol, 1.98 mL, 1.00 eq) was added dropwise to the reaction system under a nitrogen atmosphere. After completion of the addition, the mixture was reacted at 25 ° C for 3 hours. The reaction solution was filtered and evaporated to dryness to provide WX005-3. X H NMR (400 MHz, CHLOROPHORUM-c /) δ ppm 1.12 -1.23 (m, 4 H) 1.36 (t, J = 7.03 Hz, 3 H) 2.30 - 2, 41 (m, 1 H) 4.54 (q, J = 7.03 Hz, 2 H) 11.15 (br s, 1 H) 12.24 (br s, 1 H).
    Step 2: Synthesis of Compound WX005-2 [0100] WX005-1 (1.72 g, 11.46 mmol, 1.00 eq) was dissolved in hydrochloric acid (63.00 mL) and cooled to 0 ° C, followed by by dropwise addition of a sodium nitrite solution (948.49 mg, 13.75 mmol, 746.84 pL, 1.20 eq) in aqueous solution (6.00 ml). After completion of the dropwise addition, the reaction was carried out at 0 to 5 ° C for 0.5 hour. A solution of stannous chloride dihydrate (7.76 g, 34.38 mmol, 2.86 mL, 3.00 eq) in hydrochloric acid (4 mL, 37%) was added dropwise to the reaction solution and The reaction was carried out at 25 ° C for 3 hours, forming a large amount of gray precipitates. After completion of the reaction, the reaction solution was filtered and methanol (20 mL) was added to the filter cake. The filtrate was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3x100 mL). The organic phases were combined, washed with saturated brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to
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    54/105 provide a dark yellow solid. The dark yellow solid was isolated by sparkling column chromatography (silica gel: 100 to 200 mesh; DCM: MeOH = 20: 1) to provide the product WX005-2. m / z = 166.3 [M + 1].
    Step 3: Synthesis of Compound WX005-5 [0101] WX005-2 (3.00 g, 14.88 mmol, 1.00 eq) and WX005-3 (2.23 g, 14.88 mmol, 1.00 eq ) were added in a pre-dried 40 ml flask, followed by the addition of anhydrous ethanol (45.00 ml) and triethylamine (3.01 g, 29.76 mmol, 4.12 ml, 2.00 eq). The reaction was carried out at 20 ° C for 0.5 hour. The solvent was removed by rotary evaporation. Subsequently, WX005-4 (15.79 g, 148.80 mmol, 16.28 mL, 10.00 eq) and carbamic acid (1.88 g, 29.76 mmol, 2.00 eq) were added to the crude product , respectively. The temperature was raised to ° C and the reaction was carried out for 15.5 hours. The reaction system was cooled to room temperature, diluted with 50 ml of saturated sodium bicarbonate and 50 ml of ethyl acetate. The organic phase was collected after separation and the aqueous was extracted with ethyl acetate (20 mLx3). The organic phase was combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a yellow solid. The crude product was recrystallized from ethyl acetate / petroleum ether = 1/5 (30 ml) to provide the product WX005-5. H NMR (400 MHz, CHLOROFORM-d) δ = 8.01 (s, 1H), 7.54 (d, J = 5.9 Hz, 1H), 7.23 to 7.13 (m, 1H ), 2.31 - 2.21 (m, 3H), 2.05 (quin, J = 6.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 4H).
    Step 4: Synthesis of Compound WX005-6
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    55/105 [0102] WX005-5 (500.00 mg, 2.06 mmol, 1.00 eq) was added to a pre-dried 100 mL flask and dissolved in hydrochloric acid (10.20 g, 279.76 mmol, 10.00 mL, 135.81 eq). The reaction was stirred at 100 ° C for 16 hours. The reaction system was cooled to room temperature and a large amount of solid was precipitated after cooling, followed by filtration through a five-hole funnel. The filter cake was collected to provide WX005-6. H NMR (400 MHz, METHANOL-d 4) δ = 9.67 (s, 1H), 8.06 (d, J = 6.6 Hz, 1H), 7.36 (d, J = 11.0 Hz, 1H), 2.32 (s, 3H), 2.26 - 2.11 (m, 1H), 1.27 - 1.18 (m, 2H), 1.15 - 1.05 (m, 2H).
    Step 5: Synthesis of Compound WX005-7 [0103] WX005-6 (300.00 mg, 1.15 mmol, 1.00 eq) was added in a pre-dried 40 mL flask. Anhydrous dichloromethane (5.00 mL) was added to it and charged with nitrogen gas, followed by slow addition of oxalyl chloride (291.51 mg, 2.30 mmol, 201.04 pL, 2.00 eq) e / V anhydrous dimethylformamide (8.39 mg, 114.83 pmol, 8.83 pL, 0.10 eq) at 0 ° C. After completion of the addition, the reaction was carried out at 20 ° C for 1 hour. The reaction system was concentrated under reduced pressure and repeatedly dissolved with anhydrous dichloromethane, followed by evaporation to dry three times to provide WX005-7.
    Step 6: Synthesis of Compound WX005 [0104] The crude material WX005-7 (300.00 mg, 1.07 mmol, 1.00 eq) was added in a pre-dried 40 mL flask, followed by the addition of dichloromethane ( 3 mL), the reaction system was charged with nitrogen gas and
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    56/105 cooled to 0 ° C in an ice water bath. Subsequently, the crude material WXBB-3 (230.32 mg, 1.07 mmol, 1.00 eq) was added and a diisopropylethylamine solution (138.29 mg, 1.07 mmol, 186.88 μΙ_, 1.00 eq) in dichloromethane (2 ml) was added slowly at 0 ° C. The temperature was naturally raised to room temperature and the reaction was stirred at 20 ° C for 16 hours. The reaction system was diluted with 10 ml of water / 10 ml of dichloromethane. The organic phase was collected after separation and the aqueous phase was extracted with dichloromethane (5 mL x 3). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was isolated and purified by prep HPLC. (neutral) to provide pure product WX005. H NMR (400 MHz, CHLOROFORM-d) δ = 9.02 (br d, J = 14.8 Hz, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.16 8.08 (m, 2H), 7.90 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 12.3 Hz, 1H), 4.51 (t, J = 6 , 1 Hz, 2H), 3.10 (t, J = 6.5 Hz, 2H), 2.37 (s, 3H), 2.22 - 2.11 (m, 1H), 2.11 - 2 , 03 (m, 2H), 2.02 - 1.92 (m, 2H), 1.10 -1.00 (m, 4H).
    Example 006: WX006
    N.
    Synthetic route:
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    Step 1: Synthesis of Compound WX006-2 [0105] WX006-1 (100.00 g, 455.48 mmol, 1.00 eq) and EtOH (700.00 mL) were added in a 250 mL three-neck flask pre-dried. H2SO4 (223.37 g, 2.28 mol, 121.40 mL, 5.00 eq) was added dropwise to the reaction solution and refluxed at 80 ° C for 5 hours. The reaction system was cooled to room temperature, diluted with 200 mL of EA. The organic phase was collected after separation and the aqueous phase was extracted with EA (2 * 100 ml). The organic phases were combined, sequentially washed with saturated aqueous sodium bicarbonate solution (2 * 100 ml), water (2 * 100 ml) and saturated brine (2 * 100 ml), dried over anhydrous sodium sulfate and concentrated under pressure
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    58/105 reduced to provide residual WX006-2.
    Step 2: Synthesis of Compound WX006-3 [0106] WX006-2 (117.00 g, 472.52 mmol, 1.00 eq), Fe (65.98 g, 1.18 mol, 2.50 eq), NH 4 CI (27.80 g, 519.77 mmol, 18.17 mL, 1.10 eq) and the solvents H 2 O (345.00 mL) and EtOH (1.10 L) were added in a flask of pre-dried 2 L round bottom and the reaction solution was refluxed at 80 ° C for 6 hours. The reaction solution was cooled to room temperature and filtered through the Buchner funnel with diatomite. The filter cake was washed with dichloromethane (300 ml) and the filtrate was extracted with dichloromethane (2x400 ml). The organic phases were combined, washed with saturated brine (2x300 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide residual WX006-3.
    Step 3: Synthesis of Compound WX006-4 [0107] WX006-3 (37.00 g, 170.02 mmol, 1.00 eq), WXBB-1-3 (47.56 g, 187.02 mmol, 1, 10 eq) and DIEA (65.92 g, 510.06 mmol, 89.08 mL, 3.00 eq) were added to a pre-dried 500 mL round-bottom flask, followed by addition of xylene (300.00 mL) and stirred continuously at 140 ° C for 10 hours. The reaction system was cooled to room temperature and diluted with 150 ml of water. The organic phase was collected after separation and the aqueous phase was extracted with EA (2 * 150 mL). The organic phases were combined, sequentially washed with saturated ammonium chloride solution (2 * 150 mL), saturated brine (2 * 100 mL), dried over anhydrous sodium sulfate and concentrated
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    59/105 under reduced pressure to provide WX006-4.
    Step 4: Synthesis of Compound WX006-5 [0108] WX006-4 (47.80 g, 159.48 mmol, 1.00 eq) and AcOH (250.00 mL) were added in a pre-dried 500 mL flask , followed by the addition of potassium thiocyanate (31.00 g, 318.96 mmol, 31.00 mL, 2.00 eq) and stirred continuously at 110 ° C for 4 hours. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure and the residue was dissolved in DCM (150 ml), followed by addition of water (150 ml). The aqueous phase was extracted with DCM (2x100 ml). The organic phases were combined and dried over anhydrous sodium sulfate, followed by suction filtration and evaporation to dry under reduced pressure. The residue was recrystallized from EA (15 ml) to provide WX006-5.
    Step 5: Synthesis of Compound WX006-6 [0109] Acetic acid (53.19 mL), water (10.00 mL) and hydrogen peroxide (4.49 g, 39.61 mmol, 3.81 mL, 30% of purity, 3.00 eq) were added in a pre-dried 250 ml three-mouthed flask and the reaction temperature was controlled at 45 ° C with an internal thermometer, followed by addition of WX0065 (4.5 g, 13 , 20 mmol, 1.00 eq) in portions. The temperature was controlled below 55 ° C and the reaction was carried out at this temperature for 30 minutes. After the reaction of 30 minutes, the reaction solution was cooled to room temperature, followed by the addition of 20 mL of saturated sodium sulfite solution. No blue color was detected by the starch paper with potassium iodide. After rotary evaporation under reduced pressure, the residue was dissolved in
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    100 mL of water and adjusted to pH 10 with ammonia hydroxide, followed by extraction with dichloromethane (2x150 mL). The organic phases were combined and dried over anhydrous sodium sulfate, followed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (EA: PE = 1:10 -1: 2) to provide WX006-6.
    Step 6: Synthesis of Compound WX006-7 [0110] WX006-6 (3.85 g, 12.47 mmol, 1.00 eq), lithium hydroxide (895.97 mg, 37.41 mmol, 3.00 eq ) and tetrahydrofuran (38.00 ml) and water (38.00 ml) were added in a pre-dried 250 ml round bottom flask. The clear solution was stirred at 25 ° C for 2 hours and adjusted to pH 4 to 5 with 2N hydrochloric acid, followed by extraction with chloroform: isopropyl alcohol (3: 1, 5x50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, followed by suction filtration and rotary evaporation to provide WX006-7. m / z = 281.1 [M + l],
    Step 7: Synthesis of Compound WX006-8 [0111] WX006-7 (2.06 g, 7.34 mmol, 1.00 eq) was added to a pre-dried 100 mL round bottom flask and charged with nitrogen gas three times, followed by addition of dichloromethane (54.00 mL). Subsequently, oxalyl chloride (1.86 g, 14.68 mmol, 1.29 mL, 2.00 eq) and Λ /, / V-dimethylformamide (53.65 mg, 734.00 μηηοΙ, 56.47 pL, 0.10 eq) were slowly added dropwise under nitrogen atmosphere. After the completion of the dropwise addition, the reaction was carried out at 25 ° C for 1 hour, followed by rotary evaporation with
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    61/105 water. When the volume of the solution was reduced to about one third of its original volume, 10 mL of anhydrous dichloromethane was added. Such procedures were repeated three times to provide a solution of WX0068 in dichloromethane for direct use in the next reaction, m / z = 295.1 [M + 14].
    Step 8: Synthesis of Compound WX006-9 [0112] A 100 mL round-bottom flask containing WX006-8 (1.08 g, 3.61 mmol, 1.00 eq) was charged with nitrogen gas three times, followed by addition of dichloromethane (30 ml) and diisopropylethylamine (699.93 mg, 5.42 mmol, 943.30 pL, 1.5 eq). WXBB-3 (816.03 mg, 3.79 mmol, 1.05 eq) was added to it under a nitrogen atmosphere and the clear solution was reacted at 25 ° C for 0.5 hour. The product was redissolved with dichloromethane (20 ml) and extracted with water of pH = 2 (3x30 ml). Subsequently, the aqueous phase was adjusted to pH = 10 and extracted with dichloromethane (3x50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, followed by suction filtration and evaporation to dryness to provide WX006-9. m / z = 478.2 [M + 1].
    Step 9: Synthesis of Compound WX006 [0113] WX006-9 (0.3 g, 6T1.72 pmol, 1.00 eq), 3-pyridine boronic acid (154.32 mg, 1.26 mmol, 2.00 eq ), palladium acetate (14.09 mg, 62.77 pmol, 0.10 eq), n-butylbis (l-adamantyl) phosphine (22.51 mg, 62.77 pmol, 0.10 eq) and carbonate potassium (260.27 mg, 1.88 mmol, 3.00 eq) were added to a pre-dried 10 mL flask and charged with nitrogen gas three times, followed by the addition of water (0.5 mL) and dioxane ( 5 mL). The reaction system was placed in a bath
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    62/105 of oil at 90 ° C under nitrogen atmosphere and stirred for 2 hours. The reaction solution was evaporated to dryness and purified by a short silica gel column (100 to 200 mesh) to provide WX006. H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.59-.67 (m, 2 H) 0.73 to 0.83 (m, 2 H) 1.73 (ddd, J = 13, 34, 8.38, 4.96 Hz, 1 H) 1.86 - 2.07 (m, 4 H) 3.03 (br t, J = 6.28 Hz, 2 H) 4.44 (br t , J = 5.95 Hz, 2 H) 6.53 (s, 1 H) 7.16 (s, 1 H) 7.21 - 7.26 (m, 1 H) 7.32 (d, J = 11.91 Hz, 1 H) 7.85 (t, J = 8.05 Hz, 1 H) 8.05 (d, J = 7.72 Hz, 1 H) 8.17 (d, J = 7, 06 Hz, 1 H) 8.31 (d, J = 8.38 Hz, 1 H) 8.46 (d, J = 1.76 Hz, 1 H) 8.57 (dd, J = 4.52, 1.65 Hz, 1 H) 8.99 (br d, J = 13.89 Hz, 1 H).
    Example 007: WX007
    Synthetic route:
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    WX007-1 WX007-2
    WX007-3

