PLK4 regulator

Abstract

This document provides small molecule protein kinase modulators having formula (A). Pharmaceutical compositions comprising such small molecule protein kinase modulators and their use in treating one or more conditions are also disclosed.

Description

[0001] Cross-referencing This application claims the benefit of U.S. Provisional Patent Application No. 63 / 546,320, filed October 30, 2023, which is incorporated herein by reference in its entirety.

[0002] background Polo-like kinases (PLKs) are a family of Ser / Thr kinases involved in multiple functions of cell division. Five PLK family members exist, with PLK4 identified as a key component regulating centrioleum replication. Dysregulation of PLK4 leads to centrosome number abnormalities, mitotic defects, chromosomal instability, and tumorigenesis. Overexpression of PLK4 has also been reported in many human cancers. See, for example, Zhang et al., Front Oncol. 2021; 11: 587554 and Zhao et al., Journal of Cancer Research and Clinical Oncology (2019) 145:2413-2422. Although small molecules targeting PLK4 have been shown to provide significant anticancer responses, the medical field currently lacks sufficient PLK4 therapeutics to combat the growing fight against cancer.

[0003] By incorporating via reference Each patent, publication and non-patent document cited in this application is incorporated herein by reference in its entirety as if it were cited individually.

[0004] Overview This article provides compounds having formula A. (A); and its pharmaceutically acceptable salts, of which E, J, Y, X, R 4 R 5 R 6 R 7 R 9 R 10 and Q 4 As defined herein. In one aspect, a compound of formula A modulates PLK4 (e.g., a PLK4 inhibitor) and can be used to treat conditions that respond to inhibition of PLK4 (e.g., cancer).

[0005] It also includes pharmaceutical compositions comprising the said compound and pharmaceutically acceptable salts of the compound of formula A, and methods for preparing them.

[0006] Detailed Explanation 1. General description of compounds In the first embodiment, a compound having formula A is provided: (A); Or its pharmaceutically acceptable salt, wherein E is Or a bicyclic heterocyclic system comprising a 5-membered ring fused to a 6-membered ring, wherein the bicyclic heterocyclic system is optionally substituted with one to three groups independently selected from halogens, oxo- and (C1-C4) alkyl groups; R 1 and R 2 Each independently is -OR a or -NR b R c Or R 1 and R 2 With R 1 and R 2 The carbon atoms that are bonded together form 5- to 7-membered heterocyclic groups; R a The group is selected from (C1-C4)alkyl, 4- to 6-membered heterocyclic groups, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH) and -(C1-C4)alkyl [4- to 6-membered heterocyclic groups], wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic groups are each optionally substituted by one or two groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy; R b and R c Each is independently selected from hydrogen and (C1-C4) alkyl groups, or R b and R c With R b and R c The attached nitrogen atoms together form 4- to 6-membered heterocyclic groups; R 3 It is a hydrogen or (C1-C4)alkoxy group; R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl or 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups independently selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano and -NH(C1-C4)alkyl; Ring M is a 6-membered aryl or a 6-membered heteroaryl; R5 and R 7 Each of these can be independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, hydroxyl, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl]; R 6 It is a halogen, hydroxyl, cyano, (C2-C4) acyl, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, (C3-C6) cycloalkyl, -O(C3-C6) cycloalkyl, or deuterated(C1-C4) alkoxy; R 8 and R 9 Each is either hydrogen or halogen; J is O, NR 11 , S or CH2; R 10 It is a halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl; and R 11 It is hydrogen; or R 10 and R 11 With R 10 and R 11 The atoms that are bonded together form a 5-membered heterocyclic group; Q 1 and Q 2 Each of them is independently CH or N; Q 3 It is CR 8 Or N; Q 4 Is it N, CH or R? 9 Attached carbon atoms; X is N, CH, or related to R. 3 Attached carbon atoms; and Y is -NHC(O)- or -C(O)NH-; The condition is: (i) if R 4 If it is CH3, then: (a) R 5 Not hydrogen or (b) Q 3 It is CR 8 , where R 8 It is a halogen; and (ii) if Q 1 N, Q 2 It is CH, Q 3 It is CR 8 And R 4 If it is CH3 or CH2OH, then R8 It is halogen.

[0007] In the second embodiment, a compound having formula I is provided: (I); Or its pharmaceutically acceptable salt, wherein R 1 and R 2 Each independently is -OR a or -NR b R c ; R a The group is selected from (C1-C4)alkyl, 4- to 6-membered heterocyclic groups, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH) and -(C1-C4)alkyl [4- to 6-membered heterocyclic groups], wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic groups are each optionally substituted by one to two groups selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy; R b and R c Each is independently selected from hydrogen and (C1-C4) alkyl groups, or R b and R c Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered heterocyclic groups; R 3 It is a hydrogen or (C1-C4)alkoxy group; R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl or 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by 1 to 3 groups selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano and NH(C1-C4)alkyl; R 5 and R 7 Each of these can be independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl]; R 6It is halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy; R 8 and R 9 Each is either hydrogen or fluorine; R 10 It is a halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl; X is CH or N; and Y is -NHC(O)- or -C(O)NH-; the condition is that if R 4 If it is CH3, then R 5 It's not hydrogen.

[0008] 2. Definition When used in combination to describe chemical groups that can have multiple attachment points, the hyphen (-) indicates the attachment point of the group to the variable it defines. For example, -NH(C1-C4)alkyl means that the attachment point of the group is located on a nitrogen atom. In another example, the oxygen atom of (C1-C4)alkoxy is the attachment point in "-(C1-C4)alkoxy[hydroxy(C1-C4)alkyl]". In yet another example, -(C1-C4)alkyl is the attachment point in "-(C1-C4)alkyl(C3-C6)cycloalkyl".

[0009] The terms “halo” and “halogen” refer to atoms selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0010] When used alone or as part of a larger part, the term "alkyl," such as "haloalkyl," refers to a saturated straight-chain or branched monovalent hydrocarbon group. Unless otherwise stated, alkyl groups typically have 1-4 carbon atoms, i.e., (C1-C4)alkyl. The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by deuterium.

[0011] "Acyl" refers to an alkyl, alkenyl, or alkynyl group attached via a carbonyl group. For example, "(C2-C4)acyl" includes, for example, acetyl, propionyl, and butyryl.

[0012] "Alkoxy" refers to an alkyl group attached to an oxygen atom and is represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy. The term "deuterated alkoxy" refers to an alkoxy group in which one or more hydrogen atoms have been replaced by deuterium.

[0013] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl groups, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine (e.g., -CF3, -CHF2, etc.).

[0014] "Haloalkoxy" is a haloalkyl group attached to another part via an oxygen atom, such as, for example, but not limited to, -OCHF2 or -OCF3.

[0015] The term "4- to 6-membered heterocyclic group" refers to a 4- to 6-membered saturated or partially unsaturated heterocycle containing one to four heteroatoms independently selected from N, O, and S. The term "5- to 7-membered heterocyclic group" refers to a 5- to 7-membered saturated or partially unsaturated heterocycle containing one to four heteroatoms independently selected from N, O, and S. The heterocyclic ring can be attached to its side group at any heteroatom or carbon atom that produces a stable structure. Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolylalkyl, pyrrolidone, piperidinyl, oxazolyl, piperazine, dioxacyclohexyl, oxacyclobutyl, dioxacyclopentyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. Optional substituents on the heterocyclic group can be present at any substituted position, including, for example, positions where the heterocyclic group is attached.

[0016] The term "(C3-C6)cycloalkyl" refers to a fully saturated hydrocarbon ring system containing 3 to 6 carbon atoms. (C3-C6)cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It should be understood that, when specified, optional substituents on the (C3-C6)cycloalkyl group (e.g., in the case of optionally substituted (C3-C6)cycloalkyl groups) may be present at any substituted position, including, for example, positions attached to (C3-C6)cycloalkyl groups.

[0017] In some respects, the described compound can exist in multiple stereoisomers. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers that are mirror images of each other and cannot be superimposed, most commonly because they contain asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" refers to one of a pair of molecules that are mirror images of each other and cannot be superimposed. Diastereomers are stereoisomers containing two or more asymmetrically substituted carbon atoms.

[0018] "Racemate" or "racemate mixture" refers to a mixture of two enantiomers in equimolar amounts, wherein such mixtures do not exhibit optical activity, that is, they do not rotate the plane of polarized light.

[0019] If the stereochemistry of the described compound is named or described by structure, then in a composition (e.g., a pharmaceutical composition) comprising a group of molecules having a structure according to the described compound, the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 97%, 98%, 99%, or 99.9% pure by weight relative to all other stereoisomers in the group of molecules, unless otherwise stated. The percentage of purity relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of the other stereoisomers.

[0020] When a compound is named or described by its structure without indicating its stereochemistry, in a composition (e.g., a pharmaceutical composition) containing a group of molecules having the structure according to the compound described, it should be understood that, unless otherwise stated, the composition encompasses a composition containing one stereoisomer and not other stereoisomers, a mixture of stereoisomers, or a mixture of stereoisomers in which one or more stereoisomers are enriched relative to other stereoisomers.

[0021] In some embodiments, the compounds described herein are present as transisomers. Transisomers are stereoisomers resulting from restricted rotation around a single bond, wherein an energy difference due to steric strain or other contributing factors creates a sufficiently high rotational barrier to allow the separation of individual conformational isomers. Unless otherwise stated, when a described compound is named or depicted by its structure without indicating that the structure is a single transisomer, in compositions (e.g., pharmaceutical compositions) comprising a group of molecules having the structure according to the described compound, it should be understood that the composition encompasses compositions comprising one transisomer and none of the other transisomers, equal mixtures of transisomers, or mixtures of transisomers in which one transisomer is enriched relative to another transisomer.

[0022] For example, when R 5 It is not hydrogen, and when R 5 Located in R 4 and R 3 When the ring is adjacent When used to describe the structure of molecular populations in a composition, it encompasses the two transisomers that are a mixture, namely, and , and each of the transtransfer isomers enriched as described above.

[0023] As used herein, a composition comprising a “single transisomer” means that the described or named compound is enriched in a composition having one or more transisomers in amounts such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% of the single transisomer, unless otherwise stated. In some embodiments, the compound described herein is present and / or isolated as a pure single transisomer. “Pure single transisomer” means that the compound is a single transisomer, with no other detectable amounts of other transisomers.

[0024] In some embodiments, the compounds described herein (e.g., blocking isomers) are characterized by specific optical rotation (or, in other words, "specific rotation") as measured by a polarimeter. Compounds that rotate the plane of polarization of plane-polarized light clockwise correspond to positive specific rotation values, while compounds that rotate the plane of polarization of plane-polarized light counterclockwise correspond to negative specific rotation values. Specific rotation is determined by [α]. θ λ = α / γl is defined, where α is the angle by which plane-polarized light is rotated by a solution of mass concentration γ and path length l. θ is the Celsius temperature, and λ is the wavelength of the light being measured.

[0025] In some embodiments, the specific rotation of the compounds described herein is determined at the D line (589 nm) of sodium at 20°C or 25°C. In some embodiments, the specific rotation of the compounds described herein is determined using a solution of the compound. The solvent in the solution may be, for example, ethanol, methanol, DSMO, acetone, or water.

[0026] In some embodiments, the compounds described herein are characterized by their retention time (i.e., R0) during liquid chromatography. T The liquid chromatography method mentioned is, for example, high-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). For chiral compounds (e.g., the enantiomers described herein), when using a chiral stationary phase for liquid chromatography, the stereoisomers can be distinguished from each other by their retention times. For example, when performing chiral HPLC analysis, the enantiomer may elute later or earlier than its enantiomer.

[0027] The terms “subject” and “patient” are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, a subject is a human being in need of treatment.

[0028] The terms “inhibit,” “inhibition,” or “inhibiting” refer to a reduction in the baseline activity of a biological activity or process, such as the inhibition of PLK4 activity.

[0029] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, or delaying the onset or progression of a disease or disorder or one or more of its symptoms, as described herein. In some respects, treatment may be administered after one or more symptoms have developed; that is, therapeutic treatment. In other respects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a particular organism or other susceptibility factor); that is, preventative treatment. Treatment may also continue after symptoms have subsided, for example, to delay their recurrence.

[0030] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, excipient, or mediator that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, excipients, or mediators that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated plant fatty acid metaglycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0031] For pharmaceutical purposes, the salts of the compounds described herein refer to non-toxic, “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds taught in this invention that have acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts). Compounds having quaternary ammonium groups also contain counter anions such as chloride, bromide, iodide, acetate, perchlorate, etc. Other examples of such salts include hydrochlorides, hydrobromic acids, sulfates, methanesulfonates, nitrates, benzoates, and salts with amino acids such as glutamic acid.

[0032] The term “effective amount” or “therapeutic effective amount” refers to an amount of the compound described herein that will elicit a desired or beneficial biological or medical response in a subject, for example, a dose between 0.01 and 100 mg / kg body weight / day.

[0033] 3. Description of exemplary compounds: In the third embodiment, the compound of formula I has formula II: (II); Or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0034] In the fourth embodiment, the compound of formula I has formula III: (III); Or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0035] In the fifth embodiment, the compound of formula I has formula IV: (IV); Or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0036] In the sixth embodiment, the compound of formula I has formula V: (V); Or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0037] In the seventh embodiment, R is in any one of the compounds of formulas I to V or a pharmaceutically acceptable salt thereof.10 It is a halogen, wherein the remaining variables are as described above for Formula I. Alternatively, as part of the seventh embodiment, R is in any of the compounds of Formulas I to V or their pharmaceutically acceptable salts. 10 It is fluorine, and the other variables are as described above for Equation I.

[0038] In the eighth embodiment, R is in any one of the compounds of formulas I to V or a pharmaceutically acceptable salt thereof. 5 It is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, or halogen, wherein the remaining variables are as described above for Formula I or the seventh embodiment. Alternatively, as part of the eighth embodiment, R is in any compound of Formulas I to V or a pharmaceutically acceptable salt thereof. 5 It is (C1-C4)alkyl, halo(C1-C4)alkyl, or halogen, wherein the remaining variables are as described above for Formula I or the seventh embodiment. In another alternative, as part of the eighth embodiment, R is in any compound of Formulas I to V or a pharmaceutically acceptable salt thereof. 5 It is CH3, CF3, or chlorine, where the remaining variables are as described above for Formula I or the seventh embodiment.

[0039] In the ninth embodiment, X is CH in any compound of formulas I to V or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for formula I or the seventh or eighth embodiment.

[0040] In the tenth embodiment, R is in any one of the compounds of formulas I to V or a pharmaceutically acceptable salt thereof. 3 It is hydrogen, wherein the remaining variables are as described above for Formula I or any of the seventh to ninth embodiments.

[0041] In the eleventh embodiment, R is in any compound of formulas I to V or a pharmaceutically acceptable salt thereof. 9 It is hydrogen, wherein the remaining variables are as described above for Formula I or any of the seventh to tenth embodiments.

[0042] In the twelfth embodiment, R is in any compound of formulas I to V or a pharmaceutically acceptable salt thereof. 8 It is fluorine, wherein the other variables are as described above for Formula I or any of the seventh to eleventh embodiments.

[0043] In the thirteenth embodiment, each R in any one of the compounds of formulas I to V or a pharmaceutically acceptable salt thereof aThe group is independently selected from (C1-C4)alkyl, oxetyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrrolidinyl], -(C1-C4)alkyl[piperazinyl], and -(C1-C4)alkyl[morpholinyl], wherein the cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetyl groups are each optionally substituted with one to two groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy groups, wherein the remaining variables are as described above with respect to Formula I or any of the seventh to twelfth embodiments. Alternatively, as part of the thirteenth embodiment, each R in any of the compounds of Formulas I to V or their pharmaceutically acceptable salts is... a Independently selected from OCH3, , , , , , , , , , , and The remaining variables are as described above for Equation I or any of the seventh to twelfth embodiments.