    WX007-4

    WX007-6
    WX007-7
    WX007-8
    WX007-9
    Step 1: Synthesis of Compound WX007-2 [0114] 2-Bromo-1-methoxyethane (20 g, 84.75 mmol, 1 eq) and N, Ndimethylformamide (150 ml) were added in a 250 ml round bottom flask pre-dried, followed by addition of WX007-1 (14.13 g, 101.70 mmol, 9.55 mL, 1.2 eq) and potassium carbonate (23.43 g, 169.49 mmol, 2 eq) . The system was reacted at 50 ° C for 20 hours. The reaction solution was evaporated to dryness and redissolved in ethyl acetate (100 ml) and water (100 ml). The organic phase and the aqueous phase were separated and the aqueous phase was extracted with ethyl acetate (3x50 ml). The organic phases were combined, washed with saturated brine (2x150 mL) and dried over anhydrous sodium sulfate, followed by suction filtration.
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    64/105 to provide a crude product. The crude product was purified by a sparkling silica gel column (EA: PE = 1:10 - 1: 4) to provide WX007-2. H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.41 (s, 3 H) 3.73 to 3.82 (m, 2 H) 4.14 to 4.28 (m, 1 H) 4 , 14 - 4.28 (m, 1 H) 6.93 (d, J = 9.92 Hz, 1 H) 8.10 (d, J = 7.28 Hz, 1 H).
    Step 2: Synthesis of Compound WX007-3 [0115] WX007-2 (22.3 g, 75.83 mmol, 1.00 eq), Fe powder (12.71 g, 227.49 mmol, 3 eq), ammonium chloride (4.46 g, 83.41 mmol, 2.92 mL, 1.10 eq), water (130 mL) and ethanol (400 mL) were added to a 1000 mL pre-made eggplant flask dry. The reaction solution was refluxed at 80 ° C for 6 hours. The reaction solution was passed through diatomite, followed by rotary evaporation until dry and dissolved in dichloromethane (100 ml) and water (80 ml). The aqueous phase was extracted with dichloromethane (2x50 ml). The organic phases were combined, washed with saturated brine (2x100 ml), dried, filtered and concentrated to provide a crude product. WX007-3 was supplied by a sparkling silica gel column (ethyl acetate: petroleum ether = 1: 8 - 1: 1). H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.41 (s, 3 H) 3.71 to 3.77 (m, 4 H) 4.06 to 4.10 (m, 2 H) 6 , 62 (d, J = 9.92 Hz, 1 H) 6.80 (d, J = 6.84 Hz, 1 H).
    Step 3: Synthesis of Compound WX007-4 [0116] WX007-3 (12.64 g, 47.86 mmol, 1.00 eq), WXBB-10 (13.39 g, 52.65 mmol, 1.10 eq ) and toluene (120 mL) were added to a 500 mL pre-dried reaction flask. The reaction temperature was raised to 100 ° C, followed by the addition of diisopropylethylamine (12.37 g, 95.72 mmol, 16.67 mL, 2.00 eq). The reaction
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    65/105 was carried out at 100 ° C for 10 hours, followed by rotary evaporation until dry and purification by column chromatography (ethyl acetate: petroleum ether = 0 1: 10) to provide WX007-4. m / z = 346.1, 348.1 [M + l],
    Step 4: Synthesis of Compound WX007-5 [0117] WX007-4 (14.85 g, 42.90 mmol, 1.00 eq) and glacial acetic acid (200 mL) were added in a 500 mL round bottom flask pre-dried, followed by the addition of potassium thiocyanate (8.34 g, 85.79 mmol, 8.34 mL, 2.00 eq). The reaction temperature was raised to 110 ° C and reacted for 3 hours. After completion of the reaction, the reaction solution was rotary evaporated to dry under reduced pressure and the residue was redissolved in dichloromethane (60 ml), followed by addition of water (60 ml). The aqueous phase was extracted with dichloromethane (2x40 ml). The organic phases were combined, washed with saturated brine (2x50 ml) and dried over anhydrous sodium sulfate, followed by suction filtration, rotary evaporation and purification by column chromatography (ethyl acetate: petroleum ether = 1:10 - 1 : 1) to provide WX007-5. m / z = 387.1, 389.1 [M + l],
    Step 5: Synthesis of Compound WX007-6 [0118] Glacial acetic acid (100 mL), water (18 mL) and hydrogen peroxide (9.39 g, 82.80 mmol, 7.95 mL, 30% purity, 3.00 eq) were added in a pre-dried 250 ml three-mouthed flask and the reaction temperature was controlled at 45 ° C with an internal thermometer, followed by the addition of WX007-5 (10.69 g, 27, 60 mmol, 1.00 eq) in portions. The temperature was
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    66/105 controlled below 55 ° C and the reaction was carried out at this temperature for 30 minutes. The reaction was cooled to room temperature, followed by the addition of 20 mL of saturated sodium sulfite solution. No blue color was detected by the starch paper with potassium iodide. After rotary evaporation under reduced pressure, the residue was dissolved in 100 ml of water and adjusted to pH 10 with ammonium hydroxide, followed by extraction with dichloromethane (2x150 ml). The organic phases were combined and dried over anhydrous sodium sulfate, followed by rotary evaporation under reduced pressure to provide WX007-6. m / z = 355.1, 357.1 [M + 1j.
    Step 6: Synthesis of Compound WX007-7 [0119] WX007-6 (7.1 g, 19.99 mmol, 1.00 eq) and triethylamine (4.05 g, 39.98 mmol, 5.56 mL, 2 .00 eq) were added to a 250 ml hydrogenation flask followed by the addition of methanol (100 ml) and Pd (dppf) Cb (2.19 g, 3.00 mmol, 0.15 eq) and loaded with carbon three times and pressurized to 50 psi. The reaction vessel was placed in an oil bath at 70 ° C (external temperature) and stirred for 10 hours. The reaction solution was rotary evaporated and isolated by column chromatography (ethyl acetate: petroleum ether = 1:10 - 1: 1) to provide WX007-7. H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.70 to 0.78 (m, 2 H) 0.81 to 0.89 (m, 2 H) 1.81 to 1.91 (m, 1 H) 3.36 (s, 3 H) 3.66 - 3.73 (m, 2 H) 3.88 (s, 3 H) 4.14 - 4.21 (m, 2 H) 6.78 (d, J = 11.69 Hz, 1 H) 6.90 (s, 1 H) 7.66 (s, 1 H) 7.84 (d, J = 7.50 Hz, 1 H).
    Step 7: Synthesis of Compound WX007-8
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    67/105 [0120] WX007-7 (0.6 g, 1.79 mmol, 1.00 eq), lithium hydroxide (128.94 mg, 5.38 mmol, 3.00 eq), tetrahydrofuran (12 mL ) and water (12 mL) were added to a pre-dried 100 mL flask. The clear solution was stirred at 25 ° C for 1 hour. After the completion of the reaction, the reaction solution was directly rotary evaporated with a water pump, followed by the addition of toluene (2 χ 10 mL) to remove the residual water left by rotary evaporation to provide WX007-8. m / z = 321.2 [M + l],
    Step 8: Synthesis of Compound WX007-9 [0121] WX007-8 (574.83 mg, 1.79 mmol, 1.00 eq) was added in a pre-dried 100 mL round bottom flask and displaced with nitrogen three times, followed by addition of dichloromethane (20 mL). Subsequently, oxalyl chloride (455.57 mg, 3.59 mmol, 314.19 pL, 2.00 eq) and Λ /, / V-dimethylformamide (13.12 mg, 179.46 pmol, 13.81 pL, 0.10 eq) were slowly added dropwise under nitrogen atmosphere. After completion of the dropwise addition, the reaction was carried out at 25 ° C for 1 hour, followed by rotary evaporation with a water pump. When the volume of the solution was reduced to about one third of its original volume, 20 ml of anhydrous dichloromethane was added. Such procedures were repeated three times to provide a solution of WX0079 in dichloromethane for direct use in the next reaction, m / z = 335.2 [M + 14].
    Step 9: Synthesis of Compound WX007 [0122] A 100 mL round-bottom flask containing WX007-9 (721.80 mg, 2.13 mmol, 1.05 eq) was charged with nitrogen gas three times, followed by
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    68/105 addition of dichloromethane (30 ml) and diisopropylethylamine (393.39 mg, 3.04 mmol, 530.17 pL, 1.5 eq). WXBB-3 (687.43 mg, 2.03 mmol, 1.00 eq) was added to it under a nitrogen atmosphere and the clear solution was reacted at 25 ° C for 10 hours, followed by extraction with water of pH = 2 (3x30 mL). Subsequently, the aqueous phase was adjusted to pH = 10 and extracted with dichloromethane (3x50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, followed by suction filtration and rotary evaporation until dry to provide a crude product. The crude product was isolated by rapid preparation to provide WX007 (42.7 mg, 82.50 pmol, 4.07% yield). Ã H NMR (400 MHz, METANOLd4) δ ppm 0.78 - 0.91 (m, 2 H) 1.02 -1.10 (m, 2 H) 1.98 - 2.13 (m, 5 H ) 3.05 (t, J = 6.40 Hz, 2 H) 3.41 (s, 3 H) 3.77 (dd, J = 5.14, 3.39 Hz, 2 H) 4.34 - 4.42 (m, 2 H) 4.59 (t, J = 5.96 Hz, 2 H) 7.32 (d, J = 12.42 Hz, 1 H) 7.46 (s, 1 H) 7.91 (d, J = 7.15 Hz, 1 H) 7.99 - 8.06 (m, 2 H) 8.34 (d, J = 7.78 Hz, 1 H) 8.66 (s , 1 H).
    Example 008: WX008
    N
    N
    HO '
    N H
    F
    N 'n
    Synthetic route:
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    OTs
    WXBB-1-3