[0044] In the fourteenth embodiment, R is in any compound of formulas I to V or a pharmaceutically acceptable salt thereof. 4 It is a (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted with one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above with respect to any one of the seventh to thirteenth embodiments. Alternatively, as part of the fourteenth embodiment, R is in any compound of formulas I to V or a pharmaceutically acceptable salt thereof. 4It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetane, wherein the (C3-C6)cycloalkyl is optionally substituted with one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for any one of the seventh to thirteenth embodiments of formula I. In another alternative, as part of the fourteenth embodiment, R is in any compound of formula I to V or a pharmaceutically acceptable salt thereof. 4 yes , CF3, CH3 OCHF2 CH2CF3 , , , , , , or The remaining variables are as described above for Equation I or any of the seventh to thirteenth embodiments.

[0045] In the fifteenth embodiment, R is in any compound of formulas I to V or a pharmaceutically acceptable salt thereof. 7 It is hydrogen, halogen, -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl], or cyano, wherein the remaining variables are as described above with respect to any one of the seventh to fourteenth embodiments. Alternatively, as part of the fifteenth embodiment, R is in any one of the compounds of formulas I to V or a pharmaceutically acceptable salt thereof. 7 It is hydrogen, fluorine, bromine, chlorine, Or cyano.

[0046] In the sixteenth embodiment, R is in any compound of formulas I to V or a pharmaceutically acceptable salt thereof. 6 It is OCH3, fluorine, OCHF2, OCF3, , OCD3, wherein the remaining variables are as described above for Formula I or any of the seventh to fifteenth embodiments. Alternatively, as part of the sixteenth embodiment, R in any of the compounds of Formulas I to V or their pharmaceutically acceptable salts. 6 It is fluorine, wherein the other variables are as described above for Formula I or any of the seventh to fifteenth embodiments.

[0047] In the seventeenth embodiment, the compound of formula A has formula AI: (AI); Or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for formula A.

[0048] In the eighteenth embodiment, in a compound of formula A or formula AI or a pharmaceutically acceptable salt thereof yes Z 1 Z 2 and Z 3 Each independently is N, CH, or R 5 R 6 and R 7 One of the carbon atoms is bonded, and the remaining variables are as described above for formula A.

[0049] In the nineteenth embodiment, the compound of formula A has formula A-II: (A-II); Or its pharmaceutically acceptable salt, wherein Z 1 and Z 3 As described in the eighteenth implementation scheme, the remaining variables are as described above for Equation A.

[0050] In the twentieth embodiment, Z is in a compound of formula A-II or a pharmaceutically acceptable salt thereof. 1 and Z 3 Each independently is CH or R 5 and R 7 One of the bound carbon atoms, wherein the remaining variables are as described above with respect to Formula A or any of the seventeenth to nineteenth embodiments. Alternatively, as part of the twentieth embodiment, Z in the compound of Formula A-II or its pharmaceutically acceptable salt. 1 and Z 3 Each is N, where the remaining variables are as described above for formula A or any of the seventeenth to nineteenth embodiments. In another alternative, as part of the twentieth embodiment, in the compounds of formula A-II, Z 1 Is it CH or R? 7 The combined carbon atoms and Z 3 N is the variable, where the remaining variables are as described above for formula A or any of the seventeenth to nineteenth embodiments. In yet another alternative, as part of the twentieth embodiment, in the compounds of formula A-II, Z 1 It is N and Z 3 Is it CH or R? 5 The combined carbon atoms, wherein the remaining variables are as described above with respect to Formula A or any of the seventeenth to nineteenth embodiments.

[0051] In the twenty-first embodiment, the compound of formula A has formula A-III: (A-III); Or its pharmaceutically acceptable salt, wherein Z 3 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0052] In the twenty-second embodiment, the compound of formula A has formula A-IV: (A-IV); Or its pharmaceutically acceptable salt, wherein Z 3 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0053] In the twenty-third embodiment, the compound of formula A has formula AV: (AV); Or its pharmaceutically acceptable salt, wherein Z 3 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0054] In the twenty-fourth embodiment, the compound of formula A has formula A-VI: (A-VI); Or its pharmaceutically acceptable salt, wherein Z 3 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0055] In the twenty-fifth embodiment, the compound of formula A has formula A-VI-1: (A-VI-1); Or its pharmaceutically acceptable salt, wherein Z 3 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0056] In the twenty-sixth embodiment, the compound of formula A has formula A-VI-2: (A-VI-2); Or its pharmaceutically acceptable salt, wherein Z 3 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0057] In the twenty-seventh embodiment, the compound of formula A has formulas A-VII: (A-VII); Or its pharmaceutically acceptable salt, wherein Z 3 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0058] In the twenty-eighth embodiment, Z is a compound of any one of formulas A-II, A-III, A-IV, AV, A-VI, A-VI-1, A-VI-2 and A-VII, or a pharmaceutically acceptable salt thereof. 3 Let N be the variable, where the other variables are as described above for equation A.

[0059] In the twenty-ninth embodiment, the compound of formula A has formula A-VIII: (A-VIII); Or its pharmaceutically acceptable salt, wherein Z 2 As described in the eighteenth embodiment, and the remaining variables are as described above for Equation A.

[0060] In the thirtieth embodiment, Z is in the compound of formula A-VIII or the eighteenth embodiment or a pharmaceutically acceptable salt thereof. 2 Let N be the variable, where the other variables are as described above for equation A.

[0061] In the thirty-first embodiment, in any one of formula A, formula A-II, and formula A-VIII, or in the compound of the eighteenth embodiment, Q 1 and Q 2 Each is CH, and Q 3 It is CR 8 The remaining variables are as described above for Formula A or the eighteenth, twentieth, or twenty-eighth embodiments. Alternatively, as part of the thirty-first embodiment, in the compounds of any one of Formula A, A-II, and A-VIII or the eighteenth embodiment, Q 1 and Q 2 Each is CH, and Q 3 N is where the remaining variables are as described above for formula A or the eighteenth, twentieth, or twenty-eighth embodiments. In another alternative, as part of the thirty-first embodiment, in the compounds of any of formula A, A-II, and A-VIII, or the eighteenth embodiment, Q 1 It is N, Q 2 It is CH and Q 3 It is CR 8The remaining variables are as described above for Formula A or the eighteenth, twentieth, or twenty-eighth embodiments. In yet another alternative, as part of the thirty-first embodiment, in the compound of any of Formula A, A-II, and A-VIII, or the eighteenth embodiment, Q 1 It's CH, Q 2 It is N and Q 3 It is CR 8 The remaining variables are as described above for Equation A or the eighteenth, twentieth, or twenty-eighth implementation schemes.

[0062] In the thirty-second embodiment, the compound of formula A has formula A-IX: (A-IX); Or its pharmaceutically acceptable salt, wherein the remaining variables are as described above for formula A.

[0063] In the thirty-third embodiment, the compound of formula A has formula AX: (AX); Or its pharmaceutically acceptable salt, wherein the remaining variables are as described above for formula A.

[0064] In the thirty-fourth embodiment, the compound of formula A has formula A-XI: (A-XI); Or its pharmaceutically acceptable salt, wherein the remaining variables are as described above for formula A.

[0065] In the thirty-fifth embodiment, the compound of formula A has formula A-XII: (A-XII); Or its pharmaceutically acceptable salt, wherein the remaining variables are as described above for formula A.

[0066] In the thirty-sixth embodiment, the compound of formula A has formula A-XIII-1: (A-XIII-1); Or its pharmaceutically acceptable salt, wherein the remaining variables are as described above for formula A.

[0067] In the thirty-seventh embodiment, the compound of formula A has formula A-XIII-2: (A-XIII-2); Or its pharmaceutically acceptable salt, wherein the remaining variables are as described above for formula A.

[0068] In the thirty-eighth embodiment, the compound of formula A has formula A-XIV: (A-XIV); Or its pharmaceutically acceptable salt, wherein the remaining variables are as described above for formula A.

[0069] In the thirty-ninth embodiment, J is O in any compound of formula A and any of formulas A1 to A-XIV, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for any of the eighteenth, twentieth, twenty-eighth, thirtieth, and thirty-first embodiments. Alternatively, as part of the thirty-ninth embodiment, J is S in any compound of formula A and any of formulas A1 to A-XIV, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for any of the eighteenth, twentieth, twenty-eighth, thirtieth, and thirty-first embodiments. In another alternative, as part of the thirty-ninth embodiment, J is CH2 in any compound of formula A and any of formulas A1 to A-XIV, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for any of the eighteenth, twentieth, twenty-eighth, thirtieth, and thirty-first embodiments. In yet another alternative, as part of the thirty-ninth embodiment, J is NR in any of the compounds of formula A and formulas A1 to A-XIV, or a pharmaceutically acceptable salt thereof. 11 The remaining variables are as described above for Equation A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, and thirty-first implementation schemes.

[0070] In the fortieth embodiment, the compound of formula A has formula A-XV: (A-XV); Or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A or the eighteenth embodiment.

[0071] In the forty-first embodiment, R is a compound of any one of formulas A and A1 to A-XIV, or a pharmaceutically acceptable salt thereof. 10 It is a halogen, wherein the remaining variables are as described above with respect to any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, and thirty-ninth embodiments. Alternatively, as part of the forty-first embodiment, R is in a compound of formula A and any one of formulas A to A-XIV, or a pharmaceutically acceptable salt thereof. 10It is fluorine, wherein the other variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first and thirty-ninth implementation schemes.

[0072] In the forty-second embodiment, Q is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 1 N is where the remaining variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-ninth, and forty-first embodiments. Alternatively, as part of the forty-second embodiment, Q is a compound of formula A and any of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 1 It is CH, where the remaining variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-ninth, and forty-first implementation schemes.

[0073] In the forty-third embodiment, Q is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 4 N is the number of variables, where the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, and forty-second embodiments of formula A. Alternatively, as part of the forty-third embodiment, Q is a compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 4 Is with R 9 The combined carbon atoms, wherein the remaining variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, and forty-second embodiments.

[0074] In the forty-fourth embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 9 It is hydrogen, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, and forty-third embodiments. Alternatively, as part of the forty-fourth embodiment, R is in a compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 9It is fluorine, wherein the other variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, and forty-third implementation schemes.

[0075] In the forty-fifth embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 5 It is hydrogen, cyano, hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl, or halogen, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, and forty-fourth embodiments. Alternatively, as part of the forty-fifth embodiment, R is in a compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 5 It is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halogen, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, and forty-fourth embodiments. In another alternative, as part of the forty-fifth embodiment, R is in any compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 5 It is CH3, CF3, cyano, hydroxyl, fluorine, chlorine, or bromine, wherein the remaining variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, and forty-fourth embodiments.

[0076] In the forty-sixth embodiment, X is CH in any compound of formula A and formulas A1 to A-XV, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, forty-fourth, and forty-fifth embodiments. Alternatively, as part of the forty-sixth embodiment, X is N in any compound of formula A and formulas A1 to A-XV, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, forty-fourth, and forty-fifth embodiments.

[0077] In the forty-seventh embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 3 It is hydrogen, wherein the remaining variables are as described above for Equation A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth and forty-first to forty-sixth embodiments.

[0078] In the forty-eighth embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 8 It is fluorine, wherein the remaining variables are as described above for any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-ninth, and forty-first to forty-seventh embodiments. Alternatively, as part of the forty-eighth embodiment, R is present in any of the compounds of formula A and formulas A1 to A-XV, or in a pharmaceutically acceptable salt thereof. 8 It is hydrogen, wherein the other variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-ninth and forty-first to forty-seventh schemes.

[0079] In the forty-ninth embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. aThe group is independently selected from (C1-C4)alkyl, oxetyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrrolidinyl], -(C1-C4)alkyl[piperazinyl], and -(C1-C4)alkyl[morpholinyl], wherein the cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetyl are each optionally substituted with one to two groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy, wherein the remaining variables are as described above with respect to Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to forty-eighth embodiments.

[0080] In the fiftieth embodiment, R is in any compound of formula A and formulas A to A-XV or a pharmaceutically acceptable salt thereof. 1 and R 2 Each is independently selected from OCH3, , , , , , , , , , , and The remaining variables are as described above for Equation A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to forty-eighth implementation schemes.

[0081] In the fifty-first embodiment, E is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. The remaining variables are as described above with respect to Formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fiftieth embodiments. Alternatively, as part of the fifty-first embodiment, in the compound of Formula A and any of Formulas A to A-XV, or a pharmaceutically acceptable salt thereof, E is pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, each optionally substituted with one to three groups independently selected from halogens and (C1-C4) alkyl groups, the remaining variables being as described above with respect to Formula A. In another alternative, as part of the fifty-first embodiment, in the compound of Formula A and any of Formulas A to A-XV, E is , , , , , or The remaining variables are as described above for equation A.

[0082] In the fifty-second embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 4 It is a (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted with one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above with respect to Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments. Alternatively, as part of the fifty-second embodiment, R is in the compound of Formula A and any one of Formulas A to A-XV or a pharmaceutically acceptable salt thereof. 4It is a (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetane, wherein the (C3-C6)cycloalkyl is optionally substituted with one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments. In another alternative, as part of the fifty-second embodiment, R is in the compound of any one of formula A and formulas A1 to A-XV or a pharmaceutically acceptable salt thereof. 4 yes , CF3, CH3 OCHF2 CH2CF3 , , , , , , or The remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments of formula A. In yet another alternative, as part of the fifty-second embodiment, R is present in any compound of formula A and any of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 4 It is a (C2-C4)alkyl, a halo(C1-C4)alkyl, a hydroxy(C2-C4)alkyl, a halo(C1-C4)alkoxy, a (C3-C6)cycloalkyl, a -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted with one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above with respect to Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments. In yet another alternative, as part of the fifty-second embodiment, R is in the compound of Formula A and any one of Formulas A to A-XV or a pharmaceutically acceptable salt thereof. 4It is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetane, wherein the cyclopropyl group is optionally substituted with one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments. In yet another alternative, as part of the fifty-second embodiment, R is in any compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 4 yes , CF3 OCHF2 CH2CF3 , , , , , , or The remaining variables are as described above for Equation A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first implementation schemes.

[0083] In the fifty-third embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 7 It is hydrogen, halogen, -(C1-C4)alkoxy [hydroxyl(C1-C4)alkyl], or cyano, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. Alternatively, as part of the fifty-third embodiment, R is in any compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 7 It is hydrogen, fluorine, bromine, chlorine, Or cyano, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. In another alternative, as part of the fifty-third embodiment, R is in any one of the compounds of formula A and formulas A1 to A-XV, or a pharmaceutically acceptable salt thereof. 7 It is hydrogen, cyano, hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl, or halogen, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. In yet another alternative, as part of the fifty-third embodiment, R is in any compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 7 It is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halogen, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. In yet another alternative, as part of the fifty-third embodiment, R is in any compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 7 It is CH3, CF3, cyano, hydroxyl, fluorine, chlorine or bromine, wherein the remaining variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth and forty-first to fifty-second embodiments.

[0084] In the fifty-fourth embodiment, R is a compound of any one of formulas A and A1 to A-XV, or a pharmaceutically acceptable salt thereof. 6 It is a halogen, hydroxyl, cyano, (C2-C4) acyl, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, -O(C3-C6) cycloalkyl, or deuterated(C1-C4) alkoxy, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-third embodiments. Alternatively, as part of the fifty-fourth embodiment, R is in any compound of formula A and any one of formulas A to A-XV, or a pharmaceutically acceptable salt thereof. 6It contains cyano, CHF2, hydroxyl, acetyl, OCH3, OEt, fluorine, OCHF2, OCF3, Or OCD3, wherein the remaining variables are as described above for any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-third embodiments. In another alternative, as part of the fifty-fourth embodiment, R is in any one of the compounds of formula A and formulas A1 to A-XV, or a pharmaceutically acceptable salt thereof. 6 It is fluorine, wherein the other variables are as described above for formula A or any of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth and forty-first to fifty-third schemes.