    WX008-1 WX008-2
    WX008-3
    WX008-4


    Step 1: Synthesis of Compound WX008-2 [0123] WX008-1 (28 g, 118.65 mmol, 1 eq) was dissolved in anhydrous DMF (200 mL), followed by addition of K2CO3 (32.80 g, 237, 29 mmol, 2 eq) and BnBr (24.35 g, 142.38 mmol, 16.91 ml, 1.2 eq). The mixture was stirred at 20 ° C for 16 hours. The reaction solution was poured into water (600 ml) and extracted with EA (300 ml * 2). The organic phase was washed with water (300 ml) and saturated brine (300 ml) and dried
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    70/105 in anhydrous sodium sulfate, followed by filtration. The filtrate was evaporated to dryness under reduced pressure. The crude product was stuffed with PE / EA = 5/1 (120 mL) at 20 ° C for 0.5 hour, followed by filtration. The filter cake was suction-dried to dryness under reduced pressure to provide WX008-2. X H NMR (400 MHz, CHLOROPHORMUM-d) δ = 8.20 (d, J = 7.3 Hz, 1H), 7.50 - 7.38 (m, 5H), 6.94 (d, J = 9.8 Hz, 1H), 5.25 (s, 2H).
    Step 2: Synthesis of Compound WX008-3 [0124] WX008-2 (26.5 g, 81.26 mmol, 1 eq) was dissolved in MeOH (500 mL), followed by the addition of NiCI-GHzO (69.53 g , 292.53 mmol, 3.6 eq) in portions and addition of NaBH4 (15.37 g, 406.26 mmol, 5 eq) in portions at 0 ° C. The mixture was stirred at 25 ° C for 0.5 hours, followed by the addition of saturated ammonium chloride solution (500 mL). The reaction solution was rotary evaporated to remove methanol, followed by the addition of EA (500 mL) and stirred for 10 minutes. The insoluble solid was filtered off. The filtrate was separated to collect the organic phase and the aqueous phase was extracted with EA (250 ml). The organic phases were combined, washed with saturated brine (250 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure to provide WX008-3. X H NMR (400 MHz, CHLOROPHORUM-d) δ = 7.43 (br s, 5H), 6.87 (br d, J = 5.0 Hz, 1H), 6.70 (br d, J = 9.5 Hz, 1H), 5.07 (br s, 2H), 3.75 (br s, 2H).
    Step 3: Synthesis of Compound WX008-4 [0125] WX008-3 (22 g, 63.81 mmol, 1 eq) (purity: 85.59%) was added
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    71/105 to anhydrous toluene (200 mL), followed by addition of WXBB-1-3 (17.04 g, 67.00 mmol,
    I, 05 eq) and DIEA (16.49 g, 127.62 mmol, 22.23 ml, 2 eq). The mixture was stirred at 100 ° C for 16 hours. The reaction solution was rotary evaporated until dry, followed by the addition of water (200 ml) and extraction with EA (200 ml * 2). The organic phase was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure. PE / EA = 5/1 (60 mL) was added to the crude product and pasting was carried out at 20 ° C for 0.5 hour, followed by filtration. The filter cake was rotary evaporated to dry under reduced pressure to provide WX008-4. H NMR (400 MHz, CHLOROFORM-d) δ = 7.38 to 7.23 (m, 5H), 6.58 (d, J = 9.8 Hz, 1H), 6.48 (d, J = 6.8 Hz, 1H), 5.02 (br d, J = 4.8 Hz, 1H), 5.00 (s, 2H), 4.06 (d, J = 5.0 Hz, 2H) , 1.98 -1.88 (m, 1H), 1.08 (quin, J = 3.8 Hz, 2H), 0.96-0.87 (m, 2H)
    Step 4: Synthesis of Compound WX008-5 [0126] WX008-4 (15 g, 35.58 mmol, 1 eq) (purity: 89.71%) was added to AcOH (120 mL), followed by addition of KSCN ( 6.91 g, 71.15 mmol, 6.91 ml, 2 eq). The mixture was stirred at 110 ° C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water (300 mL) and stirred for 15 minutes with the precipitation of the solids, followed by filtration. The filter cake was rotary evaporated to dry under reduced pressure to provide WX008-5. H NMR (400 MHz, CHLOROFORM-d) δ =
    II, 56 (br s, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.30 - 7.21 (m, 5H), 6.79 (d, J = 9.8 Hz,
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    1H), 6.31 (s, 1H), 5.02 (s, 2H), 1.67 - 1.58 (m, 1H), 0.84 - 0.77 (m, 2H), 0.61 - 0.53 (m, 2H).
    Step 5: Synthesis of Compound WX008-6 [0127] WX008-5 was dissolved in a mixed solution of AcOH (150 mL) and H2O (15 mL), followed by dropwise addition of H2O2 (12.97 g, 114, 42 mmol, 10.99 mL, 30% purity, 3.22 eq) and the system was stirred at 45 ° C for 0.5 hour. After cooling to room temperature, the reaction solution was slowly added to a solution of sodium sulfate (30 g) in water (30 ml), followed by extraction with EA (300 ml * 2). The organic phase was washed with saturated sodium bicarbonate (300 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry. The crude product was purified by column chromatography (EA / PE = 0 -10% to 20%) to provide WX008-6. H NMR (400 MHz, CHLOROFORM-d) δ = 7.64 (d, J = 1.0 Hz, 1H), 7.48 (d, J = 7.0 Hz, 1H), 7.42 - 7.34 (m, 3H), 7.33 - 7.29 (m, 2H), 6.94 6.88 (m, 2H), 5.11 (s, 2H), 1.95 - 1.86 (m, 1H), 0.92 - 0.86 (m, 2H), 0.83 - 0.77 (m, 2H).
    Step 6: Synthesis of Compound WX008-7 [0128] WX008-6 (6 g, 14.56 mmol, 1 eq) (93.95% purity) was dissolved in anhydrous MeOH (100 mL), followed by addition of Pd (dppf) Cb (1.07 g, 1.46 mmol, 0.1 eq) and EtsN (2.95 g, 29.11 mmol, 4.05 ml, 2 eq). The system was stirred at 80 ° C for 4 hours under a CO atmosphere (50 psi). The reaction solution was filtered and the filtrate was rotary evaporated until dry. The crude product was purified by
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    73/105 column chromatography (EA / PE = 0 -10% to 20% - 40%) to provide WX0087. X H NMR (400 MHz, CHLOROPHORMUM-d) δ = 7.92 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.44 - 7.31 (m, 5H), 6.93 (d, J = 0.8 Hz, 1H), 6.87 (d, J = 11.8 Hz, 1H), 5.19 (s, 2H), 3.94 (s, 3H), 1.96 - 1.86 (m, 1H), 0.93 - 0.86 (m, 2H), 0.84 - 0.78 (m, 2H).
    Step 7: Synthesis of Compound WX008-8 [0129] WX008-7 (2.7 g, 7.37 mmol, 1 eq) was dissolved in anhydrous THF (20 mL), followed by the addition of a LiOH solution (530 mg , 22.13 mmol, 3 eq) in H2O (10 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction solution was directly dried to provide a crude product. Pasting of the crude product was carried out with (DCM: MeOH = 10: 1, 44 mL) at 20 ° C for 0.5 hour, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure to provide WX008-8. H NMR (400 MHz, DMSO-ck) δ ppm 0.59 0.65 (m, 2 H) 0.69 to 0.78 (m, 2 H) 1.73 to 1.83 (m, 1 H) 5.15 (s, 2 H) 6.99 (d, J = 11.80 Hz, 1 H) 7.08 (s, 1 H) 7.33 (br dd, J = 7.78, 4 , 77 Hz, 1 H) 7.36 (d, J = 1.51 Hz, 2 H) 7.37 (br s, 2 H) 7.57 (d, J = 7.78 Hz, 1 H) 7 , 64 (s, 1 H).
    Step 8: Synthesis of Compound WX008-9 [0130] Compound WX008-8 (690 mg, 1.96 mmol, 1 eq) was added to a pre-dried 50 mL round bottom flask and charged with nitrogen gas three times , followed by addition of dichloromethane (50.00 mL). Subsequently, oxalyl chloride (497.12 mg, 3.92 mmol, 342.84 pL, 2 eq) and N, Ndimethylformamide (14.31 mg, 195.82 pmol, 15.07 pL, 0.1 eq) were slowly
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    74/105 added dropwise to this at 25 ° C under nitrogen atmosphere. After completion of the dropwise addition, the reaction was carried out at 25 ° C for 1 hour, followed by rotary evaporation with a water pump. When the volume of the solution was reduced to about one third of its original volume, 50 ml of anhydrous dichloromethane was added. Such procedures were repeated three times to provide a solution of WX008-9 (0.726 g) in dichloromethane for direct use in the next reaction. MS: m / z = 367 [methyl ester M +1].
    Step 9: Synthesis of Compound WX008-10 [0131] Dichloromethane (30 mL) was added to a round bottom flask containing Compound WX008-9 (0.726 g, 1.96 mmol, 1 eq) and a solution of Compound WXBB-3 (442.52 mg, 2.06 mmol, 1.05 eq) in dichloromethane solution (20 mL) was quickly added dropwise to the reaction flask, followed by the addition of diisopropylethylamine (278.34 mg, 2.15 mmol , 375.13 pL, 1.1 eq) under nitrogen atmosphere. The clear solution was reacted at 25 ° C for 1 hour. The reaction solution was concentrated and the product was then redissolved with dichloromethane (100 ml), adjusted to pH = 2 to 3 with 1 Μ aqueous hydrochloric acid solution. The reaction solution was completely stirred and then left to stand for separation. The aqueous phase was collected and adjusted to pH = 8 to 9 with sodium bicarbonate with precipitation of solids, followed by filtration to provide the solids. The solids were dissolved with dichloromethane and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated to provide WX008-10 (0.8 g, 1.30 mmol, 66.17%
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    75/105 yield, 89% purity). H NMR (400 MHz, CHLOROFORM-d) δ = 8.89 (br d, J = 14.8 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.65 (d , J = 0.9 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.30 - 7.25 (m, 2H), 6.90 (s, 1H), 6.84 ( d, J = 13.5 Hz, 1H), 5.15 (s, 2H), 4.41 (t, J = 6.0 Hz, 2H), 3.02 (t, J = 6.4 Hz, 2H), 2.04 - 1.95 (m, 2H), 1.94 - 1.88 (m, 2H), 1.83 (br dd, J = 4.1, 9.2 Hz, 1H), 0.87 - 0.79 (m, 2H), 0.76 - 0.69 (m, 2H).
    Step 10: Synthesis of Compound WX008 [0132] Compound WX008-9 (0.8 g, 1.46 mmol, 1 eq) was dissolved in methanol (50 mL), followed by addition of palladium on carbon (0.8 g , 50% purity). The mixture was stirred at 25 ° C for 2 hours under an atmosphere of hydrogen (50 Psi). The reaction solution was filtered with diatomite. The filter cake was sequentially washed with methanol (500 ml), dichloromethane (500 ml), tetrahydrofuran (500 ml) and methanol (500 ml). The filtrate was concentrated under reduced pressure to provide a crude product. Pasting of the crude product was carried out with methanol (10 mL), followed by filtration. The filtrate was concentrated to provide WX008 (0.15 g, 319.93 pmol, 21.98% yield, 98% purity). H NMR (400 MHz, DMSO-d6) δ = 10.66 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.80 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.23 ( d, J = 0.9 Hz, 1H), 6.90 (d, J = 11.9 Hz, 1H), 4.47 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H), 1.92 (br d, J = 4.6 Hz, 2H), 1.88 - 1.79 (m, 3H), 0.82 0.75 (m, 2H ), 0.71 - 0.64 (m, 2H).
    Example 009: WX009
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    Synthetic route:

    WX009
    Step 1: Synthesis of Compound WX009 [0133] Compound WX008 (200 mg, 435.28 pmol, 1 eq), potassium carbonate (120.32 mg, 870.56 pmol, 2 eq), acetone (50 mL) and 2-bromoethanol (81.59 mg, 652.92 pmol, 46.36 pL, 1.5 eq) was added in a pre-dried 40 ml vial. The reaction solution was stirred at 75 ° C for 16 hours. The reaction solution was concentrated under reduced pressure with an oil pump to provide a crude solid. The solid crude product was dissolved in N, N-dimethylformamide (8 ml) and then isolated and purified by flash preparation (water (10 mM NHziHCOsJ-CAN) to give the WX009 compound. NMR H (400 MHz, METHANOL-d 4) δ = 8.32 (d, J = 8.2 Hz, 1H), 8.02 - 7.88 (m, 4H), 7.23 (m, 2H), 4.57 (t, J = 5, 8 Hz, 2H), 4.30 - 4.22 (m, 2H), 3.90 (t, J = 4.4 Hz, 2H), 3.07 - 2.99 (m, 2H), 2, 06 (br d, J = 4.2 Hz, 2H), 2.00 (br s, 2H), 1.89 (br s, 1H), 0.87 (br d, J = 6.0 Hz, 2H ), 0.75 (br s, 2H).
    Example 010: WX010
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    Step 1: Synthesis of Compound WX010-2 [0134] Compound WX010-1 (200 mg, 1.96 mmol, 194.17 pL, 1 eq) and dichloromethane (5 mL) were added in a 40 mL reaction flask pre-drying, followed by sequential addition of triethylamine (297.24 mg, 2.94 mmol, 408.85 pL, 1.5 eq), dimethylaminopyridine (23.92 mg, 195.83 pmol, 0.1 eq) and chloride p-toluenesulfonyl (448.01 mg, 2.35 mmol, 1.2 eq). The reaction solution was stirred at 25 ° C for 3 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction solution and extracted with dichloromethane (10 mLx3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a crude product. The crude product was purified by thin layer chromatography silica gel plate (petroleum ether: ethyl acetate = 3: 1) to provide WX010-2. H NMR (400 MHz, CHLOROFORM-d) δ = 7.82 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 4.44 - 4.30 (m, 4H), 4.12 (s, 2H), 2.47 (s, 3H), 1.32 (s, 3H).
    Step 2: Synthesis of Compound WX010 [0135] Compound WX008 (100 mg, 217.64 pmol, 1 eq), carbonate
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    78/105 potassium (45.12 mg, 326.46 pmol, 1.5 eq), / V, / V-dimethylformamide (4 mL) and Compound WX010-2 (66.94 mg, 261.17 pmol, 1, 2 eq) were sequentially added to a pre-dried 40 mL reaction flask. The reaction solution was stirred at 80 ° C for 16 hours. The reaction solution was isolated and purified by rapid preparation (water (10 mM NHziHCChJ-ACN) to provide WX010. 1H NMR (400 MHz, CHLOROPHORUM-d) δ = 8.99 (d, J = 14.8 Hz , 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 7.7 Hz, 1H ), 7.91 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 1.3 Hz, 1H), 6.98 - 6.89 (m, 2H), 4.54 - 4.49 (m, 2H), 4.48 (s, 4H), 4.23 (s, 2H), 3.11 (t, J = 6.4 Hz, 2H), 2.09 - 2, 08 (m, 2H), 2.06 - 2.00 (m, 2H), 1.99 -1.91 (m, 1H), 1.39 (s, 3H), 0.90 - 0.88 ( m, 2H), 0.82 - 0.79 (m, 2H).
    Example 011: WX011
    Step 1: Synthesis of Compound WX011-2 [0136] Compound WX011-1 (200 mg, 2.27 mmol, 1 eq) and dichloromethane (5 mL) were added to a pre-dried 40 mL reaction flask, followed by triethylamine (344.56 mg, 3.41 mmol, 473.94 pL, 1.5 eq), dimethylaminopyridine
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    79/105 (27.73 mg, 227.00 pmol, 0.1 eq) and p-toluenesulfonyl chloride 1 (519.34 mg, 2.72 mmol, 1.2 eq). The reaction solution was stirred at 25 ° C for 16 hours. A saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction solution and extracted with dichloromethane (20 mLx3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a crude product. The crude product was purified by thin layer chromatography silica gel plate (petroleum ether: ethyl acetate = 3: 1) to provide WX011-2. NMR of à H (400 MHz, CHLOROPHORUM-d) δ = 7.78 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.70 (dd , J = 7.6, 6.4 Hz, 2H), 4.30 (t, J = 6.4 Hz, 2H), 4.23 (d, J = 76.8 Hz, 2H), 3.29 - 3.22 (m, 1H), 2.43 (s, 3H).
    Step 2: Synthesis of Compound WX011 [0137] Compound WX008 (100 mg, 217.64 pmol, 1 eq) and N, Ndimethylformamide (4 mL) were added in a pre-dried 40 mL reaction flask, followed by addition sequential potassium carbonate (45.12 mg, 326.46 pmol, 1.5 eq), potassium iodide (18.06 mg, 108.82 pmol, 0.5 eq) and Compound WX011-2 (63.28 mg, 261.17 pmol, 2.32 pL, 1.2 eq). The reaction solution was stirred at 80 ° C for 16 hours. The reaction solution was filtered, separated and purified by rapid preparation. The reaction solution was separated and purified by rapid preparation to provide WX011. 1H NMR (400 MHz, DMSO-d6) δ = 10.83 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.00 (t, J = 8.0 Hz , 1H), 7.87 (dd, J = 0.8, 7.6 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.40 (d, J = 12.1 Hz, 1H), 7.24 (d, J = 1.3 Hz, 1H), 4.68 (dd, J = 6.2, 7.9 Hz, 2H), 4.47 (br t, J = 5, 7 Hz, 2H), 4.43 - 4.37 (m, 4H), 3.44
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    3.36 (m, 1H), 2.92 (t, J = 6.3 Hz, 2H), 1.97 - 1.89 (m, 2H), 1.84 (br dd, J = 5.2 , 8.5 Hz, 3H), 0.81 - 0.75 (m, 2H), 0.68 - 0.63 (m, 2H).
    Example 012: WX012
    Synthetic route:
    Step 1: Synthesis of Compound WX012
    [0138] Compound WX008 (150 mg, 221.99 pmol, 1 eq), potassium carbonate (61.36 mg, 443.99 pmol, 2 eq), Λ /, / V-dimethylformamide (4 ml) and 1bromo -2-fluoro-ethane (56.37 mg, 443.99 pmol, 30.91 pL, 2 eq) were sequentially added to a pre-dried 40 mL reaction flask. The reaction solution was stirred at 100 ° C for 5 hours. The reaction solution was filtered through a filter to provide a clear solution, which was isolated and purified by rapid preparation to provide WX012. X H NMR (400 MHz, CHLOROPHORMUM-d) δ = 8.98 (br d, J = 14.8 Hz, 1H), 8.39 - 8.33 (m, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 0.9, 7.7 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.73 (d, J = 1.1 Hz, 1H), 6.99 (d, J = 1.1 Hz, 1H), 6.89 (d, J = 13.2 Hz, 1H), 4.86 - 4.81 (m , 1H), 4.75 4.68 (m, 1H), 4.50 (t, J = 6.1 Hz, 2H), 4.41 - 4.37 (m, 1H), 4.36 - 4 , 31 (m, 1H), 3.10 (t, J = 6.4 Hz, 2H), 2.11 - 2.03 (m, 2H), 2.02 -1.95 (m, 2H), 1.95 -1.88 (m, 1H), 0.94
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    - 0.87 (m, 2H), 0.87 - 0.81 (m, 2H).
    Example 013: WX013
    Step 1: Synthesis of Compound WX013 [0139] Compound WX008 (100 mg, 148.00 μηηοΙ, 1 eq), potassium carbonate (40.91 mg, 295.99 pmol, 2 eq), / V, / / -dimethylformamide (1 ml) and 1-bromo3-fluoro-propane (41.73 mg, 295.99 pmol, 30.91 pL, 2 eq) were sequentially added in a pre-dried 40 ml reaction flask. The reaction solution was stirred at 90 ° C for 2 hours. The reaction solution was filtered through a filter to provide a clear solution. The clear solution was isolated and purified by rapid preparation to provide WX013. 1 H NMR (400 MHz, CHLOROPHORM) -δ = 8.99 (br d, J = 15.2 Hz, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.67 (d , J = 0.9 Hz, 1H), 6.96 - 6.86 (m, 2H), 4.64 (t, J = 5.5 Hz, 1H), 4.56 - 4.47 (m, 3H), 4.25 (t, J = 6.1 Hz, 2H), 3.10 (t, J = 6.4 Hz, 2H), 2.24 (t, J = 5.7 Hz, 1H) , 2.18 (t, J = 5.7 Hz, 1H), 2.11 - 2.03 (m, 2H), 2.02 - 1.95 (m, 2H), 1.94 -1.87 (m, 1H), 0.94 - 0.86 (m, 2H), 0.85 0.79 (m, 2H).
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    Example 014: WX014


    WX014
    Step 1: Synthesis of Compound WX014-2 [0140] Compound WX014-1 (24 g, 101.70 mmol, 1 eq) was dissolved in anhydrous dichloromethane (200 mL), followed by the addition of dimethylaminopyridine (0.65 g, 5.32 mmol, 0.05 eq) and diisopropylethylamine (26.29 g, 203.39 mmol, 35.43 ml, 2 eq). The system was cooled to 0 ° C, followed by slow addition of trifluoromethanesulfonic anhydride (43.04 g, 152.55 mmol, 25.17 ml, 1.5 eq) at 0 ° C. O
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    83/105 The system was then heated to 20 ° C and stirred for 2 hours. Water (200 mL) was added to the reaction solution while stirring. The organic phase was rotary evaporated until it dried under reduced pressure to provide a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0 to 5%) to provide Compound WX014-2. H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29 (d, J = 7.53 Hz, 1 H) 8.51 (d, J = 6.52 Hz, 1 H).
    Step 2: Synthesis of Compound WX014-3 [0141] Compound WX014-2 (24 g, 65.21 mmol, 1 eq) was dissolved in dry toluene (200 mL) and charged with nitrogen gas three times, followed by addition of dimethylamine (4.80 g, 58.86 mmol, 5.39 mL, 0.9 eq, HCI), sodium tert-butoxide (9.36 g, 97.39 mmol, 1.49 eq) and Pd2 (dba ) s (4.80 g, 5.24 mmol, 0.08 eq). The mixture was stirred at 105 ° C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, followed by the addition of water (400 mL) and extraction with ethyl acetate (200 mL * 3). The organic phases were combined, washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure to provide a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0 to 5%) to provide Compound WX014-3. H NMR (400 MHz, CLOROFÓRMIOd) δ ppm 2.91 (s, 6 H) 6.75 (d, J = 11.04 Hz, 1 H) 8.02 to 8.07 (m, 1H) .
    Step 3: Synthesis of Compound WX014-4
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    84/105 [0142] Compound WX014-3 (9 g, 28.59 mmol, 1 eq) (purity: 83.568%) was dissolved in acetic acid (80 mL), followed by addition of Fe powder (6.39 g, 114.36 mmol, 4 eq) in portions. The mixture was stirred at 20 ° C for 16 hours. The reaction solution was added dropwise to saturated NaOH (100 ml) and extracted with ethyl acetate (50 ml * 3). The organic phases were combined, washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure. The crude product was purified by column (ethyl acetate / petroleum ether = 0 - 25%) to provide Compound WX014-4. NMR of à H (400 MHz, CHLOROPHORMUM-d) δ ppm 2.65 (s, 6 H) 6.80 (d, J = 10.29 Hz, 1 H) 6.86 (d, J = 6.78 Hz, 1 H).
    Step 4: Synthesis of Compound WX014-5 [0143] Compound WX014-4 (1.1 g, 3.42 mmol, 1 eq) (72.474% purity) was dissolved in anhydrous toluene (10 mL), followed by addition Compound WXBB-1-3 (3 g, 11.80 mmol, 3.45 eq) and diisopropylethylamine (928.29 mg, 7.18 mmol, 1.25 ml, 2.1 eq). The mixture was reacted at 140 ° C for 0.5 hour under microwave condition. The reaction solution was cooled to room temperature, followed by the addition of water (50 mL) and extraction with ethyl acetate (50 mL * 3). The organic phases were combined, washed with sodium chloride (50 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0 to 10%) to
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    85/105 provide Compound WX014-5. H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93 (dq, J = 7.47, 3.70 Hz, 2 H) 1.09 (quin, J = 3.83 Hz, 2 H) 1.90 - 1.99 (m, 1 H) 2.56 (s, 6 H) 4.07 (d, J = 3.51 Hz, 2 H) 6.49 (d, J = 6.53 Hz , 1 H) 6.73 (d, J = 10.04 Hz, 1 H).
    Step 5: Synthesis of Compound WX014-6 [0144] Compound WX014-5 (750 mg, 2.38 mmol, 1 eq) was dissolved in acetic acid (8 mL) and charged with nitrogen gas three times, followed by addition of potassium thiocyanate (463 mg, 4.76 mmol, 463.00 pL, 2 eq). The mixture was stirred at 110 ° C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH = 8 with saturated sodium bicarbonate (20 ml) and extracted with dichloromethane (20 ml * 3). The organic phase was washed with saturated sodium chloride (30 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure. Compound WX014-6 was supplied as the product, which was used directly in the next reaction without purification. H NMR (400 MHz, DMSO-d6) δ ppm 0.64 to 0.71 (m, 2 H) 0.78 to 0.89 (m, 2 H) 1.67 -1.76 (m, 1 H) 2.57 (s, 6 H) 6.75 (d, J = 1.51 Hz, 1 H) 7.00 (d, J = 11.80 Hz, 1 H) 7.40 (d, J = 7.53 Hz, 1 H) 12.28 (br s, 1 H).
    Step 6: Synthesis of Compound WX014-7 [0145] Compound WX014-6 (500 mg, 1.40 mmol, 1 eq) was dissolved in acetic acid (5 mL), followed by addition of water (1 mL) and peroxide hydrogen (477 mg, 4.21 mmol, 404.24 pL, 30% purity, 3 eq). The mixture was stirred at
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    86/105 ° C for 1 hour. The reaction solution was cooled to room temperature and saturated sodium sulfite was added to it until no blue color was detected by the starch paper with potassium iodide. Part of the solvent was separated by evaporation and no residual hydrogen peroxide was detected by the starch paper with potassium iodide. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (20 mL * 3). The organic phase was washed with saturated sodium chloride (50 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure. Compound WX014-7 was supplied as the product, which was used directly in the next reaction without purification. H NMR (400 MHz, DMSO-d6) δ ppm 0.62 to 0.71 (m, 2 H) 0.77 to 0.82 (m, 2 H) 2.32 to 2.34 (m, 1 H) 2.43 (s, 6 H) 7.08 (d, J = 11.29 Hz, 1 H) 7.14 (s, 1 H) 7.56 (d, J = 7.53 Hz, 1 H) 7.69 (s, 1 H).
    Step 7: Synthesis of Compound WX014-8 [0146] Compound WX014-7 (400 mg, 1.09 mmol, 1 eq) (88.522% purity) was dissolved in methanol (4 mL), followed by the addition of Pd ( dppf) Cb (120 mg, 164.00 pmol, 0.15 eq) and triethylamine (221 mg, 2.18 mmol, 303.99 pL, 2 eq) and introduction of carbon monoxide (50 Psi). The mixture was stirred at 70 ° C for 16 hours. The reaction solution was concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0 to 30%). The product was further purified by prep TLC. (ethyl acetate) to provide Compound WX014-8. H NMR (400 MHz, CHLOROFORM-d) δ ppm from 0.77 to 0.83
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    87/105 (m, 2 Η) 0.85 - 0.92 (m, 2 Η) 1.86 - 1.95 (m, 1 Η) 2.61 (s, 6 Η) 3.89 (s, 3 Η) 6.63 (d, J = 13.30 Hz, 1 Η) 6.86 (d, J = 1.00 Hz, 1 Η) 7.54 (d, J = 1.00 Hz, 1 Η ) 7.73 (d, J = 7.78 Hz, 1 Η).
    Step 8: Synthesis of Compound WX014-9 [0147] Compound WX014-8 (200 mg, 566.13 pmol, 1 eq) (85.863% purity) was dissolved in a mixture of tetrahydrofuran (1 ml) and water (1 mL) (volume ratio: 1: 1), followed by the addition of lithium hydroxide (41 mg, 1.71 mmol, 3.02 eq). The mixture was stirred at 20 ° C for 1 hour. The reaction solution was concentrated to provide Compound WX014-9. Ã H NMR (400 MHz, DMSOd6) δ ppm 0.65 - 0.71 (m, 2 H) 0.75 - 0.81 (m, 2 H) 1.79 - 1.88 (m, 1 H ) 2.41 (s, 6 H) 6.67 (d, J = 12.30 Hz, 1 H) 7.06 (s, 1 H) 7.44 (d, J = 8.03 Hz, 1 H ) 7.61 (s, 1 H).
    Step 9: Synthesis of Compound WX014 [0148] Compound WX014-9 (160 mg, 553.05 pmol, 1 eq) was dissolved in dichloromethane (2 mL), followed by addition of Λ /, / V-dimethylformamide (4 mg , 54.72 pmol, 4.21 pL, 0.1 eq) and oxalyl chloride (120 mg, 945.43 pmol, 82.76 pL, 1.71 eq). The mixture was stirred at 20 ° C for 2 hours. The solvent was evaporated off under reduced pressure until the mixture was viscous, followed by the addition of 5 ml of anhydrous dichloromethane. Such procedures were repeated three times, followed by the addition of Compound WXBB-3 (119 mg, 552.84 pmol, 1 eq) and diisopropylethylamine (72 mg, 557.09 pmol, 97.04 pL, 1.01 eq). The mixture was stirred at 20 ° C for 1 hour, followed by addition of water (50 ml) and extraction with dichloromethane (20 ml * 3). The organic phase was washed with sodium chloride
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    88/105 saturated (50 mL) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure. The dry crude product was purified by prep TLC. (dichloromethane / methanol = 10/1) and isolated by rapid preparation to provide WX014. H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (br s, 2 H) 0.79 (br d, J = 8.03 Hz, 2 H) 1.24 (br s, 1H ) 1.80 - 2.00 (m, 6 H) 2.53 (br s, 6 H) 4.43 - 4.51 (m, 2 H) 6.97 (br d, J = 13.05 Hz , 1 H) 7.15 (s, 1 H) 7.55 (br d, J = 7.28 Hz, 1 H) 7.71 (s, 1 H) 7.85 (d, J = 7.53 Hz, 1 H) 7.98 (t, J = 7.91 Hz, 1 H) 8.15 (d, J = 8.03 Hz, 1 H) 10.61 (s, 1 H).
    Example 015: WX015
    Synthetic route:
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    89/105
    WX015-1
    WX015-2