[0085] In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0086] In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-1-(5-cyano-4-fluoro-2-tolyl)-6-cyclopropyl-2-oxo-1,2-dihydronicotinamide. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-1-(5-cyano-4-fluoro-2-tolyl)-6-cyclopropyl-2-oxo-1,2-dihydronicotinamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-1-(5-cyano-4-fluoro-2-tolyl)-6-cyclopropyl-2-oxo-1,2-dihydronicotinamide, wherein the compound has negative specific rotation.

[0087] In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-ethoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-ethoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-ethoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0088] In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0089] In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0090] In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-1,5-diaza-4-naphthyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-1,5-diaza-4-naphthyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-1,5-diaza-4-naphthyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0091] In some embodiments, the compound of formula A is N-(4-((6,7-dimethoxy-1,5-naphthidin-4-yl)oxy)-3-fluorophenyl)-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-2H-[1,3'-bipyridine]-3-carboxamide. In some embodiments, the compound of formula A is N-(4-((6,7-dimethoxy-1,5-naphthidin-4-yl)oxy)-3-fluorophenyl)-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-2H-[1,3'-bipyridine]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-(4-((6,7-dimethoxy-1,5-naphthid-4-yl)oxy)-3-fluorophenyl)-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-2H-[1,3'-bipyridine]-3-carboxamide, wherein the compound has negative specific rotation.

[0092] In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0093] In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0094] In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-4-quinazolinyloxy)-3-fluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-4-quinazolinyloxy)-3-fluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[4-(6,7-dimethoxy-4-quinazolinyloxy)-3-fluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0095] In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinylthio)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinylthio)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridinyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinylthio)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0096] In some embodiments, the compound of formula A is 6-cyclopropyl-N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluoro-phenyl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-pyridin-3-carboxamide. In some embodiments, the compound of formula A is 6-cyclopropyl-N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluoro-phenyl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-pyridin-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is 6-cyclopropyl-N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluoro-phenyl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-pyridin-3-carboxamide, wherein the compound has negative specific rotation.

[0097] In some embodiments, the compound of formula A is N-[6-(3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)-5-fluoro-3-pyridyl]-6-cyclopropyl-quinolinylamino)phenyl]-6'-ethoxymethoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of formula A is N-[6-(3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)-5-fluoro-3-pyridyl]-6-cyclopropyl-quinolinylamino)phenyl]-6'-ethoxymethoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has positive specific rotation. In some embodiments, the compound of formula A is N-[6-(3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolinyloxy)-5-fluoro-3-pyridyl]-6-cyclopropyl-quinolinylamino)phenyl]-6'-ethoxymethoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has negative specific rotation.

[0098] In some embodiments, this disclosure provides compounds selected from any of the compounds in Table 1, or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure provides compounds selected from any of the compounds in Table 2, or pharmaceutically acceptable salts thereof.

[0099] In some embodiments, the compound described herein (e.g., as in any one of the first to fifty-fourth embodiments) is a single transisomer.

[0100] Compounds having the disclosed formula are further disclosed in the examples and are included in this disclosure. This includes pharmaceutically acceptable salts and neutral forms.

[0101] 4. Uses, formulations, and application The compounds and compositions described herein are generally used to modulate the activity of PLK4. In some aspects, the compounds and pharmaceutical compositions described herein inhibit the activity of PLK4.

[0102] In some aspects, the compounds and pharmaceutical compositions described herein can be used to treat PLK4-related conditions. Therefore, this document provides a method for treating PLK4-related conditions, comprising administering to a subject with a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof. Use is also provided for manufacturing a medicament for treating PLK4-related conditions using a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof. Furthermore, use is provided for the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, in the treatment of protein PLK4-related conditions.

[0103] In some embodiments, this disclosure provides a pharmaceutical composition comprising a group of molecules having the structure of a compound provided herein, wherein at least about 60%, 70%, 80%, 90%, 97%, 98%, 99%, or 99.9% of the molecules in said group have the same transisomer configuration.

[0104] In some aspects, the compounds and pharmaceutical compositions described herein can be used to treat cancer. Such cancers include, but are not limited to, lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasm, osteosarcoma, germ cell tumors, glioma, and mesothelioma. In one embodiment, the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer. In another embodiment, the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer. In yet another specific embodiment, the cancer is breast cancer. In another embodiment, the cancer is basal subtype breast cancer or luminal B subtype breast cancer. In one embodiment, basal subtype breast cancer is ER (estrogen receptor), HER2, and PR (progesterone receptor) negative breast cancer. In another embodiment, the cancer is soft tissue cancer. "Soft tissue cancer" is a recognized term in this field, encompassing tumors originating from any soft tissue in the body. Such soft tissues connect, support, or surround a variety of structures and organs of the body, including but not limited to smooth muscle, skeletal muscle, tendons, fibrous tissue, adipose tissue, blood vessels and lymphatic vessels, perivascular tissue, nerves, mesenchymal cells, and synovial tissue. Therefore, soft tissue cancer can be cancer of adipose tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymphatic vessels, and fibrous tissue. Soft tissue cancer can be benign or malignant. Malignant soft tissue cancer is often referred to as sarcoma or soft tissue sarcoma. Soft tissue tumors exist in many types, including lipomas, lipoblastomas, hibernating tumors, liposarcomas, leiomyomas, leiomyosarcomas, rhabdomyomas, neurofibromas, Schwannomas (neurilemomas), neuromas, malignant Schwannomas, neurofibrosarcomas, neurogenic sarcomas, nodular tenosynovitis, synovial sarcomas, hemangiomas, glomus tumors, hemangiopericytomas, hemangioendotheliomas, angiosarcomas, Kaposi's sarcoma, lymphangiomas, fibromas, elastic fibromatosis, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxomas, granular cell tumors, malignant mesenchymal tumors, alveolar soft tissue sarcomas, epithelioid sarcomas, clear cell sarcomas, and connective tissue proliferative small cell tumors. In one implementation, soft tissue cancer is a sarcoma selected from the group consisting of: fibrosarcoma, gastrointestinal sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma. In some implementations, cancer is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer, or prostate cancer.In some implementations, the cancer is acute myeloid leukemia. In some implementations, the cancer is myelodysplastic syndrome. In some implementations, the cancer is chronic myelomonocytic leukemia. In some implementations, the cancer is triple-negative breast cancer. In some implementations, the cancer is advanced breast cancer. In some implementations, the cancer is metastatic breast cancer. In some implementations, the cancer is prostate cancer.

[0105] In some aspects, the pharmaceutical compositions described herein are formulated for administration to patients in need of such compositions. The pharmaceutical compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, sublingually, vaginally, or via an implanted reservoir. As used herein, the term "parenterical" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the pharmaceutical compositions described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art.

[0106] The pharmaceutical compositions disclosed herein may be used, for example, before, during, or after treatment of a subject with another pharmaceutical agent.

[0107] Subjects may be, for example, elderly people, adults, adolescents, pre-adolescent children, children, toddlers, infants, newborns, and non-human animals. In some implementations, subjects are patients.

[0108] The pharmaceutical compositions disclosed herein can be combinations of any pharmaceutical compound described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical compositions facilitate the administration of the compound to a living organism. The pharmaceutical compositions can be administered in therapeutically effective amounts via a variety of forms and routes, including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ocular, subcutaneous, transdermal, nasal, vaginal, and topical administration.

[0109] The pharmaceutical composition can be administered locally, for example, by direct injection of the compound into an organ, optionally as a reservoir-type or sustained-release formulation or implant. The pharmaceutical composition can be provided as a rapid-release formulation, a prolonged-release formulation, or an intermediate-release formulation. Rapid-release formulations provide immediate release. Prolonged-release formulations provide controlled release or sustained delayed release.

[0110] For oral administration, pharmaceutical compositions can be formulated by combining the active compound with a pharmaceutically acceptable carrier or excipient. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions for oral ingestion by a subject. Non-limiting examples of solvents for oral soluble formulations may include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate-buffered saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1-piperazine ethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline-sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in oral soluble formulations may include sucrose, urea, cremoprolol, DMSO, and potassium phosphate buffer.

[0111] Pharmaceutical preparations can be formulated for intravenous administration. Pharmaceutical compositions can be in the form of sterile suspensions, solutions, or emulsions suitable for use as oily or aqueous media for parenteral injection, and may contain formulations such as suspending agents, stabilizers, and / or dispersants. Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in a water-soluble form. Suspensions of the active compound can be prepared as oily injectable suspensions. Suitable lipophilic solvents or media include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Suspensions may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for preparation with a suitable media such as sterile, pyrogen-free water prior to use.

[0112] The active compound can be applied topically and can be formulated into a variety of topically applicable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions may contain solubilizers, stabilizers, tension enhancers, buffers, and preservatives.

[0113] The compounds of this disclosure can be applied topically to the skin or body cavities of a subject, such as the oral cavity, vaginal cavity, bladder cavity, cranial cavity, spinal cavity, thoracic cavity, or pelvic cavity. The compounds of this disclosure can be applied to accessible body cavities.

[0114] The compounds can also be formulated into rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories, or retention enemas, comprising a conventional suppository base such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone and PEG. In the suppository form of the composition, a mixture of low-melting-point waxes, such as fatty acid glycerides, optionally combined with cocoa butter, can be melted.

[0115] When practicing the treatments or uses provided herein, a therapeutically effective amount of the compounds described herein is administered as a pharmaceutical composition to a subject suffering from the disease or condition to be treated. In some embodiments, the subject is a mammal, such as a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0116] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the processing of the active compound into a pharmaceutically usable article. The formulation can be modified depending on the chosen route of administration. Pharmaceutical compositions containing the compounds described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, embedding, or compressing processes.

[0117] The pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier, diluent, or excipient, and the compound described herein as a free base or a pharmaceutically acceptable salt. The pharmaceutical composition may comprise a solubilizer, stabilizer, tension enhancer, buffer, and preservative.

[0118] Methods for preparing compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solid compositions, semi-solid compositions, or liquid compositions. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and granules. Liquid compositions include, for example, solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, for example, gels, suspensions, and creams. Compositions may be in the form of liquid solutions or suspensions, suitable for solid forms dissolved or suspended in a liquid prior to use, or as emulsions. These compositions may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, and other pharmaceutically acceptable additives.

[0119] Non-limiting examples of dosage forms suitable for use in this disclosure include liquids, powders, gels, nanosuspensions, nanoparticles, microgels, aqueous or oily suspensions, emulsions, and any combination thereof.

[0120] Non-limiting examples of pharmaceutically acceptable excipients suitable for use in this disclosure include binders, disintegrants, anti-adhesion agents, antistatic agents, surfactants, antioxidants, coating agents, colorants, plasticizers, preservatives, suspending agents, emulsifiers, antimicrobial agents, pelleting agents, and any combination thereof.

[0121] The compositions disclosed herein can be, for example, immediate-release forms or controlled-release formulations. Immediate-release formulations can be formulated to allow the compound to act rapidly. Non-limiting examples of immediate-release formulations include readily soluble formulations. Controlled-release formulations can be pharmaceutical formulations that have been adapted to match the release rate and profile of the active agent to physiological and time-dependent therapeutic requirements, or alternatively, have been formulated to achieve the release of the active agent at a programmed rate. Non-limiting examples of controlled-release formulations include granules, delayed-release granules, hydrogels (e.g., synthetically or naturally derived hydrogels), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed therein), matrix-integrated granules, polymer mixtures, and granular masses.

[0122] In some embodiments, the controlled-release formulation is a delayed-release form. The delayed-release form can be formulated to prolong the duration of the compound's effect. The delayed-release form can be formulated to delay the release of one or more compounds of an effective dose, for example, for about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0123] Controlled-release formulations can be in a sustained-release form. Sustained-release forms can be formulated to sustain the action of, for example, a compound over an extended period of time. Sustained-release forms can be formulated to provide an effective dose of any compound described herein (e.g., to provide a physiologically effective blood profile) over about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0124] Non-limiting examples of pharmaceutically acceptable excipients can be found, for example, in: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams and Wilkins 1999), which are incorporated herein by reference in their entirety.

[0125] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, the compounds of this disclosure are administered in combination with another therapeutic agent, before or after treatment with the other therapeutic agent. If administered simultaneously, the multiple therapeutic agents can be provided in a single, uniform form or in multiple forms, such as as multiple separate pills. The agents can be packaged together or separately in a single package or more than one package. One or all of the therapeutic agents can be administered in multiple doses. If not simultaneously, the time between the multiple doses can vary up to about one month.

[0126] The therapeutic agents described herein can be administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the therapeutic agent can vary. For example, the composition can be used as a preventative agent and can be administered continuously to a subject with a condition or predisposition to reduce the likelihood of the disease or condition occurring. The composition can be administered to the subject as soon as possible during or after the onset of symptoms. Administration of the therapeutic agent can be initiated within 48 hours before the onset of symptoms, within 24 hours before the onset of symptoms, within 6 hours before the onset of symptoms, or within 3 hours of the onset of symptoms. Initial administration can be performed using any of the formulations described herein via any feasible route, such as those described herein.

[0127] The compound can be administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the duration necessary to continue treatment, such as, for example, from about 1 month to about 3 months. In some embodiments, the duration for which the compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, and so on. Treatment durations are estimated as follows: 22 weeks, approximately 23 weeks, approximately 24 weeks, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 1 year, approximately 13 months, approximately 14 months, approximately 15 months, approximately 16 months, approximately 17 months, approximately 18 months, approximately 19 months, approximately 20 months, approximately 21 months, approximately 22 months, approximately 23 months, approximately 2 years, approximately 2.5 years, approximately 3 years, approximately 3.5 years, approximately 4 years, approximately 4.5 years, approximately 5 years, approximately 6 years, approximately 7 years, approximately 8 years, approximately 9 years, or approximately 10 years. The duration of treatment may vary for each individual subject.

[0128] The pharmaceutical compositions described herein can be presented in unit dosage forms suitable for precise single-dose administration. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit doses can be in the form of packages containing discrete amounts of the formulation. Non-limiting examples are packages of injectable, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose, non-reclosable containers. Multi-dose, reclosable containers can be used, for example, with or without preservatives. Formulations for injection can be presented in unit dosage forms, for example, in ampoules or in multi-dose containers with preservatives.

[0129] The pharmaceutical compositions provided herein can be administered in combination with other therapies, such as chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. These other agents may be administered before, after, or concurrently with the pharmaceutical compositions.

[0130] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semi-solid, or liquid dosage form, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in a unit dosage form suitable for a precise dose for a single administration.

[0131] For solid compositions, non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.

[0132] Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of this disclosure include anti-infective agents such as aminoglycosides, antiviral agents, antimicrobial agents, anticholinergic / antispasmodic agents, antidiabetic agents, antihypertensive agents, antitumor agents, cardiovascular agents, central nervous system agents, coagulation modulators, hormones, immunomodulators, immunosuppressants, and ophthalmic products.

[0133] Compounds can be delivered via liposome technology. Using liposomes as drug carriers can increase the therapeutic index of compounds. Liposomes contain natural phospholipids and may contain mixed lipid chains with surfactant properties (e.g., lecithin ethanolamine). Liposomes can be designed with surface ligands to attach to unhealthy tissues. Non-limiting examples of liposomes include multilayered vesicles (MLVs), small unlayered vesicles (SUVs), and large unlayered vesicles (LUVs). The physicochemical properties of liposomes can be tuned to optimize penetration across biological barriers and retention at the application site, and to reduce the likelihood of premature degradation and toxicity to non-target tissues. Optimal liposome properties depend on the route of administration: large-size liposomes show good retention during local injection, while small-size liposomes are better suited for passive targeting. Polyethylene glycolization reduces hepatic and splenic uptake of liposomes and increases circulation time, leading to increased localization at the site of inflammation due to enhanced permeability and retention (EPR) effects. Additionally, the liposome surface can be modified to achieve selective delivery of encapsulated drugs to specific target cells. Non-limiting examples of targeted ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides that are specific to receptors concentrated on the surface of disease-related cells.

[0134] Non-limiting examples of dosage forms suitable for use in this disclosure include liquids, elixirs, nanosuspensions, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically acceptable excipients suitable for use in this disclosure include granulators, binders, lubricants, disintegrants, sweeteners, gliding agents, anti-adhesion agents, antistatic agents, surfactants, antioxidants, gums, coating agents, colorants, flavoring agents, plasticizers, preservatives, suspending agents, emulsifiers, plant cellulose materials, and pelleting agents, and any combination thereof.

[0135] The compositions disclosed herein can be packaged as kits. In some embodiments, the kit includes written instructions for use regarding the administration / use of the composition. The written material may be, for example, a label. The written material may suggest the conditions and methods of administration. The instructions for use provide optimal guidance to subjects and supervising physicians to achieve the best clinical outcomes from the administration of the therapy. The written material may be a label. In some embodiments, the label may be approved by a regulatory agency such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.

[0136] In some cases, the pharmaceutical composition is administered orally.

[0137] The specific dosage and treatment regimen for any given patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, timing of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound described herein in the composition will also depend on the specific compound in the pharmaceutical composition.

[0138] Implementation plan with numbering Implementation Scheme 1. A compound of formula A: (A); Or its pharmaceutically acceptable salt, wherein E is Or a bicyclic heterocyclic system comprising a 5-membered ring fused to a 6-membered ring, wherein the bicyclic heterocyclic system is optionally substituted with one to three groups independently selected from halogens, oxo- and (C1-C4) alkyl groups; R 1 and R 2 Each independently is -OR a or -NR b R c Or R 1 and R 2 With R 1 and R 2 The carbon atoms that are bonded together form 5- to 7-membered heterocyclic groups; R a The group is selected from (C1-C4)alkyl, 4- to 6-membered heterocyclic groups, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH) and -(C1-C4)alkyl [4- to 6-membered heterocyclic groups], wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic groups are each optionally substituted by one or two groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy; R b and R c Each is independently selected from hydrogen and (C1-C4) alkyl groups, or R b and R c With R b and R c The attached nitrogen atoms together form 4- to 6-membered heterocyclic groups; R 3 It is a hydrogen or (C1-C4)alkoxy group; R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl or 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups independently selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano and -NH(C1-C4)alkyl; Ring M is a 6-membered aryl or a 6-membered heteroaryl; R 5 and R 7 Each of these can be independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, hydroxyl, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl]; R 6 It is a halogen, hydroxyl, cyano, (C2-C4) acyl, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, (C3-C6) cycloalkyl, -O(C3-C6) cycloalkyl, or deuterated(C1-C4) alkoxy; R 8 and R 9 Each is either hydrogen or halogen; J is O, NR 11 , S or CH2; R 10 It is a halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl; and R 11 It is hydrogen; or R 10 and R 11 With R 10 and R 11 The atoms that are bonded together form a 5-membered heterocyclic group; Q1 and Q 2 Each of them is independently CH or N; Q 3 It is CR 8 Or N; Q 4 Is it N, CH or R? 9 Attached carbon atoms; X is N, CH, or related to R. 3 Attached carbon atoms; and Y is -NHC(O)- or -C(O)NH-.

[0139] Implementation Scheme 2. The compound according to Implementation Scheme 1, provided that R 4 If it is CH3, then: (a) R 5 Not hydrogen or (b) Q 3 It is CR 8 , where R 8 It is halogen.

[0140] Implementation Scheme 3. The compound according to Implementation Scheme 1 or Implementation Scheme 2, provided that Q 1 N, Q 2 It is CH, Q 3 It is CR 8 And R 4 If it is CH3 or CH2OH, then R 8 It is halogen.

[0141] Implementation Scheme 4. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula AI: (AI); Or its pharmaceutically acceptable salt.

[0142] Implementation Scheme 5. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 4, wherein yes Z 1 Z 2 and Z 3 Each independently is N, CH, or R 5 R 6 and R 7 One of the carbon atoms in the bond.

[0143] Implementation Scheme 6. The compound according to Implementation Scheme 5, wherein the compound has the formula A-II: (A-II); Or its pharmaceutically acceptable salt.

[0144] Implementation Scheme 7. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 5 or Implementation Scheme 6, wherein Z 1 and Z 3 Each independently is CH or R 5 and R 7 One of the carbon atoms in the bond.

[0145] Implementation Scheme 8. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme 5 or Implementation Scheme 6, wherein Z 1 and Z 3 Each is N.

[0146] Implementation Scheme 9. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 5 or Implementation Scheme 6, wherein Z 1 Is it CH or R? 7 The bonded carbon atoms, and Z 3 It is N.

[0147] Implementation Scheme 10. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 5 or Implementation Scheme 6, wherein Z 1 It is N and Z 3 Is it CH or R? 5 The bonded carbon atoms.

[0148] Implementation Scheme 11. The compound according to Implementation Scheme 5, wherein the compound has the formula A-III: (A-III); Or its pharmaceutically acceptable salt.

[0149] Implementation Scheme 12. The compound according to Implementation Scheme 5, wherein the compound has formula A-IV: (A-IV); Or its pharmaceutically acceptable salt.

[0150] Implementation Scheme 13. The compound according to Implementation Scheme 5, wherein the compound has the formula AV: (AV); Or its pharmaceutically acceptable salt.

[0151] Implementation Scheme 14. The compound according to Implementation Scheme 5, wherein the compound has formula A-VI: (A-VI); Or its pharmaceutically acceptable salt.

[0152] Implementation Scheme 15. The compound according to Implementation Scheme 5, wherein the compound has the formula A-VI-1: (A-VI-1); Or its pharmaceutically acceptable salt.

[0153] Implementation Scheme 16. The compound according to Implementation Scheme 5, wherein the compound has the formula A-VI-2: (A-VI-2); Or its pharmaceutically acceptable salt.

[0154] Implementation Scheme 17. The compound according to Implementation Scheme 5, wherein the compound has formulas A-VII: (A-VII); Or its pharmaceutically acceptable salt.

[0155] Implementation Scheme 18. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 5 and 11 to 17, wherein Z 3 It is N.

[0156] Implementation Scheme 19. The compound according to Implementation Scheme 5, wherein the compound has formula A-VIII: (A-VIII); Or its pharmaceutically acceptable salt.

[0157] Implementation Scheme 20. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 5 and 19, wherein Z 2 It is N.

[0158] Implementation Scheme 21. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 10, 19 and 20, wherein Q 1 and Q 2 Each is CH, and Q 3 It is CR 8 .

[0159] Implementation Scheme 22. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 10, 19 and 20, wherein Q 1 and Q 2 Each is CH, and Q 3 It is N.

[0160] Implementation Scheme 23. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 10, 19 and 20, wherein Q 1 It is N, Q2 It is CH and Q 3 It is CR 8 .

[0161] Implementation Scheme 24. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 10, 19 and 20, wherein Q 1 It's CH, Q 2 It is N and Q 3 It is CR 8 .

[0162] Implementation Scheme 25. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula A-IX: (A-IX); Or its pharmaceutically acceptable salt.

[0163] Implementation Scheme 26. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula AX: (AX); Or its pharmaceutically acceptable salt.

[0164] Implementation Scheme 27. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula A-XI: (A-XI); Or its pharmaceutically acceptable salt.

[0165] Implementation Scheme 28. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula A-XII: (A-XII); Or its pharmaceutically acceptable salt.

[0166] Implementation Scheme 29. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula A-XIII-1: (A-XIII-1); Or its pharmaceutically acceptable salt.

[0167] Implementation Scheme 30. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula A-XIII-2: (A-XIII-2); Or its pharmaceutically acceptable salt.

[0168] Implementation Scheme 31. The compound according to any one of Implementation Schemes 1 to 3, wherein the compound has the formula A-XIV: (A-XIV); Or its pharmaceutically acceptable salt.

[0169] Implementation Scheme 32. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 31, wherein J is O.

[0170] Implementation Scheme 33. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 31, wherein J is S.

[0171] Implementation Scheme 34. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 31, wherein J is CH2.

[0172] Implementation Scheme 35. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 31, wherein J is NR 11 .

[0173] Implementation Scheme 36. The compound according to any one of embodiments 1 to 5, wherein the compound has the formula A-XV: (A-XV); Or its pharmaceutically acceptable salt.

[0174] Implementation Scheme 37. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1-35, wherein R 10 It is halogen.

[0175] Implementation Scheme 38. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1-35, wherein R 10 It's fluorine.

[0176] Implementation Scheme 39. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 20, 25 to 31 and 36, wherein Q 1 It is N.

[0177] Implementation Scheme 40. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 20, 25 to 31 and 36, wherein Q 1 It is CH.

[0178] Implementation Scheme 41. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 40, wherein Q 4 It is N.

[0179] Implementation Scheme 42. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 40, wherein Q 4 Is with R 9 The bonded carbon atoms.

[0180] Implementation Scheme 43. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 42, wherein R 9 It is hydrogen.

[0181] Implementation Scheme 44. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 42, wherein R 9 It's fluorine.

[0182] Implementation Scheme 45. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 44, wherein R 5 It is hydrogen, cyano, hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl or halogen.

[0183] Implementation Scheme 46. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 45, wherein R 5 It is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halogen.

[0184] Implementation Scheme 47. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 46, wherein R 5 It is CH3, CF3, cyano, hydroxyl, fluorine, chlorine, or bromine.

[0185] Implementation Scheme 48. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein X is CH.

[0186] Implementation Scheme 49. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein X is N.

[0187] Implementation Scheme 50. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 49, wherein R 3 It is hydrogen.

[0188] Implementation Scheme 51. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 21, 23 to 31, 36, 39 and 40, wherein R 8 It's fluorine.

[0189] Implementation Scheme 52. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 51, wherein each R aThe group is independently selected from (C1-C4)alkyl, oxetyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrrolidinyl], -(C1-C4)alkyl[piperazinyl] and -(C1-C4)alkyl[morpholinyl], wherein the cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl and oxetyl are each optionally substituted by one or two groups selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy.

[0190] Implementation Scheme 53. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 51, wherein R 1 and R 2 Each is independently selected from OCH3, , , , , , , , , , , and .

[0191] Implementation Scheme 54. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 51, wherein E is .

[0192] Implementation Scheme 55. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 51, wherein E is .

[0193] Implementation Scheme 56. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 3, wherein E is pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, each optionally substituted with one to three groups independently selected from halogens and (C1-C4) alkyl groups.

[0194] Implementation Scheme 57. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 3, wherein E is , , , , , or .

[0195] Implementation Scheme 58. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 57, wherein R 4 It is a (C1-C4)alkyl, a halo(C1-C4)alkyl, a hydroxy(C1-C4)alkyl, a halo(C1-C4)alkoxy, a (C3-C6)cycloalkyl, a -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

[0196] Implementation Scheme 59. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 57, wherein R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl] or oxetane, wherein the (C3-C6)cycloalkyl is optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl and halo(C1-C4)alkyl.

[0197] Implementation Scheme 60. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 57, wherein R 4 yes , CF3, CH3 OCHF2 CH2CF3 , , , , , , or .

[0198] Implementation Scheme 61. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 57, wherein R 4 It is a (C2-C4)alkyl, a halo(C1-C4)alkyl, a hydroxy(C2-C4)alkyl, a halo(C1-C4)alkoxy, a (C3-C6)cycloalkyl, a -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

[0199] Implementation Scheme 62. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 57, wherein R 4 It is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl] or oxetane, wherein the cyclopropyl is optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl and halo(C1-C4)alkyl.

[0200] Implementation Scheme 63. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 57, wherein R 4 yes , CF3 OCHF2 CH2CF3 , , , , , , or .

[0201] Implementation Scheme 64. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 63, wherein R 7 It is hydrogen, halogen, -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl] or cyano.

[0202] Implementation Scheme 65. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 63, wherein R 7 It is hydrogen, fluorine, bromine, chlorine, Or cyano.

[0203] Implementation Scheme 66. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 63, wherein R 7 It is hydrogen, cyano, hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl or halogen.

[0204] Implementation Scheme 67. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 63, wherein R 7 It is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halogen.

[0205] Implementation Scheme 68. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 63, wherein R 7 It is CH3, CF3, cyano, hydroxyl, fluorine, chlorine, or bromine.

[0206] Implementation Scheme 69. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 68, wherein R 6 It can be halogen, hydroxyl, cyano, (C2-C4) acyl, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, -O(C3-C6) cycloalkyl or deuterated(C1-C4) alkoxy.

[0207] Implementation Scheme 70. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 68, wherein R 6 It contains cyano, CHF2, hydroxyl, acetyl, OCH3, OEt, fluorine, OCHF2, OCF3, Or OCD3.

[0208] Implementation Scheme 71. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 68, wherein R 6 It's fluorine.

[0209] Implementation Scheme 72. The compound according to Implementation Scheme 1, wherein the compound has Formula I: (I); Or its pharmaceutically acceptable salt, wherein R 1 and R 2 Each independently is -OR a or -NR b R c ; R 5 and R 7 Each of these can be independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl]; R 6 It is a halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl or deuterated(C1-C4)alkoxy; R 8 and R 9 Each is either hydrogen or fluorine; The condition is if R 4 If it is CH3, then R 5 It's not hydrogen.

[0210] Implementation Scheme 73. The compound according to Implementation Scheme 72, wherein the compound has Formula II: (II); Or its pharmaceutically acceptable salt.

[0211] Implementation Scheme 74. The compound according to Implementation Scheme 72 or Implementation Scheme 73, wherein the compound has Formula III: (III); Or its pharmaceutically acceptable salt.

[0212] Implementation Scheme 75. The compound according to any one of Implementation Schemes 72 to 74, wherein the compound has Formula IV: (IV); Or its pharmaceutically acceptable salt.

[0213] Implementation Scheme 76. The compound according to any one of Implementation Schemes 72 to 75, wherein the compound has Formula V: (V); Or its pharmaceutically acceptable salt.

[0214] Implementation Scheme 77. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 76, wherein R 10 It is halogen.

[0215] Implementation Scheme 78. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 77, wherein R 10 It's fluorine.

[0216] Implementation Scheme 79. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 78, wherein R 5 It is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl or halogen.

[0217] Implementation Scheme 80. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 79, wherein R 5 It is (C1-C4)alkyl, halo(C1-C4)alkyl, or halogen.

[0218] Implementation Scheme 81. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 80, wherein R 5 It is CH3, CF3, or chlorine.

[0219] Implementation Scheme 82. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 81, wherein X is CH.

[0220] Implementation Scheme 83. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 82, wherein R 3 It is hydrogen.

[0221] Implementation Scheme 84. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 83, wherein R 9 It is hydrogen.

[0222] Implementation Scheme 85. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 84, wherein R 8 It's fluorine.

[0223] Implementation Scheme 86. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 85, wherein each R a The group is independently selected from (C1-C4)alkyl, oxetyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrrolidinyl], -(C1-C4)alkyl[piperazinyl] and -(C1-C4)alkyl[morpholinyl], wherein the cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl and oxetyl are each optionally substituted by one or two groups selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy.