    WX015-4
    WXBB-1-3


    WXBB-3
    WX015
    Step 1: Synthesis of Compound WX015-2 [0149] WX015-1 (24 g, 101.70 mmol, 1 eq) was dissolved in anhydrous dichloromethane (200 mL), followed by addition of DMAP (0.65 g, 5, 32 mmol, 0.05 eq) and diisopropylethylamine (26.29 g, 203.39 mmol, 35.43 ml, 2 eq). The system was cooled to 0 ° C, followed by slow addition of Tf 2 O (43.04 g, 152.55 mmol, 25.17 ml, 1.5 eq) at 0 ° C. Subsequently, the system was gradually heated to 20 ° C and stirred for 2 hours. Water (200 ml) was added to the reaction solution while stirring and the organic phase was rotary evaporated until dry under reduced pressure to provide a crude product. The crude product was purified
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    90/105 by column chromatography with 0 to 5% ethyl acetate / petroleum ether to provide the product WX015-2. X H NMR (400 MHz, CHLOROPHORM) -δ ppm 7.20 (d, J = 7.28 Hz, 1 H) 8.41 (d, J = 6.53 Hz, 1 H).
    Step 2: Synthesis of Compound WX015-3 [0150] WX015-2 (13 g, 35.32 mmol, 1 eq) was dissolved in anhydrous toluene (130 mL), sodium tert-butoxide (5.20 g, 54, 11 mmol, 1.53 eq) and Pd2 (dba) s (2.60 g, 2.84 mmol, 0.08 eq). The system was stirred at 105 ° C for 20 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, added to water (200 ml) and extracted with ethyl acetate (200 ml * 2). The organic phase was sequentially washed with water (300 ml), saturated brine (300 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure to provide a crude product. The crude product was purified by column chromatography with 0 to 20% ethyl acetate / petroleum ether to provide the product WX015-3. Å H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 3.04 - 3.09 (m, 4 H) 3.84 - 3.87 (m, 4 H) 6.86 (d, J = 10, 04 Hz, 1 H) 8.12 (d, J = 7.03 Hz, 1 H).
    Step 3: Synthesis of Compound WX015-4 [0151] WX015-3 (8 g, 26.22 mmol, 1 eq) was dissolved in glacial acetic acid (80 mL), followed by a slow addition of Fe powder (5.86 g, 104.88 mmol, 4 eq) in portions while stirring. The system was stirred at 20 ° C for 1 hour. The reaction solution was rotary evaporated until it dried under reduced pressure to provide a crude material and diluted with water (200 ml). The solution was
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    91/105 adjusted to pH 8 to 9 with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (100 mL * 2). The organic phase was washed with water (200 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness to provide the product WX015-4.
    Step 4: Synthesis of Compound WX015-5 [0152] WXBB-1-3 (6.98 g, 27.47 mmol, 3 eq) was dissolved in anhydrous toluene (30 mL), followed by addition of WX015-4 (3 g, 9.16 mmol, 1 eq) (purity: 83.959%) and diisopropylethylamine (2.49 g, 19.27 mmol, 3.36 mL, 2.1 eq). The system was heated to 140 ° C under microwave condition and stirred for 1 hour. The reaction solution was cooled to room temperature, followed by the addition of water (50 mL) and extraction with ethyl acetate (50 mL * 2). The organic phase was dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure to provide a crude product. The crude product was purified by column chromatography (0 to 12% ethyl acetate / petroleum ether) to provide the product WX015-5.
    Step 5: Synthesis of Compound WX015-6 [0153] WX015-5 (1.2 g, 2.71 mmol, 1 eq) (80.641% purity) was dissolved in glacial acetic acid (20 mL), followed by addition of potassium thiocyanate (0.36 g, 3.70 mmol, 360.00 pL, 1.37 eq). The system was stirred at 110 ° C for 3 hours. The reaction solution was cooled to room temperature, diluted with water (100 ml) and extracted with dichloromethane (50 ml * 3). The organic phases were combined, followed by addition of saturated sodium bicarbonate solution
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    92/105 (200 mL) and stirred for 5 minutes. The pH of the organic phase was 7 to 8 measured by pH test paper. The organic phase was isolated, washed with water (200 ml) and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure to provide the product WX015-6.
    Step 6: Synthesis of Compound WX015-7 [0154] WX015-6 (1.2 g, 2.62 mmol, 1 eq) (87,114 purity) was dissolved in a mixture of glacial acetic acid (12 mL) and water ( 2.5 mL), followed by the addition of hydrogen peroxide (0.9 g, 7.94 mmol, 762.71 pL, 30% purity, 3.02 eq) while stirring. The system was stirred at 45 ° C for 0.5 hour. The reaction solution was cooled to room temperature, diluted with water (100 ml) and extracted with dichloromethane (50 ml * 3). The organic phases were combined, followed by the addition of saturated sodium sulfite solution (50 mL) and stirred for 5 minutes. No blue color was detected by the starch paper with potassium iodide. Subsequently, saturated Na 2 CÜ3 solution (200 mL) was added to it and stirred for 5 minutes. The pH of the organic phase was 7 to 8 measured by the pH test paper. The organic phase was isolated, washed with water (200 ml) and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure to provide the product WX015-7.
    Step 7: Synthesis of Compound WX015-8 [0155] WX015-7 (1 g, 1.78 mmol, 1 eq) (65.303% purity) was dissolved in methanol (10 mL), followed by addition of Pd (dppf) CI 2 (0.04 g, 54.67 pmol, 0.15
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    93/105 eq) and triethylamine (400.00 mg, 3.95 mmol, 550.21 μΙ_, 2.22 eq). The system was stirred at 70 ° C for 16 hours under a CO atmosphere (50 psi). The reaction solution was rotary evaporated to dryness under reduced pressure to provide a crude material, which is purified by column chromatography with 0 to 40% ethyl acetate / petroleum ether to provide the product WX015-8.
    Step 8: Synthesis of Compound WX015-9 [0156] WX015-8 (0.6 g, 1.55 mmol, 1 eq) (purity: 89.457%) was dissolved in anhydrous tetrahydrofuran (5 ml), followed by the addition of an solution of lithium hydroxide (0.112 g, 4.68 mmol, 3.01 eq) in water (5 mL). The system was stirred at 20 ° C for 1 hour. The reaction solution was rotary evaporated until it dried under reduced pressure to provide a crude material. A mixed solution of dichloromethane / methanol = 10/1 (15 mL) was added to the crude product and stirred for 15 min, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure to provide the product WX015-9. Å H NMR (400 MHz, DMSO-c / δ) δ ppm 0.66 (br d, J = 3.01 Hz, 2 H) 0.72 - 0.84 (m, 2 H) 1.77 - 1.91 (m, 1 H) 2.58 (br s, 4 H) 3.55 (br s, 4 H) 6.74 (d, J = 11.80 Hz, 1 H) 7.16 (s , 1 H) 7.50 (d, J = 7.78 Hz, 1 H) 7.72 (s, 1 H).
    Step 9: Synthesis of Compound WX015 [0157] WX015-9 (0.1 g, 301.80 pmol, 1 eq) was dissolved in anhydrous dichloromethane (2 mL), followed by the addition of Λ /, / V-dimethylformamide (5 mg, 68.41 pmol, 5.26 pL, 2.27e-1 eq) and addition of oxalyl chloride (0.08 g, 630.29 pmol, 55.17 pL, 2.09 eq) under a nitrogen atmosphere . The system was stirred at 20 ° C for 0.5 hours.
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    94/105
    The reaction solution was rotary evaporated until dry under reduced pressure until it was viscous, followed by the addition of anhydrous dichloromethane (2 ml). Such procedures were repeated three times, followed by sequential addition of anhydrous dichloromethane (2 mL), WXBB-3 (0.065 g, 301.97 pmol, 1.00 eq) and diisopropylethylamine (0.08 g, 618.99 pmol, 107 , 82 pL, 2.05 eq). The system was stirred at 20 ° C for 1 hour. The reaction solution was diluted with water (20 ml) and extracted with dichloromethane (20 ml * 2). The organic phase was washed with water (30 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure to provide a crude product. The crude product was isolated and purified by rapid preparation to provide WX015. X H NMR (400 MHz, CHLOROPHORUM-d) δ ppm 0.80 (br d, J = 3.26 Hz, 2 H) 0.91 (br d, J = 8.03 Hz, 2 H) 1, 87 - 1.94 (m, 1 H) 1.96 - 2.09 (m, 4 H) 2.79 (br d, J = 4.02 Hz, 4 H) 3.10 (br t, J = 6.27 Hz, 2 H) 3.73 (br s, 4 H) 4.50 (br t, J = 6.02 Hz, 2 H) 6.81 (d, J = 13.80 Hz, 1 H ) 6.99 (s, 1 H) 7.71 (s, 1 H) 7.84 - 7.96 (m, 1 H) 8.05 (dd, J = 15.69, 7.91 Hz, 2 H) 8.36 (d, J = 8.28 Hz, 1 H) 9.00 (br d, J = 15.56 Hz, 1 H)
    Example 016: WX016
    Synthetic route:
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    95/105
    Step 1: Synthesis of Compound WX016-2 [0158] WX016-1 (20 g, 201.75 mmol, 1 eq) was dissolved in CHCI 3 (200 ml) in a pre-dried 100 ml round bottom flask. After the reaction system was cooled to 0 ° C, PCIs (84.03 g, 403.51 mmol, 2 eq) were added to it in portions. The system was reacted at 0 ° C for 30 minutes. Subsequently, ZnCb (1.37 g, 10.09 mmol, 472.48 pL, 0.05 eq) and Br 2 (64.48 g, 403.51 mmol, 20.80 ml, 2 eq) were added to the system . The reaction temperature was then raised to 0 to 25 ° C and the reaction was carried out for 5 hours. Saturated sodium sulfite solution was slowly added to the reaction solution while stirring until the pH = 8 to 9. The organic phase was collected after separation and the aqueous phase was extracted with dichloromethane (3 * 100 mL). The organic phases were combined, washed with saturated brine (1 * 200 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under pressure
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    96/105 reduced to provide WX016-2.
    Step 2: Synthesis of Compound WX016-3 [0159] The crude material WX016-2 (10 g, 38.92 mmol, 1 eq) was added in a pre-dried 250 ml round bottom flask, followed by the addition of a mixture of H2O (5 ml) and MeOH (45 ml). PPhs (10.21 g, 38.92 mmol, 1 eq) was slowly added to the system at 40 ° C and stirred for 3 hours. The reaction system solvent was concentrated to about half of its original volume in vacuo and water was added slowly until no solid was precipitated. The solids were separated by filtration and the filtrate was extracted with dichloromethane (3 * 30 ml). The organic phase was washed with saturated brine (2 * 40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide WX016-3. H NMR (400 MHz, CHLOROFORM-c /) δ ppm 1.73 to 1.87 (m, 2 H) 2.13 to 2.23 (m, 2 H) 2.23 to 2.31 (m , 3 H) 3.37 - 3.49 (m, 2 H) 4.51 (t, J = 4.39 Hz, 1 H), m / z = 178.09 [M + l],
    Step 3: Synthesis of Compound WX016-4 [0160] WX016-3 (7.2 g, 28.31 mmol, 1 eq) was added to a dry round-bottom flask, followed by addition of ACN (20 mL), KOAc (11.11 g, 113.24 mmol, 4 eq) and 18-crown-6 (2.24 g, 8.49 mmol, 0.3 eq) while stirring and heated to reflux at 85 ° C for 1 hour. The reaction system was cooled to room temperature, adjusted to pH = 3 to 4 with 1M hydrochloric acid and extracted with dichloromethane (3x20 mL). The organic phases were combined, adjusted with saturated sodium bicarbonate to pH = 8 to 9 and extracted with dichloromethane
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    97/105 (3x30 mL). The organic phases were washed with saturated brine (2x40 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 100: 0 to 40: 1 to 20: 1) to provide WX016. NMR of à H (400 MHz, CHLOROPHORMUM-d) δ ppm 1.79 -1.96 (m, 4 H) 2.01 - 2.08 (m, 1 H) 2.22 - 2.32 (m, 2 H) 3.25 - 3.37 (m, 3 H) 5.17 - 5.25 (m, 1H), m / z = 158.1 [M + 1].
    Step 4: Synthesis of Compound WX016-6 [0161] Compound WX016-4 (20.00 g, 127.25 mmol, 1 eq) and Compound WX016-5 (14.52 g, 38.18 mmol, 0, 3 eq) were added to a dry round-bottom flask, followed by the addition of acetonitrile (250 ml). The reaction system was heated to 60 ° C and stirred for 4 hours. The reaction solution was cooled to room temperature, followed by rotary evaporation until dry. Water (250 ml) and dichloromethane (250 ml) were added to the reaction flask. After the organic phase and the aqueous phase were separated, the aqueous phase was extracted with dichloromethane (200 ml * 2). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered and rotary evaporated until dry under reduced pressure to provide WX016-6. H NMR (H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.86 to 1.93 (m, 2 H) 1.96 to 2.07 (m, 2 H) 2.11 (s , 3 H) 3.28 - 3.35 (m, 2 H) 5.41 5.47 (m, 1 H)
    Step 5: Synthesis of Compound WX016-7 [0162] Compound WX016-6 (12.00 g, 67.29 mmol, 1 eq) was added in
    Petition 870190067738, of 7/17/2019, p. 210/336
    98/105 a dry round-bottom flask, followed by sequential addition of Compound WXBB-4 (10.54 g, 69.27 mmol, 1 eq) and cyclohexanol (200 mL). The air in the system was charged with a nitrogen balloon and the procedures were repeated twice. The reaction system was heated to 135 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature, followed by the addition of water (250 mL) and adjusted to pH = 4 to 5 with 1M hydrochloric acid. The aqueous phase was washed with ethyl acetate (200 mL * 3) and the obtained aqueous phase was adjusted to pH = 9 with 1 M sodium hydroxide, followed by extraction with dichloromethane (250 mL * 3). The organic phases were combined, washed with saturated brine (250 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated to dryness under reduced pressure (water pump, 50 ° C) to provide a crude product. The crude product was isolated and purified by prep HPLC. (water (0.04% ΝΗ3Ή2Ο + 10 mM NHziHCChJ-CAN) to provide Compound WX016-7. Ã H NMR (400 MHz, CHLOROPHORM-d) δ ppm 1.99 - 2.09 (m, 2 H) 2.11 (s, 3 H) 2.14 - 2.26 (m, 2 H) 4.21 - 4.37 (m, 1 H) 4.56 (br s, 2 H) 4.75 (dt, J = 13.93, 4.83 Hz, 1 H) 6.24 (t, J = 4.02 Hz, 1 H) 6.51 - 6.58 (m, 1 H) 7.51 - 7.57 (m, 1 H) 7.60 - 7.65 (m, 1 H) MS m / z: 274 [M + H] +.
    Step 6: Synthesis of Compound WX016-8 [0163] Compound WXBB-1 (3.50 g, 13.39 mmol, 1 eq) was added to a dry round-bottom flask, followed by the addition of dichloromethane (35 mL) . The air in the system was charged with a nitrogen balloon twice. N, Ndimethylformamide (0.1 ml, 1.3 mmol, 0.1 eq) and oxalyl chloride (2 ml, 22.85
    Petition 870190067738, of 7/17/2019, p. 211/336
    99/105 mmol, 1.7 eq) were added to it under nitrogen atmosphere. The reaction system was stirred at room temperature (20 ° C) for 3 hours until the reaction solution was clear. The reaction solution was concentrated to 15 ml, followed by the addition of anhydrous dichloromethane (20 ml) and then concentrated to 15 ml. Such procedures were repeated three times. Subsequently, anhydrous dichloromethane (20 mL) was added and the air in the system was charged with a nitrogen flask twice. Compound WX016-7 (3.50 g, 12.03 mmol, 0.9 eq) and Λ /, / V-dimethylformamide (2.4 ml, 13.78 mmol, 1 eq) were added to it under an atmosphere of nitrogen. The reaction system was stirred at room temperature (20 ° C) for 1 hour, followed by the addition of water (50 ml) and then adjusted to pH = 9 with solid potassium carbonate and extracted with dichloromethane (50 ml * 3). The organic phases were combined, washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure to provide WX016-8. H NMR (400 MHz, DMSO-d6) δ ppm 0.68 to 0.73 (m, 2 H) 0.78 to 0.83 (m, 2 H) 1.81 -1.89 (m, 1 H) 1.99 - 2.08 (m, 4 H) 2.09 (s, 3 H) 2.25 (s, 3 H) 4.28 - 4.36 (m, 1 H) 4.71 - 4.81 (m, 1 H) 6.19 (s, 1 H) 7.19 (d, J = 1.25 Hz, 1 H) 7.49 (d, J = 11.04 Hz, 1 H ) 7.64 (d, J = 6.53 Hz, 1 H) 7.70 (d, J = 1.25 Hz, 1 H) 7.93 (d, J = 7.03 Hz, 1 H) 8 , 04 (t, J = 7.91 Hz, 1 H) 8.22 (d, J = 8.03 Hz, 1 H) 11.03 (s, lH) o MS m / z: 516.4 [M + H] +.
    Step 7: Synthesis of Compound WX016 [0164] Compound WX016-8 (3.00 g, 4.23 mmol, 1 eq) (72.65% purity)
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    100/105 was added to a dry round-bottom flask and a mixture of tetrahydrofuran (15 ml) and water (5 ml) was added to the reaction flask, followed by the addition of lithium hydroxide monohydrate (532 mg, 12.68 mmol , 3 eq). The reaction system was stirred at room temperature (24 ° C) for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with dichloromethane (50 mL * 3). The organic phases were combined, washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was rotary evaporated until dry under reduced pressure to provide WX016. H NMR (400 MHz, DMSO-d6) δ ppm 0.68 to 0.73 (m, 2 H) 0.78 to 0.83 (m, 2 H) 1.81 to 1.89 (m, 1 H) 1.99 - 2.08 (m, 4 H) 2.09 (s, 3 H) 2.25 (s, 3 H) 4.28 - 4.36 (m, 1 H) 4.71 - 4.81 (m, 1 H) 6.19 (s, 1 H) 7.19 (d, J = 1.25 Hz, 1 H) 7.49 (d, J = 11.04 Hz, 1 H ) 7.64 (d, J = 6.53 Hz, 1 H) 7.70 (d, J = 1.25 Hz, 1 H) 7.93 (d, J = 7.03 Hz, 1 H) 8 , 04 (t, J = 7.91 Hz, 1 H) 8.22 (d, J = 8.03 Hz, 1 H) 11.03 (s, 1 H). MS m / z: 474.2 [M + H] +.
    Example 017: WX017-WX018
    Step 1: Synthesis of Compound WX017, WX018 [0165] Compound WX016 was separated by SFC (column: YMC CHIRAL Amylose-C (250 mm * 30 mm, 10 pm): mobile phase: [0.1% NH3.H2O EtOH]: B: 55% to 55%, min) to provide WX017 and WX018 with a retention time of 0.921 min and 1.459 min, respectively.
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    101/105 [0166] The retention time of WX017 is 0.921 min. X H NMR (400 MHz, DMSO-d6) δ ppm 0.67 - 0.73 (m, 2 H) 0.77 - 0.84 (m, 2 H) 1.82 -1.97 (m, 4 H) 2.14 (br dd, J = 9.16, 5.65 Hz, 1 H) 2.25 (s, 3 H) 4.20 - 4.30 (m, 1 H) 4.68 ( br d, J = 13.80 Hz, 1 H) 4.90 (br d, J = 4.77 Hz, 1 H) 5.81 (d, J = 5.27 Hz, 1 H) 7.19 ( d, J = 1.25 Hz, 1 H) 7.49 (d, J = 10.79 Hz, 1 H) 7.63 (d, J = 6.53 Hz, 1 H) 7.70 (d, J = 1.25 Hz, 1 H) 7.91 (d, J = 7.53 Hz, 1 H) 8.02 (t, J = 7.91 Hz, 1 H) 8.20 (d, J = 8.28 Hz, 1 H) 10.99 (s, 1 H). MS m / z: 474.5 [M + H] +.
    [0167] The retention time of WX018 is 1.459 min. X H NMR (400 MHz, DMSO-d6) δ ppm 0.68 - 0.73 (m, 2 H) 0.77 - 0.84 (m, 2 H) 1.81 -1.98 (m, 4 H) 2.14 (br dd, J = 8.91, 5.40 Hz, 1 H) 2.25 (s, 3 H) 4.21 - 4.29 (m, 1 H) 4.68 ( br d, J = 14.31 Hz, 1 H) 4.87 - 4.93 (m, 1 H) 5.82 (d, J = 5.02 Hz, 1 H) 7.19 (d, J = 1.00 Hz, 1 H) 7.49 (d, J = 10.79 Hz, 1 H) 7.63 (d, J = 6.53 Hz, 1 H) 7.70 (d, J = 1, 00 Hz, 1 H) 7.91 (d, J = 7.28 Hz, 1 H) 8.02 (t, J = 7.91 Hz, 1 H) 8.20 (d, J = 8.03 Hz , 1 H) 11.00 (s, 1 H). MS m / z: 474.2 [M + H] +.
    Biological activity test:
    Experimental Example 1: Enzyme activity
    Reagents:
    [0168] Primary reaction buffer solution: 20 mM Hepes (pH 7.5), 10 mM MgCb, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO
    Compound treatment:
    [0169] The tested compounds were formulated in a stock solution
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    102/105 of 10 mM in DMSO, diluted in a 3-fold gradient to a total of 10 concentrations and placed in a 384-well plate (Olefin Copolymer LDV Echo® Cyclic).
    [0170] Kinase Name: ASK1 / MAP3K5 (Invitrogen, Carlsbad, CA).
    [0171] Type: Recombinant human-sized protein, labeled with GST.
    [0172] Concentration of the final enzyme reaction: 20 nM.
    [0173] Substrate: Myelin basic protein, MBP (Active Motif, Carlsbad, CA).
    [0174] Concentration of the final substrate reaction: 20 μΜ.
    Experimental procedures:
    1. The substrate was dissolved in a freshly prepared primary reaction buffer solution,
    2. The desired coenzyme factor has been added to the substrate solution above,
    3. The kinase was added to the substrate solution and mixed gently,
    4. The compound tested in DMSO solution was added to the kinase reaction solution and incubated at room temperature for 20 minutes.
    5. The reaction was started by adding 33 P-ATP (specific activity 10 pCi / pL) to the reaction solution.
    6. Incubated at room temperature for 2 hours.
    7. A small portion of the reagents was placed on the P-81 ion exchange filter paper.
    8. The filter paper was washed three times with 0.75% phosphate buffer
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    103/105 to wash away unbound phosphate and then dry.
    9. The remaining radioactivity on the filter paper was determined,
    10. The data for kinase activity was expressed as the ratio of kinase activity remaining in the test sample to kinase activity in the vehicle (DMSO).
    11. IC50 values and curve adjustment were collected by Prisma (GraphPad software). The experimental results were shown in Table 1 and Table 2:
    Table 1: Results of the in vitro screening test of the compounds of the invention
    N 2 Compound IC 5 o (nM) 1 Example 001: WX001 1.82 2 Example 002: WX002 5.6 3 Example 003: WX003 943 4 Example 004: WX004 > 1000 5 Example 005: WX005 35.3 6 Example 006: WX006 19.20 7 Example 007: WX007 16.60 8 Example 008: WX008 5.44 9 Example 010: WX010 7.20 10 Example Oil: WX011 7.61 11 Example 012: WX012 7.04 12 Example 013: WX013 7.93
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    104/105
    13 Example 014: WX014 10.70 14 Example 015: WX015 10.10 15 Example 016: WX016 4.12 16 Example 017: WX017 12.50 17 Example 017: WX018 6.57
    Table 2: Results of the in vitro screening test of the compounds of the invention
    N 2 Compound IC50 value 1 Example 001 THE 2 Example 002 THE 3 Example 003 B 4 Example 004 B 5 Example 005 THE
    Note: A <100 nM; B> 100 nM.
    [0175] Conclusion: The compounds of the present invention have a significant inhibitory effect against ASK1.
    Experimental Example 2: Study of pharmacokinetic characteristics
    Experimental methods:
    [0176] Male C57BL / 6 mice were used in this study. The concentration of drug in the plasma of mice submitted to intravenous or oral administration of the test compound at different points in time was quantitatively determined by the LC / MS / MS method, respectively, in order to assess the pharmacokinetic characteristics of the
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    105/105 drugs tested in mice.
    [0177] A clear solution of the test compound was injected into C57BL / 6 mice through the caudal vein (overnight fasting, 7 to 10 weeks old) and the test compound was intragastrically administered to C57BL / 6 mice (overnight fasting, 7 to 10 weeks of age). 30 μΙ_ of blood was collected from the jugular or caudal veins of animals 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration and placed in the tube with anticoagulant containing EDTA -K2, followed by centrifugation at 4 ° C for 15 minutes to collect plasma. The plasma concentration was determined by LC-MS / MS. Pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method of a non-compartmental model using the pharmacokinetic software WinNonlin ™ Version 6.3 (Pharsight, Mountain View, CA). The experimental results were shown in Table 3:
    Table 3. Results of the pharmacokinetic test
    Compound Exposure (nM-h) Bioavailability WX002 408566 156% WX017 59396 165% WX018 53367 102%
    [0178] Experimental Conclusion: The compounds of the invention have high exposure and bioavailability in mice.
    权利要求:
    Claims (14)
    [1]
    1. A compound as shown in formula (II), a pharmaceutically acceptable salt thereof and a tautomer thereof,