[0224] Implementation Scheme 87. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 86, wherein R 1 and R 2 Each is independently selected from OCH3, , , , , , , , , , , and .

[0225] Implementation Scheme 88. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 87, wherein R 4It is a (C1-C4)alkyl, a halo(C1-C4)alkyl, a hydroxy(C1-C4)alkyl, a halo(C1-C4)alkoxy, a (C3-C6)cycloalkyl, a -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

[0226] Implementation Scheme 89. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 88, wherein R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl] or oxetane, wherein the cyclopropyl is optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl and halo(C1-C4)alkyl.

[0227] Implementation Scheme 90. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 89, wherein R 4 yes , CF3, CH3 OCHF2 CH2CF3 , , , , , , or .

[0228] Implementation Scheme 91. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 90, wherein R 7 It is hydrogen, halogen, -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl] or cyano.

[0229] Implementation Scheme 92. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 91, wherein R 7 It is hydrogen, fluorine, bromine, chlorine, Or cyano.

[0230] Implementation Scheme 93. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 92, wherein R 6 It is OCH3, fluorine, OCHF2, OCF3, 、OCD3.

[0231] Implementation Scheme 94. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 72 to 93, wherein R 6 It's fluorine.

[0232] Implementation Scheme 95. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound is selected from any of the compounds in Table 1.

[0233] Implementation Scheme 96. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound is selected from any of the compounds in Table 2.

[0234] Implementation Scheme 97. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 94, wherein the compound is a single transisomer.

[0235] Implementation Scheme 98. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 97, wherein the single transisomer has a negative specific rotation.

[0236] Implementation Scheme 99. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 97, wherein the single transisomer has a positive specific rotation.

[0237] Implementation Scheme 100. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of Implementation Schemes 1 to 99.

[0238] Implementation Scheme 101. A pharmaceutical composition comprising a group of molecules having the structure of a compound according to any one of Implementation Schemes 1 to 96, wherein at least about 97% of the molecules in the group have the same transisomer configuration.

[0239] Implementation Scheme 102. The pharmaceutical composition according to Implementation Scheme 101 further comprises a pharmaceutically acceptable carrier.

[0240] Implementation Scheme 103. A method of treating a condition, comprising administering to a subject in need a therapeutically effective amount of any one of Implementation Schemes 1 to 99, or a pharmaceutically acceptable salt thereof; or any one of Implementation Schemes 100 to 102, a pharmaceutical composition.

[0241] Implementation Scheme 104. The method according to Implementation Scheme 103, wherein the condition is responsive to the adjustment of PLK4.

[0242] Implementation Scheme 105. The method according to Implementation Scheme 103, wherein the condition is cancer.

[0243] Example The described compounds can be prepared according to the following examples. As used below and throughout this specification, unless otherwise indicated, the following abbreviations should be understood to have the following meanings: ACN or MeCN: Acetonitrile ℃: degrees Celsius d: Chemical shift from the low field of tetramethylsilane-dichloromethane (CH2Cl2), in parts per million. DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide Et2O: Diethyl ether EtOAc: Ethyl acetate ES + Electrospray ionization Et: Ethyl g: grams HATU: Hexafluorophosphate aziridinetriazole tetramethylurea Hex: Hexane h: hours HOBt: Hydroxybenzotriazole HPLC: High Performance Liquid Chromatography Hz: Hertz J Coupling constant (in NMR spectroscopy) LCMS: Liquid Chromatography-Mass Spectrometry m: micro m: multiple peaks (spectral); meter; millimeter M: Molar concentration M + : Parent molecular ion Me: Methyl MeOH: Methanol MHz: Megahertz min: minutes mol: mole; molecules (in mol wt) mL: milliliters NIS: N -Iodosuccinimide NMI: N-methylimidazole MS: Mass spectrometry nm: nanometer NMR: Nuclear Magnetic Resonance pH: Hydrogen potential; a measure of the acidity or alkalinity of an aqueous solution. PE: Petroleum ether rt: room temperature s: Single peak (spectral) T3P: Propanephosphonic anhydride t: triplet (spectral) T: Temperature TCHF: Tetramethylchloromethanemid hexafluorophosphate TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran EDC.HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide SOR: Specific rotation ee: Enantiomer excess TLC: Thin-layer chromatography ES: Electrospray Analytical techniques LCMS Method A Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid: ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 μL Column: Waters X-Select CSH (3.0 × 50) mm, 2.5 µm.

[0244] Method B Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 μL Column: Waters X-Bridge CSH (3.0 × 50 mm) 2.5 µm.

[0245] Method C Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.05% formic acid Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 μL Column: Waters XSelect-C18 (3.0 × 50) mm, 2.5 µm.

[0246] Method D Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: H₂O containing 2.5 mM ammonium bicarbonate + 5% ACN Solvent B: Acetonitrile Injection volume: 2.0 µL Column: X Select CSH C18 (3.0) 50) mm 2.5 µm.

[0247] Method E Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: H₂O containing 2.5 mM ammonium bicarbonate + 5% ACN Solvent B: Acetonitrile Injection volume: 2.0 µL Column: X-Bridge BEH C18 (3.0 × 50) mm 2.5 µm.

[0248] Method F Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm.

[0249] Method G Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm.

[0250] Method H Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm.

[0251] Method I Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: X-Bridge CSH C18 (3.0 × 50) mm 2.5 µm.

[0252] Method J Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: X-Select CSH (3.0 × 50) mm 2.5 µm.

[0253] Method K Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: 2.5 mM ammonium bicarbonate + 50 mL ACN Solvent B: Acetonitrile Injection volume: 2.0 µL Column: X-Bridge BEH C18 (3.0 × 50) mm 2.5 µm.

[0254] Method L Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: H2O containing 0.1% TFA Solvent B: ACN containing 0.1% TFA Injection volume: 2.0 µL Column: Merck Milipore Chromolith SpeedROD C18 (50 × 4.6 mm).

[0255] Method M Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: H2O containing 0.1% TFA Solvent B: ACN containing 0.1% TFA Injection volume: 2.0 µL Column: Water Cortex C18 (3 × 50 mm) 2.7 µm.

[0256] Method N Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.05% formic acid Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm.

[0257] Method P Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: 0.05 mM ammonium bicarbonate Solvent B: Acetonitrile containing 100% FA Injection volume: 2.0 µL Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm.

[0258] Method Q Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 μL Column: Waters X-Select CSH (3.0 × 50) mm, 2.5 µm.

[0259] Method R Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 50 °C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water (95%) containing 0.05% formic acid; ACN (5%) Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 μL Column: Waters X-Select CSH C18 (3.0 × 50) mm, 2.5 µm.

[0260] Method S Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: H2O containing 0.1% TFA Solvent B: Acetonitrile Injection volume: 2.0 µL Column: X-Select CSH C18 (3 × 50) mm, 2.5 µm.

[0261] Method T Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 45°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.05% TFA Solvent B: Acetonitrile containing 0.05% TFA Injection volume: 2.0 µL Column: CORTECS UPLC C18 (3 × 30) mm, 1.6 μm.

[0262] Method U Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.05% formic acid Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: XTERA MS C18 (50 mm × 2.1 mm, 3.5 μm).

[0263] Method V Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 2.5 mM ammonium bicarbonate Solvent B: Acetonitrile Injection volume: 2.0 µL Column: XSelect CSH-C18 (3.0 × 50 mm, 2.5 μm).

[0264] Method W Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.05% formic acid Solvent B: Acetonitrile containing 0.05% formic acid Injection volume: 2.0 µL Column: XSelect CSH-C18 (3.0 × 50 mm, 2.5 μm).

[0265] Method AC Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 40°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 2.5 mM NH4HCO3 + 5% acetonitrile Solvent B: Acetonitrile Injection volume: 2.0 µL Column: XSelect CSH-C18 (3.0×50 mm, 2.5 µm).

[0266] Method AD Liquid chromatography-mass spectrometry (LCMS) was performed on a Shimadzu LCMS system with the following parameters: column temperature: 45°C. The system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler coupled to the Shimadzu LCMS (SQD) mass spectrometer, using LabSolutions, v.3.70.390 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.05% TFA Solvent B: Acetonitrile containing 0.05% TFA Injection volume: 2.0 µL Column: CORTECS UPLC C18 (3.0 × 30 mm, 1.6 μm).

[0267] Analytical HPLC Method A HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% TFA Solvent B: Acetonitrile containing 0.1% TFA Injection volume: 5.0 μL Column: Waters X-Select CSH C18 (4.6 150) mm 5 µm.

[0268] Method B HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% formic acid : Acetonitrile (95:05) Solvent B: Acetonitrile Injection volume - 5.0 μL Column: Waters X-Select CSH C18 (4.6 150) mm 5 µm.

[0269] Method C HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 5 mM ammonium bicarbonate Solvent B: Acetonitrile Injection volume: 5.0 μL Column: Waters X-Bridge CSH C18 (4.6) 150) mm 5 µm.

[0270] Method D HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% TFA Solvent B: Acetonitrile Injection volume - 5.0 μL Column: Waters X-Select CSH C18 (4.6 150) mm 5 µm.

[0271] Method E HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Mobile phase A: 0.05% TFA; ACN (95; 05) Mobile phase B: 0.05% TFA; ACN (0.5; 9.5) Injection volume: 5.0 μL Column: Waters X SELECT CSH C18 (150 × 4.6 mm, 3.5 µm).

[0272] Method F HPLC analysis was performed on an AMC-UPLC-04 HPLC system with the following parameters: column temperature: 30°C. This AMC-UPLC-04 HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Mobile phase A: (water:ACN) (95:5) containing 0.1% FA. Mobile phase B: Acetonitrile Injection volume: 5.0 μL Column: X-Select CSH C18, (50 mm) 3.0 mm, 2.5 µm).

[0273] Method G HPLC analysis was performed on an AMC-UPLC-04 HPLC system with the following parameters: column temperature: 50°C. This AMC-UPLC-04 HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Mobile phase A: Water containing 0.05% formic acid:acetonitrile (95:5) Mobile phase B: Acetonitrile containing 0.05% formic acid Injection volume - 5.0 μL Column: X-Select CSH C18, (50 mm) 3.0 mm, 2.5 µm).

[0274] Gradient program (B%): 0.0 / 2, 6.0 / 98, 8.0 / 98, 9.0 / 2, 10.0 / 2.

[0275] Method H HPLC analysis was performed on an AMC-UPLC-04 HPLC system with the following parameters: column temperature: 30°C. This AMC-UPLC-04 HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Mobile phase A: Water containing 0.1% FA Mobile phase B: Acetonitrile Injection volume: 5.0 μL Column: X-select CSH C18 (4.6) 150 mm × 5 µm).

[0276] Preparative HPLC Method A HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% TFA Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-SELECT (250) 30 mm), 5.0 µm.

[0277] Method B HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solubility: ACN: H2O: DMSO: TFA Solvent A: Water containing 0.1% TFA Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-select: C-18 (30 × 250 mm), 5 nm.

[0278] Method C HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 5 mM ammonium bicarbonate Solvent B: Acetonitrile Injection volume: 5.0 µL Column: X-SELECT (250) 30 mm), 5.0 µm.

[0279] Method D HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 5 mM ammonium bicarbonate Solvent B: Acetonitrile Injection volume: 5.0 µL Column: X-Bridge C18 (4.6) 150) mm 5 μm.

[0280] Method E HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC system with the following parameters: column temperature: 35°C. This Shimadzu HPLC 2010CHT HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% formic acid Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-SELECT (250) 30 mm), 5.0 µm.

[0281] Method F HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 10 mM ammonium bicarbonate Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-SELECT CSH (250 30 mm), 5.0 µm.

[0282] Method G HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: (ACN:water) (50:950) containing 0.1% FA Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-SELECT CSH (250 30 mm), 5.0 µm.

[0283] Method H HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.01% FA Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-SELECT CSH (250 30 mm), 5.0 µm.

[0284] Method I HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% formic acid; Water containing 0.01% FA Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-select (250) 30 mm, 5 μm).

[0285] Method J HPLC analysis was performed on a Shimatzu Autoprep HPLC system with the following parameters: column temperature: 35°C. This Shimatzu Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% formic acid Solvent B: Acetonitrile Injection volume: 5.0 μL Column: YMS Trait C18 (250) 30 mm) 5 μm.

[0286] Method K HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% ammonium carbonate Solvent B: Acetonitrile Injection volume: 5.0 μL Column: YMC trait C18 (250) 30 mm) 5 μm.

[0287] Method L HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% ammonium bicarbonate Solvent B: Acetonitrile Injection volume: 5.0 μL Column: YMC trait C18 (250) 30 mm) 5 μm.

[0288] Method N: Preparation-purification method: Instrument: Gilson autoprep HPLC, Column: X-select 30 mm, Mobile phase: A: water containing 10 mM formic acid, B: acetonitrile, Flow rate: 25 mL / min, Gradient time / % of B: 0.01 / 1, 3 / 10, 10 / 20, 20 / 35, 30 / 55, 40 / 70, 45 / 85, 45.1 / 98, 49 / 98, RT-35 min.

[0289] Method M HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% ammonium bicarbonate Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-SELECT CSH (250 30 mm), 5.0 µm.

[0290] Method N HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 10 mM formic acid Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-SELECT CSH (250 30 mm), 5.0 µm.

[0291] Method O HPLC analysis was performed on a TELEDYNE-02 HPLC system with the following parameters: column temperature: 35°C. This TELEDYNE-02 HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: 2.5 mM ammonium bicarbonate + 5% ACN Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-Select CSH C18 (3.0 × 50) mm, 2.5 µm.

[0292] Method P HPLC analysis was performed on a Gilson Autoprep HPLC system with the following parameters: column temperature: 35°C. This Gilson Autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: H₂O containing 10 mM formic acid Solvent B: 100% acetonitrile Injection volume: 5.0 μL Column: X BRIDGE C18 (30 × 250) mm, 5 µm.

[0293] Method Q HPLC analysis was performed on a Shimatzu autoprep HPLC system with the following parameters: column temperature: 35°C. This Shimatzu autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.1% formic acid : Acetonitrile (95:05) Solvent B: Acetonitrile Injection volume: 5.0 μL Column: X-Select CSH C18 (4.6 × 150) mm 5 μm.

[0294] Method R HPLC analysis was performed on a TELEDYNE autoprep HPLC system with the following parameters: column temperature: 35°C. This TELEDYNE autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LC Solutions, v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 10 mM ABC Solvent B: Acetonitrile Injection volume: 5.0 μL Column: GOLD C-18 50 g.

[0295] Method S HPLC analysis was performed on a TFA CORTECS 2.5 Min autoprep HPLC system with the following parameters: column temperature: 45 °C. This TFA CORTECS 2.5 Min autoprep HPLC system consisted of an LC 20 AD prominence pump, a DGU-20 A3 prominence degasser, an SPD-M20A prominence DAD detector, and a SIL-HTC autosampler, using LCSolutions v.1.25 software. The gradient elution method, mobile phase eluent, PDA detection, and column are described below. Solvent A: Water containing 0.05% TFA Solvent B: Acetonitrile containing 0.05% TFA Injection volume: 5.0 μL Column: CORTECS UPLC C18 (3 × 30) mm, 1.6 μm.

[0296] General procedures for preparing compounds: Method A TEA (3.00 equivalents) and T3P (1.50 equivalents) were added to fraction B (1.20 equivalents) in a stirred solution of DMF (0.50 mL), followed by fraction A (1.00 equivalents). The reaction was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice water (5 mL), and precipitation was observed. The obtained precipitate was filtered, washed with water (3 × 10 mL), and dried to obtain the crude product. The crude product was purified by preparative HPLC. The pure fraction was evaporated under reduced pressure to provide the title compound.

[0297] Method B Under an inert (N2 / Ar) atmosphere, DIPEA (3-5 equivalents) and HATU (1.3-1.5 equivalents) were added to a stirred solution of fraction B (1-1.5 equivalents) in DMF (2.0-5.0 mL) at room temperature, followed by fraction A (1-1.5 equivalents). The reaction mixture was stirred for 16 h. The reaction progress was monitored by TLC. After the starting materials were consumed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC. The pure fraction was evaporated under reduced pressure to provide the title compound.

[0298] Method C NMI (5.00 equivalents) and TCFH (2.00 equivalents) were added to a stirred solution of fraction B (1.20 equivalents) in MeCN (0.50 mL), followed by fraction A (1.00 equivalents). The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, as monitored by TLC, the mixture was poured into an ice-water mixture (5 mL), resulting in precipitation. The obtained precipitate was filtered, washed with water (3 × 10 mL), and dried to obtain a crude product. The crude product was purified by preparative HPLC. The pure fraction was evaporated under reduced pressure to provide the title compound.

[0299] Method D TEA (3.00 equivalents), HOBt (1.50 equivalents), and EDC·HCl (1.50 equivalents) were added to a stirred solution of fraction B (1.20 equivalents) in pyridine (5 mL) at room temperature, followed by the addition of fraction A (1.00 equivalents) under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 16 h. The crude compound was purified, and the pure fraction was evaporated under reduced pressure to provide the title compound.

[0300] Method E Add portion B (1.20 equivalent) and zinc trifluoromethanesulfonate (1.00 equivalent) to a stirred solution of portion A (1.00 equivalent) in ethanol (2 mL). Then stir the reaction at 90 °C for 16 h.

[0301] Method F Oxaloyl chloride (3.00 equivalents) was added to a stirred solution of fraction B (1.00 to 1.02 equivalents) in DCM (2 mL) at room temperature, followed by a catalytic amount of DMF (0.300 equivalents). The reaction mixture was stirred for 1 h. The reaction mixture was evaporated under a nitrogen atmosphere to remove excess oxaloyl chloride to obtain acyl chloride. The acyl chloride was dissolved in DCM (1 mL) and added to a stirred solution of fraction A (1.00 to 1.2 equivalents) and TEA (5.00 equivalents) in DCM (3 mL) at room temperature. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with DCM (20 mL) and washed with a saturated sodium bicarbonate solution (3 × 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure.

[0302] Example: Partial synthesis of intermediate A: Synthesis of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluoroaniline [intermediate 1]: At rt, cesium carbonate (65.55 g, 201 mmol, 3.00 equivalent) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (15.00 g, 67.1 mmol, 1.00 equivalent) and 4-amino-2-fluorophenol (12.79 g, 101 mmol, 1.50 equivalent) in DMF (200 mL, 0.3353 M). The reaction mixture was heated to 110 °C and stirred for 16 h. The reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with cold water (2 × 300 mL), brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by Combi flash column chromatography with hexane containing 90% EtOAc to give 8.50 g of intermediate 1 as a light brown solid in 36.21% yield. 1 H NMR (400 MHz, DMSO-d6): δ 8.45(d, J= 5.3 Hz, 1H), 7.50 (s, 1H), 7.44 - 7.32 (m, 1H), 7.07 (t, J = 9.1 Hz, 1H), 6.55 (dd, J = 2.5, 13.3 Hz, 1H), 6.50 - 6.43 (m, 1H), 6.43 - 6.35 (m,1H), 5.50 (s, 2H), 3.94 (s, 6H); MS(ES) + m / z, [M+H] + [C 17 H 15 FN2O3+H] + Calculated value: 315.32, Measured value: 315.0 t R = 1.22 min, [method N].

[0303] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]aniline [intermediate 2]: Synthesis of 4-chloro-6,7-dimethoxy-quinoline-3-carboxylic acid[4]: At rest, a solution of NaOH (1.62 g, 40.6 mmol, 3.00 equivalent) in water (16 mL, 0.2818 M) was added dropwise to a stirred solution of ethyl 4-chloro-6,7-dimethoxy-quinoline-3-carboxylate (4.00 g, 13.5 mmol, 1.00 equivalent) in ethanol (32 mL, 0.2818 M). The reaction mixture was stirred at rest for 4 h. The reaction mixture was concentrated under reduced pressure to remove ethanol, and the resulting aqueous layer was washed with dichloromethane (2 × 200 mL) and separated. The aqueous layer was acidified to pH 3–6 with 1 NHCl (100 mL) to give a white precipitate, which was filtered and washed with water (2 × 200 mL), and dried under reduced pressure to provide 4-chloro-6,7-dimethoxy-quinoline-3-carboxylic acid (3.2 g, 88% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 13.66 (br s, 1H), 8.94 (s, 1H), 7.49 (d, J =18.1 Hz, 2H), 3.97 (s, 6H); MS(ES) +m / z, [M+H] + [C 12 H 10 ClNO4+H] + Calculated value: 268.04, Measured value: 267.90 t R = 1.040 min, [Method G].

[0304] N Synthesis of tert-butyl 4-(4-chloro-6,7-dimethoxy-3-quinolinyl)carbamate[5]: A stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carboxylic acid (7.30 g, 27.3 mmol, 1.00 equivalent) in DMF (150 mL, 0.1818 M) was cooled to 0 °C, and triethylamine (15 mL, 81.8 mmol, 3.00 equivalent) and diphenylphosphoazide (12 mL, 54.5 mmol, 2.00 equivalent) were added. The reaction mixture was slowly heated to rt and stirred for 1 h. Then, tert-butanol (52 mL, 545 mmol, 20.0 equivalent) was added dropwise to the reaction mixture under a nitrogen atmosphere and the mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to rt, water was added, and the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product as a brown solid. The crude product was purified by Combi flash using an 80 g column and eluted with heptane containing 20%–50% ethyl acetate to provide 1.2 g of N-(4-chloro-6,7-dimethoxy-3-quinolinyl)carbamate as a grayish-white solid in 12% yield. 1 H NMR (400 MHz, DMSO- d 6): δ 9.13 (br s, 1H), 8.71 (s, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 3.96 (d, J = 7.9 Hz, 6H), 1.48 (s, 9H); MS(ES + ) m / z, [M+H] + [C 16 H 19 ClN2O4+H] + Calculated value: 339.06, Measured value: 339.00 t R = 1.730min, [Method A].

[0305] Synthesis of 4-chloro-6,7-dimethoxy-quinoline-3-amine[6]: Will N A stirred solution of tert-butyl 4-chloro-6,7-dimethoxy-3-quinolinyl)carbamate (1.20 g, 3.54 mmol, 1.00 equivalent) in DCM (10 mL, 0.3542 M) was cooled to 0 °C, and trifluoroacetic acid (20 mL, 10.6 mmol, 3.00 equivalent) was added. The reaction mixture was allowed to be slowly heated to rt and stirred for 2 h. The reaction mixture was evaporated under reduced pressure to give a crude product. The crude product was ground with ether (50 mL), and the resulting solid was filtered and dried under vacuum to provide 4-chloro-6,7-dimethoxy-quinolin-3-amine (660 mg, 67% yield) as an off-white solid. MS (ES) + m / z, [M+H] + [C 11 H 11 ClN2O2+H] + Calculated value: 239.06, Measured value: 238.80 t R = 0.960 min, [Method A].

[0306] Synthesis of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline[7]: A stirred solution of 4-chloro-6,7-dimethoxy-quinoline-3-amine (2.40 g, 10.1 mmol, 1.00 equivalent) in THF (50 mL, 0.1915 M) was cooled to 0 °C and HBF4 (5.5 mL, 40.2 mmol, 4.00 equivalent) was added (Note: the reaction was carried out in a plastic reaction vessel). The reaction mixture was stirred for 5 min and NaNO2 (1.04 g, 15.1 mmol, 1.50 equivalent) in water (2.5 mL, 0.1915 M) was added, and stirring was continued for 30 min. The resulting yellow solid was filtered, washed with THF (2 × 5 mL), and dried under reduced pressure to give a yellow solid (1.2 g). The solid was carefully heated to 160 °C until gas was observed to be released, and then heated at 160 °C until no further gas release was observed. The obtained black crude product was purified by elution with heptane containing 20%-30% EtOAc via a combi flash to provide 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (600 mg, 23% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J = 0.8 Hz, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H); MS (ES + ) m / z, [M+H] + [C 11 H9ClFNO2+H] + Calculated value: 242.04, Measured value: 241.80 t R = 1.730 min, [Method A].

[0307] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]aniline [intermediate 2]: At rest, potassium tert-butoxide (1.07 g, 9.56 mmol, 3.00 equivalent) was added to a stirred solution of 4-amino-2-fluorophenol (810 mg, 6.37 mmol, 2.00 equivalent) in DMF (20 mL, 0.1593 M) and stirred for 20 min. Then, 4-chloro-3-fluoro-6,7-dimethoxyquinoline (770 mg, 3.19 mmol, 1.00 equivalent) was added to the reaction mixture, and the reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to rest, filtered through a diatomaceous earth pad, and washed with ethyl acetate (100 mL). The filtrate was then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by combi flash using a 24 g column and eluted with heptane containing 40%–50% ethyl acetate, and concentrated under reduced pressure. The obtained material was ground with diethyl ether (10 mL) to provide 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]aniline (110 mg, 10% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6): δ 8.66 (d, J = 3.5 Hz, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 6.87(t, J = 9.2 Hz, 1H), 6.48 (d, J = 13.6 Hz, 1H), 6.30 (d, J= 8.8 Hz, 1H), 5.28 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H); MS(es + ) m / z, [M+H] + [C 17 H 14 F2N2O3+H] + Calculated value: 333.11, Measured value: 332.90 t R = 1.50 min and 1.61 min, [Method A].

[0308] Synthesis of 3,5-difluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]aniline [intermediate 3]: Synthesis of 2-fluoromalonic acid [9]: LiOH·H₂O (72.24 g, 1684 mmol, 3.00 equivalent) was added to a stirred solution of diethyl 2-fluoromalonate (100.00 g, 561 mmol, 1.00 equivalent) in methanol and water (1000 mL) and stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was acidified with 1 N HCl aqueous solution (200 mL), and the resulting precipitate was filtered, washed with water (100 mL), and dried under reduced pressure to provide 60 g of the title compound as a white solid in 82% yield; MS (ES). + m / z, [MH] + [C3H3FO4-H] + Calculated value: 123.05, Measured value: 121.1 t R = 1.02 min. [Method N].

[0309] Synthesis of 2,4-dichloro-3-fluoro-6,7-dimethoxy-quinoline

[11] : A stirred solution of 2-fluoromalonic acid (100.00 g, 819 mmol, 1.00 equivalent) in POCl3 (1200 mL, 819 mmol, 1.00 equivalent) was heated at 120 °C for 30 min. The reaction mixture was then cooled to 60 °C, and 3,4-dimethoxyaniline (125.51 g, 819 mmol, 1.00 equivalent) was added in portions, followed by heating to 120 °C for 72 h. Excess POCl3 was removed from the reaction mixture by downward distillation to remove approximately 1 L of POCl3. The reaction mixture was poured into ice-cold water (2 L), stirred at room temperature for 20 min, and the resulting precipitate was filtered, washed with water (2 × 200 mL), and dried under vacuum to give the crude product. The crude product was purified by column chromatography using 60-120 silica gel and eluting with n-heptane containing 10%-20% ethyl acetate to provide 13.00 g, 6% yield, as a pale yellow solid; MS (ES). + m / z, [M+H] + [C 11 H8Cl2FNO2+H] + Calculated value: 277.09, Measured value: 275.8 t R = 2.14 min, [method N].

[0310] Synthesis of 4-chloro-3-fluoro-6,7-dimethoxy-1H-quinoline-2-one

[12] : A stirred solution of 2,4-dichloro-3-fluoro-6,7-dimethoxyquinoline (27.00 g, 97.8 mmol, 1.00 equivalent) in acetic acid (420 mL, 0.2328 M) was heated to reflux at 130 °C for 48 h. The reaction mixture was allowed to cool to rt, and water was added, thereby precipitating the solid. The precipitate was filtered, and the resulting solid was washed with acetone (50 mL) and diethyl ether (50 mL), and co-distilled with toluene, dried under reduced pressure to provide 22 g, 84% yield, as an off-white solid in 12; MS (ES). + m / z, [M+H] + [C 11 H9ClFNO3+H] + Calculated value: 258.65, Measured value: 257.9 t R = 1.58min, [method N].

[0311] Synthesis of (4-chloro-3-fluoro-6,7-dimethoxy-2-quinolinyl)trifluoromethanesulfonate

[13] : A stirred solution of 4-chloro-3-fluoro-6,7-dimethoxy-1H-quinolin-2-one (22.00 g, 85.4 mmol, 1.00 equivalent) in DCM (400 mL, 0.2135 M) was cooled to 0 °C, and TEA (18 mL, 128 mmol, 1.50 equivalent) and trifluoromethanesulfonic anhydride (17 mL, 102 mmol, 1.20 equivalent) were added. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (300 mL) and washed with water (100 mL), and the combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography using 100 g–200 g silica gel and eluting with 100% DCM to provide 24.00 g of a 68% yield as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 7.42 (s, 1H), 7.34 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H); MS(ES) + m / z, [M+H] + [C 12 H8ClF4NO5S+H] + Calculated value: 390.7, Measured value: 389.80 t R = 2.23 min, [method N].

[0312] Synthesis of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline[7]: A stirred solution of (4-chloro-3-fluoro-6,7-dimethoxy-2-quinolinyl)trifluoromethanesulfonate (24.00 g, 61.6 mmol, 1.00 equivalent) in THF (200 mL, 0.3079 M) was degassed with nitrogen for 10 min, and Pd tetrakis (1.17 g, 1.02 mmol, 0.0165 equivalent) was added under nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 10 min, and pyridine (50 mL, 616 mmol, 10.0 equivalent) and triethylsilane (98 mL, 616 mmol, 10.0 equivalent) were added. The reaction was stirred at rt for 5 h, and then concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (400 mL) and washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (2 × 200 mL), and the combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by passing it through a 120 g column using a combi flash and eluting with 20%–30% ethyl acetate / heptane to give the product. The product was further ground with MeOH (100 mL) and Et₂O (2 × 100 mL). The resulting precipitate was filtered and dried under reduced pressure to provide 9.50 g, 61% yield, as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.81 (s, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H); MS(ES) + m / z, [M+H] + [C 11 H9ClFNO2+H] + Calculated value: 242.04, Measured value: 241.90 t R = 1.850min, [method N].

[0313] Synthesis of 3,5-difluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]aniline [intermediate 3]: At rest, potassium tert-butoxide (8.36 g, 74.5 mmol, 3.00 equivalent) was added to a stirred solution of 4-amino-2,6-difluorophenol (7.21 g, 49.7 mmol, 2.00 equivalent) in DMF (60 mL, 0.4138 M) and stirred for 10 min. Then, 4-chloro-3-fluoro-6,7-dimethoxyquinoline (6.00 g, 24.8 mmol, 1.00 equivalent) was added and the mixture was heated to 120 °C for 6 h. The reaction mixture was cooled to rest and then filtered through a diatomaceous earth pad. The diatomaceous earth was washed with ethyl acetate (500 mL), and the filtrate was washed with brine (200 mL) and cold water (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by passing it through a YMC-80 g column via a Combi flash and eluting with heptane containing 40%–60% ethyl acetate to give the title product. The product was ground with methanol (100 mL) and acetonitrile (3 × 50 mL), and the resulting precipitate was filtered and dried under vacuum to provide 4.30 g, 48% yield, as an off-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.63 (d, J = 4.0 Hz, 1H), 7.46 (s, 1H), 7.40 (s,1H), 6.31 (d, J = 11.0 Hz, 2H), 5.68 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H); MS(ES) + m / z, [M+H] + [C 17 H 13 F3N2O3+H] + Calculated value: 351.3, Measured value: 351.4 t R = 2.003 min, [method H'].