    [2]
    2/5 in any of the above cases, the number of the heteroatom or heteroatomic group is independently selected from 1, 2 or 3.
    The compound, the pharmaceutically acceptable salt thereof and the tautomer thereof according to claim 1, wherein, R is selected from F, Cl, Br, I, OH, NH2, or selected from the group consisting of Me, and cFZ, each of which is optionally substituted with 1, 2 or 3 R '.
    [3]
    The compound, the pharmaceutically acceptable salt thereof and the tautomer thereof according to claim 2, wherein, R is selected from
    F, Cl, Br, I, OH, NH 2 , Me, / ° e.
    [4]
    The compound, ο pharmaceutically acceptable salt thereof and the tautomer thereof according to any one of claims 1 to 3, wherein, Ri is selected from H, F, Cl, Br, I, OH, NH2, or selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, C1-3 alkylamino, morpholinyl and pyridyl, each of which is optionally substituted with 1, 2 or 3 R.
    [5]
    The compound, the pharmaceutically acceptable salt thereof and the tautomer thereof according to claim 4, wherein, R1 is selected from H, F, Cl, Br, I, OH, NH2, or selected from group consisting of Me, Γ ^ ν. -, - Ν '' OJ <J o ', cr, O' t h t θ, each of which is optionally substituted with 1, 2 or 3 R.
    [6]
    The compound, the pharmaceutically acceptable salt thereof and the tautomer thereof according to claim 5, wherein, Ri is selected from
    Petition 870190067738, of 7/17/2019, p. 220/336
    3/5

    [7]
    The compound, ο pharmaceutically acceptable salt thereof and the tautomer thereof according to any one of claims 1 to 3, wherein, the

    [8]
    8. The compound, the pharmaceutically acceptable salt thereof and the tautomer

    [9]
    The compound, the pharmaceutically acceptable salt thereof and the tautomer thereof according to any one of claims 1 to 6, is selected from the group consisting of

    [10]
    10. The compound, the pharmaceutically acceptable salt thereof and the tautomer thereof according to claim 9, which is selected from
    Petition 870190067738, of 7/17/2019, p. 221/336
    4/5 from the group consisting of

    [11]
    11. The compound, the pharmaceutically acceptable salt thereof and the tautomer thereof which is selected from the group consisting of

    [12]
    A pharmaceutical composition comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, as the active ingredient and a pharmaceutically acceptable carrier.
    [13]
    A use of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 in the manufacture of a medicament for treating diseases related to ASK1.
    [14]
    A use of the composition according to claim 12 in the manufacture of a medicament for treating diseases related to ASK1.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    TWI625121B|2009-07-13|2018-06-01|基利科學股份有限公司|Apoptosis signal-regulating kinase inhibitors|
    UY34573A|2012-01-27|2013-06-28|Gilead Sciences Inc|QUINASE INHIBITOR REGULATING THE APOPTOSIS SIGNAL|EP3590931A4|2017-03-03|2020-11-18|Jiangsu Hansoh Pharmaceutical Group Co., Ltd.|Amide derivative inhibitor and preparation method and application thereof|
    TW201838983A|2017-04-05|2018-11-01|美商錫爾羅克醫療公司|Ask1 inhibitor compounds and uses thereof|
    US10683279B2|2017-05-12|2020-06-16|Enanta Pharmaceuticals, Inc.|Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof|
    US10450301B2|2017-05-25|2019-10-22|Enanta Pharmaceuticals, Inc.|Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof|
    US10246439B2|2017-05-25|2019-04-02|Enanta Pharmaceuticals, Inc.|Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof|
    US10253018B2|2017-05-25|2019-04-09|Enanta Pharmaceuticals, Inc.|Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof|
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    法律状态:
    2021-04-13| B15K| Others concerning applications: alteration of classification|Free format text: A CLASSIFICACAO ANTERIOR ERA: C07D 471/04 Ipc: C07D 471/04 (2006.01), A61P 3/00 (2006.01), ¢...! |
    2021-05-18| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2021-06-15| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-07-13| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-08-10| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 22/01/2018, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    CN201710054224|2017-01-22|
    CN201710054224.4|2017-01-22|
    PCT/CN2018/073640|WO2018133866A1|2017-01-22|2018-01-22|Pyridine derivative as ask1 inhibitor and preparation method and use thereof|
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