[0314] Synthesis of 1-[[4-(4-amino-2-fluoro-phenoxy)-3-fluoro-6-methoxy-7-quinolinyl]oxy]-2-methyl-prop-2-ol [intermediate 4]: Synthesis of 4-chloro-3-fluoro-6-methoxy-quinoline-7-ol

[16] : At rt, methanesulfonic acid (1.7 mL, 26.9 mmol, 1.90 equivalent) was added to a solution of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline (4.50 g, 14.2 mmol, 1.00 equivalent) in TFA (30 mL, 14.2 mmol, 1.00 equivalent). The reaction mixture was heated to 90 °C for 3 h. The reaction mixture was allowed to cool to rt and evaporated under reduced pressure to give a residue. The residue was dissolved in saturated NaHCO3 solution (50 mL) and adjusted to pH 7–9 and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with aqueous brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was milled with DCM and diethyl ether, and the resulting precipitate was filtered, washed with diethyl ether, to provide 3.10 g, 90% yield, as an off-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.56 (brs, 1H), 7.17 (s, 1H), 7.07 (br s, 1H), 3.93 (s, 3H); MS (ES + ) m / z, [M+H] + [C 10 H7ClFNO2+H] + Calculated value: 228.12, Measured value: 227.90 t R = 1.690 min, [method N].

[0315] Synthesis of 1-[(4-chloro-3-fluoro-6-methoxy-7-quinolinyl)oxy]-2-methyl-prop-2-ol

[18] : At rt, NaOH (1.48 g, 36.9 mmol, 3.00 equivalent) was added to a solution of 4-chloro-3-fluoro-6-methoxy-quinoline-7-ol (2.80 g, 12.3 mmol, 1.00 equivalent) in a 1:1 mixture of THF and water (30 mL), followed by the addition of 1,2-epoxy-2-methylpropane (13 mL, 123 mmol, 10.0 equivalent). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with a saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude compound was purified by Combi flash column chromatography using a 40 g column and eluted with n-heptane containing 30%–80% ethyl acetate to provide 2.10 g, 53%, as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.81 (d, J =0.8 Hz, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 4.68 (br s, 1H), 4.01 (s, 3H), 3.91(s, 2H), 1.26 (s, 6H); MS(ES + ), [M+H] + [C 14 H 15 ClFNO3+H] + Calculated value: 300.08, Measured value: 299.90 t R = 1.810 min, [method N].

[0316] Synthesis of 1-[[4-(4-amino-2-fluoro-phenoxy)-3-fluoro-6-methoxy-7-quinolinyl]oxy]-2-methyl-prop-2-ol [intermediate 4]: At rest, potassium tert-butoxide (898 mg, 8.01 mmol, 3.00 eq) was added to a stirred solution of 4-amino-2-fluorophenol (679 mg, 5.34 mmol, 2.00 eq) in DMF (10 mL, 0.2669 M) and stirred for 10 min. Then, 1-[(4-chloro-3-fluoro-6-methoxy-7-quinolinyl)oxy]-2-methyl-prop-2-ol (800 mg, 2.67 mmol, 1.00 eq) was added. The reaction mixture was heated to 110 °C for 4 h. The reaction mixture was cooled to rest, filtered through a diatomaceous earth pad, and washed with ethyl acetate (100 mL). The filtrate was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by passing it through a YMC-40 g column via a Combi flash and eluting with heptane containing 40%–60% ethyl acetate to obtain the product. The product was further purified by preparative HPLC, and the collected fraction was evaporated under vacuum to provide 300 mg, 28% yield, as a light brown solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.65 (d, J = 3.6 Hz, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 6.86 (t, J = 9.2 Hz, 1H), 6.47 (dd, J = 13.6, 2.8 Hz, 1H), 6.32-6.27 (m, 1H), 5.28 (s,2H), 4.66 (s, 1H), 3.91 (s, 3H), 3.88 (s, 2H), 1.25 (s, 6H); MS(ES + ) m / z, [M+H] + [C 20 H 20 F2N2O4+H] + Calculated value: 391.15, Measured value: 390.90 t R = 3.970 min, [method N].

[0317] Synthesis of 3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-4-quinolinyl]oxy]aniline [intermediate 5]: Synthesis of 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline

[21] : At rt, 2-fluoro-4-nitrophenol (20.96 g, 133 mmol, 2.00 equivalent) was added to a stirred solution of 7-benzyloxy-4-chloro-6-methoxy-quinoline (20.00 g, 66.7 mmol, 1.00 equivalent) in diphenyl ether (350 mL, 2224 mmol, 33.3 equivalent), and the reaction mixture was heated to 140 °C for 24 h. The reaction mixture was diluted with diethyl ether (200 mL), and the resulting precipitate was filtered and washed with heptane (200 mL), dried under vacuum to provide 26.00 g of the title compound as a pale brown solid in 76% yield. MS (ES) + m / z, [M+H] + [C 23 H 17 FN2O+H] + Calculated value: 421.4, Measured value: 421.0 t R = 1.71 min, [method N].

[0318] Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline-7-ol

[22] : 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (15.00 g, 35.7 mmol, 1.00 equivalent) was cooled to 0 °C and a solution of 33% hydrogen bromide in acetic acid (150 mL, 922 mmol, 25.8 equivalent) was added dropwise. After the addition, the reaction mixture was heated to 60 °C for 2 h. The reaction mixture was cooled to 0 °C and diluted with diethyl ether (150 mL) and stirred for 30 min. The resulting precipitate was filtered and washed with diethyl ether (2 × 50 mL), and dried under reduced pressure to provide 7.00 g of the title compound in 55% yield as an off-white solid. MS (ES) + m / z, [M+H] + [C 16 H 11 FN2O5+H] + Calculated value: 331.27, Measured value: 331.0 t R = 1.38 min, [method N].

[0319] Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methoxyethoxy)quinoline

[24] : At rt, 2-bromoethyl methyl ether (2.8 mL, 30.3 mmol, 2.00 equivalent) was added to a stirred solution of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline-7-ol (5.00 g, 15.1 mmol, 1.00 equivalent) in acetonitrile (50 mL, 0.3028 M), followed by the addition of K₂CO₃ (6.27 g, 45.4 mmol, 3.00 equivalent) under a nitrogen atmosphere. After the addition, the reaction mixture was heated to 70 °C for 16 h. The reaction mixture was treated with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with a brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by Combi flash chromatography via an 80 g column eluting with heptane containing 30%–50% ethyl acetate to provide 3.50 g of the title compound as a pale yellow solid in 52% yield. MS (ES) + m / z, [M+H] + [C 19 H 17 FN2O6+H] + Calculated value: 389.35, Measured value: 389.0 t R = 1.50min, [method N].

[0320] Synthesis of 3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-4-quinolinyl]oxy]aniline [intermediate 5]: At rt, NH4Cl (2.41 g, 45.1 mmol, 5.00 equivalent) and Fe (2.52 g, 45.1 mmol, 5.00 equivalent) were added to a stirred solution of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methoxyethoxy)quinoline (3.50 g, 9.01 mmol, 1.00 equivalent) in 5:1 ethanol / water (50 mL). The reaction mixture was heated to 70 °C for 2 h. After cooling, the reaction mixture was filtered through a diatomaceous earth pad and washed with ethanol (70 mL) and DCM containing 10% methanol (3 × 100 mL). The filtrate was concentrated to give a crude product. The crude product was purified by combi flash using a 70 g column and DCM containing 4%–5% MeOH, followed by milling with Et2O (50 mL) to provide 1.70 g, 50% yield, as a pale yellow solid. 1HNMR (400 MHz, DMSO- d 6): δ 8.45 (d, J = 5.4 Hz, 1H), 7.51 (s, 1H), 7.45-7.33(m, 1H), 7.07 (t, J = 9.0 Hz, 1H), 6.59-6.51 (m, 1H), 6.50-6.43 (m, 1H), 6.39(d, J = 4.9 Hz, 1H), 5.47 (s, 2H), 4.34-4.20 (m, 2H), 3.95 (s, 3H), 3.80-3.71(m, 2H), 3.35 (s, 3H); MS(ES + M / Z, [M+H] + [C 19 H 19 FN2O4+H] + Calculated value: 359.37, Measured value: 359.0 t R = 1.31 min, [method N].

[0321] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline-7-ol [V117540] and 3-fluoro-4-[[3-fluoro-6-methoxy-7-(2-methoxyethoxy)-4-quinoline]oxy]aniline [intermediate 6]: Synthesis of 7-benzyloxy-3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline

[25] : In a sealed tube under a nitrogen atmosphere, 2-fluoro-4-nitrophenol (3.46 g, 22.0 mmol, 2.50 equivalent) was added to a solution of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline (4.00 g, 8.81 mmol, 1.00 equivalent) in diphenyl ether (36 mL, 224 mmol, 25.4 equivalent). The reaction mixture was heated to 200 °C for 72 h. The reaction mixture was allowed to cool to rt and DCM (50 mL) was added. The reaction was concentrated under reduced pressure, and the crude mixture was purified by combiflash using a YMC-40 g column and eluted with 25%–30% ethyl acetate / heptane to provide 2.80 g of the title compound as a pale yellow solid in 32% yield. MS (ES) +m / z, [M+H] + [C 23 H 16 F2N2O5+H] + Calculated value: 439.39, Measured value: 438.9 t R = 2.18 min, [method N].

[0322] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline-7-ol hydrogen bromide

[26] : A solid sample of 7-benzyloxy-3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (2.80 g, 3.19 mmol, 1.00 equivalent) was cooled to 0 °C and a 33% solution of hydrogen bromide in acetic acid (30 mL, 184 mmol, 57.7 equivalent) was added dropwise under a nitrogen atmosphere. The reaction mixture was heated to 60 °C for 3 h. The reaction mixture was cooled to 0 °C and diluted with Et₂O (10 mL) and stirred for 30 min. The resulting precipitate was filtered, washed with Et₂O (3 × 5 mL), and dried under reduced pressure to give the title compound, 1.20 g, in 81% yield, as an off-white solid of HBr salt. MS (ES) + m / z, [M+H] + [C 16 H 10 F2N2O5+H] + Calculated value: 349.26, Measured value: 348.8 t R =1.85 min, [method N].

[0323] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methoxyethoxy)quinoline

[27] : At rt, under a nitrogen atmosphere, K₂CO₃ (785 mg, 5.69 mmol, 5.00 equivalent) and KI (94 mg, 0.569 mmol, 0.500 equivalent) were added to a solution of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline-7-ol (600 mg, 1.14 mmol, 1.00 equivalent) in acetonitrile (8 mL, 0.1421 M) and the mixture was stirred for 30 min. Then, 2-bromoethyl methyl ether (1.1 mL, 11.4 mmol, 10.0 equivalent) was added to the reaction mixture and the mixture was stirred at 90 °C for 12 h. The reaction mixture was evaporated under reduced pressure to give a residue, which was treated with water (10 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with a saline solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 230 mg of the title compound as a pale brown solid in 40% yield. MS (ES) + m / z, [M+H] + [C 19 H 16 F2N2O6+H] + Calculated value: 407.34, Measured value: 406.9 t R = 1.96 min, [method N].

[0324] Synthesis of 3-fluoro-4-[[3-fluoro-6-methoxy-7-(2-methoxyethoxy)-4-quinolinyl]oxy]aniline [intermediate 6]: At rt, NH4Cl (151 mg, 2.83 mmol, 5.00 equivalent) was added to a stirred solution of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methoxyethoxy)quinoline (230 mg, 0.566 mmol, 1.00 equivalent) in ethanol (8 mL, 0.0566 M) and water (2 mL, 0.0566 M), followed by the addition of Fe (158 mg, 2.83 mmol, 5.00 equivalent). The reaction mixture was heated to 80 °C for 6 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with ethanol (10 mL) and 20% methanol / DCM (2 × 10 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was diluted with water (5 mL) and 10% methanol and extracted and separated with DCM (50 mL). The organic layer was washed with a brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude compound was ground with Et₂O (3 × 5 mL) to give a precipitate, which was filtered and dried under reduced pressure to provide 150 mg of the title compound in 56% yield as a pale brown solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.66 (d, J = 3.4 Hz,1H), 7.43 (s, 1H), 7.36 (s, 1H), 6.87 (t, J = 9.0 Hz, 1H), 6.48 (dd, J = 2.4,13.7 Hz, 1H), 6.33 - 6.27 (m, 1H), 5.30 (s, 2H), 4.29 - 4.24 (m, 2H), 3.90(s, 3H), 3.77 - 3.72 (m, 2H), 3.34 (s, 3H); MS(ES + ) m / z, [M+H] + [C 19 H 18 F2N2O4+H] + Calculated value: 377.36, Measured value: 376.9 t R = 1.68 min, [method N].

[0325] Synthesis of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline

[15] : Synthesis of 7-benzyloxy-6-methoxy-quinoline-4-ol

[28] : Acetic acid (350 mL, 0.7625 M) was added to a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinoline (80.00 g, 267 mmol, 1.00 equivalent) and heated at 130 °C for 72 h. The reaction mixture was cooled to rt and poured into crushed ice (2000 mL), and basified with solid NaHCO3. The resulting precipitate was filtered, washed with water (1000 mL) and acetone (500 mL), and dried under reduced pressure to provide 60.00 g of the title compound in 73.62% yield as a pale brown solid. 1 H NMR (400 MHz, DMSO- d 6): δ 11.53 (br s, 1H), 7.78 (d, J = 7.5 Hz, 1H),7.58 - 7.34 (m, 6H), 7.08 (s, 1H), 5.95 (d, J = 7.0 Hz, 1H), 5.21 (s, 2H), 3.86 (s, 3H); MS(ES + ) m / z, [M+H] + [C 17 H 15 NO3+H] + Calculated value: 282.11, Measured value: 281.9 t R =1.54 min, [method N].

[0326] Synthesis of 7-benzyloxy-6-methoxy-3-nitro-quinoline-4-ol

[29] : At rt, HNO3 (9.3 mL, 224 mmol, 2.10 equivalent) was added to a solution of 7-benzyloxy-6-methoxy-quinoline-4-ol (30.00 g, 107 mmol, 1.00 equivalent) in propionic acid (400 mL, 107 mmol, 1.00 equivalent), and the reaction mixture was heated to 100 °C for 8 h. The reaction mixture was allowed to cool at rt, and the resulting precipitate was filtered, washed with heptane (200 mL) and 1:5 methanol:MTBE (500 mL), and dried under reduced pressure to provide 27.00 g of the title compound as an off-white solid in 55.09% yield. 1 H NMR (400 MHz, DMSO-d 6): δ 12.76 (s, 1H), 9.06 (s, 1H), 7.62 (s, 1H), 7.52 - 7.47 (m, 2H), 7.45 - 7.41 (m, 3H), 7.24 (s, 1H), 5.24 (s, 2H), 3.89 (s, 3H);MS(ES) + m / z, [M+H] + [C 17 H 14 N2O5+H] + Calculated value: 327.09, Measured value: 326.9 t R = 1.65 min, [method N].

[0327] Synthesis of 7-benzyloxy-4-chloro-6-methoxy-3-nitro-quinoline

[30] : At rt, DMF (1.3 mL, 16.5 mmol, 0.100 equivalent) was added to a solution of 7-benzyloxy-6-methoxy-3-nitro-quinoline-4-ol (54.00 g, 165 mmol, 1.00 equivalent) in SOCl2 (600 mL, 8274 mmol, 50.0 equivalent), and the resulting reaction mixture was heated to 90 °C for 6 h. The reaction mixture was evaporated under reduced pressure to give the title compound as a brown solid, in a crude form, at a yield of 50.00 g (77.12%). MS (ES) + m / z, [M+H] + [C 17 H 13 ClN2O4+H] + Calculated value: 345.06, Measured value: 344.9 t R = 2.25 min, [method N].

[0328] Synthesis of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-amine

[31] : At rt, under a nitrogen atmosphere, Fe powder (14.36 g, 261 mmol, 3.00 equivalent) and NH4Cl (14.04 g, 261 mmol, 3.00 equivalent) were added to a solution of 7-benzyloxy-4-chloro-6-methoxy-3-nitro-quinoline (30.00 g, 87.0 mmol, 1.00 equivalent) in ethanol (700 mL, 0.0989 M) and water (180 mL, 0.0989 M). The resulting reaction mixture was heated to 90 °C for 12 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate (100 mL). The filtrate was evaporated under reduced pressure to give a crude product. The crude product was diluted with water (50 mL) and DCM containing 10% methanol (2 × 500 mL) and separated. The organic layer was washed with a brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was ground with diethyl ether and stirred for 30 min to obtain a solid. The solid was filtered and dried under reduced pressure to provide 25.00 g of the title compound as a brown solid in 76.67% yield. 1 H NMR (400MHz, DMSO- d 6): δ 8.36 (s, 1H), 7.50 - 7.48 (m, 2H), 7.43 - 7.40 (m, 2H), 7.37(s, 2H), 7.18 (s, 1H), 5.21 (s, 2H), 3.94 (s, 3H); MS(ES) + m / z, [M+H] + [C 17 H 15 ClN2O2+H] + Calculated value: 315.08, Measured value: 314.9 t R = 1.71 min, [method N].

[0329] Synthesis of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline

[15] : At rest, HBF4 (18 mL, 143 mmol, 3.00 equivalent) was added to a stirred solution of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-amine (15.00 g, 47.7 mmol, 1.00 equivalent) in THF (150 mL, 0.3177 M) and stirred at rest for 30 min. The reaction mixture was cooled to 0 °C and NaNO2 (4.93 g, 71.5 mmol, 1.50 equivalent) was added to 15 mL of water. The reaction mixture was stirred at 0 °C for another 30 min. The resulting precipitate was filtered and washed with THF (5 mL), and dried under reduced pressure for 5 h to obtain diazonium tetrafluoroborate. The diazonium tetrafluoroborate was dissolved in naphthalene (150 mL) and heated to 150 °C for 30 min. The reaction mixture was dissolved in DCM and purified directly by combiflash column using YMC-80 g and heptane containing 60%–90% DCM to provide 4.00 g of the title compound as a grayish-white solid in 17.17% yield. 1 H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 1.0 Hz, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.45 (s, 1H), 7.41 - 7.36 (m, 4H), 5.30 (s, 2H), 4.07 (s, 3H); MS(ES) + m / z, [M+H] + [C 17 H 13 ClFNO2] + Calculated value: 318.09, Measured value: 317.8 t R =2.15 min, [method N].

[0330] Synthesis of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3,5-difluoroaniline [intermediate A-17]: Synthesis of 4-(2,6-difluoro-4-nitro-phenoxy)-6,7-dimethoxy-quinoline A mixture of 4-bromo-6,7-dimethoxyquinoline (2.00 g, 7.46 mmol, 1.00 equivalent) and 2,6-difluoro-4-nitrophenol (2.61 g, 14.92 mmol, 2.00 equivalent) in chlorobenzene (30 mL) was added in a single step under N2. The mixture was stirred at 140 °C for 12 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent, treated with CH2Cl2 (100 mL), and washed with 10% NaOH aqueous solution (3 × 20 mL) and water (20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The crude product was ground with petroleum ether (100 mL) at 25 °C for 0.5 h, filtered, and the filter cake was dried to provide 4-(2,6-difluoro-4-nitro-phenoxy)-6,7-dimethoxy-quinoline (2.2 g, 81.40% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.53 (d, J=5.25 Hz, 1 H) 8.43 (d, J=7.50 Hz, 2 H) 7.55 (s, 1 H) 7.45 (s, 1 H) 6.76 (d, J=5.25 Hz, 1 H) 3.96 (d,J=1.63 Hz, 6 H). MS(ES+) m / z,[M+H] + [C 17 H 12 F2N2O5+H] + Calculated value: 363.07, Measured value: 363.1 t R = 1.346 min.

[0331] Synthesis of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3,5-difluoroaniline [intermediate A-17]: At 70 °C, saturated NH₄Cl (3.04 mmol, 3 mL, 1.00 equivalent) was added in a single batch to a mixture of 4-(2,6-difluoro-4-nitro-phenoxy)-6,7-dimethoxy-quinoline (1.10 g, 3.04 mmol, 1.00 equivalent) in EtOH (12 mL), followed by the addition of Fe (847.81 mg, 15.18 mmol, 5.00 equivalent). The mixture was stirred at 70 °C for 1 hour. LCMS showed the reaction was complete. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to provide 4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3,5-difluoro-aniline (330 mg) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.48 (d, J=5.13 Hz, 1 H) 7.50 (s, 1 H) 7.40 (s,1 H) 6.50 (d, J=5.25 Hz, 1 H) 6.41 - 6.44 (m, 1 H) 6.38 - 6.41 (m, 1 H) 5.82(s, 2 H) 3.94 (s, 6 H). MS(ES+) m / z,[M+H] + [C 17 H 14 F2N2O3+H] + Calculated value: 333.09, Measured value: 333.2 t R = 1.256 min.

[0332] Synthesis of 5-fluoro-6-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]pyridine-3-amine [intermediate 18]: Synthesis of 3-fluoro-6,7-dimethoxy-quinoline-4-ol Ethanol (1.86 g, 24.83 mmol, 4.00 equivalent) and K₂CO₃ (4.29 g, 31.04 mmol, 5.00 equivalent) were added to a solution of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (1.50 g, 6.21 mmol, 1.00 equivalent) in DMSO (30.00 mL), and the mixture was then stirred at 90 °C under N₂ for 16 h. LCMS showed the reaction was complete. The mixture was diluted with H₂O (150 mL) and extracted with EtOAC (2 × 40 mL). The aqueous phase was adjusted to pH 2 with 2 N HCl. The precipitated solid was collected and washed with water (2 × 20 mL), and dried under vacuum to provide 3-fluoro-6,7-dimethoxy-quinoline-4-ol (1.1 g, 78.64% yield) as a yellow solid. MS(ES+)m / z, [M+H] + [C11H10FNO3 +H] + Calculated value: 224.06, measured value: 224.0, t R = 0.646 min Synthesis of 3-fluoro-4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline K₂CO₃ (309.60 mg, 2.24 mmol, 2.00 equivalent) and 2-chloro-3-fluoro-5-nitropyridine (296.59 mg, 1.68 mmol, 1.50 equivalent) were added to a solution of 3-fluoro-6,7-dimethoxy-quinoline-4-ol (0.25 g, 1.12 mmol, 1.00 equivalent) in MeCN (7.50 mL), and the mixture was stirred at 70 °C under N₂ for 4 h. LCMS showed little residue of the starting material, and the main peak was the desired product. The mixture was diluted with EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL), the organic layer was separated, dried over Na₂SO₄, filtered, and concentrated. The residue was subjected to preparative TLC (SiO₂, petroleum ether / EtOAC = 3 / 1, R f =0.35) purified to provide 3-fluoro-4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (0.115 g, 25.44% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d) 6): δ 8.94 (dd, J=9.51, 2.38 Hz, 1 H) 8.88 (d, J=1.75 Hz, 1 H) 8.85 (d,J=2.38 Hz, 1 H) 7.49 (s, 1 H) 7.26 (s, 1 H) 3.95 (s, 3 H) 3.87 (s, 3H). MS(ES+) m / z,[M+H] + [C16H11F2N3O5 +H] + Calculated value: 364.07, measured value: 363.9, t R = 1.228 min.

[0333] Synthesis of 5-fluoro-6-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]pyridine-3-amine [intermediate 18]: Fe (88.39 mg, 1.58 mmol, 5.00 equivalent) was added in portions to a mixture of 3-fluoro-4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (115.00 mg, 316.57 μmol, 1.00 equivalent) in EtOH (4.50 mL) and saturated NH4Cl (1.50 mL), and the mixture was then stirred at 70 °C for 1 hour. LCMS showed that the reaction was complete. The mixture was filtered through diatomaceous earth and washed with EtOAc (50 mL). The filtrate was diluted with H2O (20 mL), the organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 15 mL). The organic layer was washed with brine (20 mL) and dried over Na2SO4 to provide 0.07 g of 5-fluoro-6-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)oxy]pyridine-3-amine as a yellow crude solid. MS (ES+) m / z, [M+H] + [C16H13F2N3O3 +H] + Calculated value: 334.09, measured value: 334.0, t R = 1.044 min Synthesis of 6-[(6,7-dimethoxy-4-quinolinyl)oxy]-5-fluoro-pyridine-3-amine [intermediate 19]: Synthesis of 4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline Cs₂CO₃ (2.86 g, 8.77 mmol, 1.80 equivalent) and 2-chloro-3-fluoro-5-nitropyridine (946.28 mg, 5.36 mmol, 1.10 equivalent) were added to a mixture of 6,7-dimethoxyquinoline-4-ol (1.00 g, 4.87 mmol, 1.00 equivalent) in MeCN (20 mL). The mixture was stirred at 25 °C for 16 h. LC-MS showed the remaining 22% of the starting material and the formation of two peaks with the desired MS. The reaction mixture was poured into 100 mL of H₂O and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over Na₂SO₄, filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 50 / 50 to 20 / 80) to provide 4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (0.62 g, 34.93% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.91 (d, J=2.38 Hz, 1 H) 8.87 - 8.93 (m, 1 H)8.88 (t, J=2.20 Hz, 1 H) 8.72 (d, J=5.02 Hz, 1 H) 7.47 (s, 1 H) 7.31 (d, J=5.02 Hz, 1 H) 7.24 (s, 1 H) 3.96 (s, 3 H) 3.85 (s, 3 H). MS(ES+) m / z,[M+H] + [C16H12FN3O5 +H] + Calculated value: 346.08, Measured value: 346.0 t R = 0.360 min.

[0334] Synthesis of 6-[(6,7-dimethoxy-4-quinolinyl)oxy]-5-fluoro-pyridine-3-amine [intermediate 19]: Fe (776.34 mg, 13.90 mmol, 8.00 equivalent) was added to a solution of 4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (600.00 mg, 1.74 mmol, 1.00 equivalent) in MeOH (12 mL) and saturated NH4Cl (6 mL) at 70 °C. The mixture was stirred at 70 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated to remove MeOH, then poured into 60 mL of H2O and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated to give crude 6-[(6,7-dimethoxy-4-quinoline)oxy]-5-fluoro-pyridin-3-amine (500.00 mg) as a brown solid. MS(ES+) m / z, [M+H] + [C16H14FN3O3+H] + Calculated value: 316.10, Measured value: 316.2 t R = 0.318 min.

[0335] Synthesis of 2-fluoro-N1-(3-fluoro-6,7-dimethoxy-4-quinolinyl)phenyl-1,4-diamine [intermediate 20]: Synthesis of 3-fluoro-N-(2-fluoro-4-nitro-phenyl)-6,7-dimethoxy-quinoline-4-amine A mixture of 4-chloro-3-fluoro-6,7-dimethoxyquinoline (200.00 mg, 827.66 μmol, 1.00 equivalent), 2-fluoro-4-nitroaniline (155.05 mg, 993.19 μmol, 1.20 equivalent), NaOtBu (2 M in THF, 827.66 μL, 2.00 equivalent), and RuPhos Pd G4 (70.38 mg, 82.77 μmol, 0.10 equivalent) in dioxane (3 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C under N2 atmosphere for 12 h. LC-MS showed the reaction was complete. The reaction mixture was quenched by adding 20 mL of H2O and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with 20 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / EtOAc = 1 / 0 to 60 / 40) to provide 3-fluoro-N-(2-fluoro-4-nitro-phenyl)-6,7-dimethoxy-quinoline-4-amine (150.00 mg, 50.16% yield) as a yellow solid. MS (ES+) m / z, [M+H] + [C 17 H 13 N3F2O4+H] + Calculated value: 362.08, Measured value: 362.2 t R = 0.393 min.

[0336] Synthesis of 2-fluoro-N1-(3-fluoro-6,7-dimethoxy-4-quinolinyl)phenyl-1,4-diamine [intermediate 20]: Saturated NH4Cl (0.5 mL) and Fe (92.74 mg, 1.66 mmol, 5.00 equivalent) were added to a solution of 3-fluoro-N-(2-fluoro-4-nitro-phenyl)-6,7-dimethoxy-quinoline-4-amine (120.00 mg, 332.13 μmol, 1.00 equivalent) in EtOH (2 mL). The mixture was stirred at 70 °C for 1 h. LC-MS showed that the starting material was completely consumed and a main peak with the desired m / z mass was detected. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EtOAc (2 × 20 mL). The resulting filtrate was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed sequentially with water (2 × 20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to provide 130.00 mg of 2-fluoro-N₁-(3-fluoro-6,7-dimethoxy-4-quinolinyl)phenyl-1,4-diamine as a yellow solid. MS (ES+) m / z, [M+H + [C 17 H 15 N3F2O2+H] + Calculated value: 332.11, Measured value: 332.1 t R = 0.299 min.

[0337] Synthesis of 4-[(6,7-dimethoxy-1,5-naphthid-4-yl)oxy]-3-fluoroaniline [intermediate 21]: Synthesis of 2,3-dimethoxy-5-nitro-pyridine 2-Chloro-3-methoxy-5-nitro-pyridine (24.00 g, 127 mmol, 1.00 equivalent) was added in portions to a stirred solution of NaOMe (28.56 g, 255 mmol, 2.00 equivalent) in methanol (150 mL, 0.8485 M) at room temperature and stirred for 1 h. The reaction progress was monitored by LCMS. The reaction was concentrated to dryness to give a residue. The residue was treated with water (200 mL), and the resulting solid was filtered and dried under vacuum to provide 2,3-dimethoxy-5-nitro-pyridine (15.00 g, 62% yield) as an off-white solid; MS (ES+) m / z, [M+H] + [C7H8N2O4+H] + Calculated value: 185.06, measured value: 184.90, t R= 1.690 min.

[0338] Synthesis of 5,6-dimethoxypyridine-3-amine Iron powder (22.75 g, 407 mmol, 5.00 equivalent) and ammonium chloride (21.79 g, 407 mmol, 5.00 equivalent) were added to a stirred solution of 2,3-dimethoxy-5-nitropyridine (15.00 g, 81.5 mmol, 1.00 equivalent) in ethanol (100 mL, 0.6516 M) and water (25 mL, 0.6516 M) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was concentrated under vacuum to give a crude product. The crude product was diluted with ethyl acetate (500 mL) and water (100 mL). The combined organic layers were washed with a brine solution (120 mL), dried over Na2SO4, filtered, and concentrated to provide 5,6-dimethoxypyridine-3-amine (11.00 g, 81% yield) as a brown solid. 1 H NMR (400 MHz, DMSO- d 6): δ 7.05 (d, J = 2.5 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 4.89 (br s, 2H), 3.71 (s, 3H), 3.69 (s, 3H). MS(ES+) m / z,[M+H] + [C7H 10 N2O2+H] + Calculated value: 155.08, Measured value: 155.00 t R = 0.690 min and t R =0.80 min.

[0339] Synthesis of 5-[[(5,6-dimethoxy-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione A stirred solution of 5,6-dimethoxypyridin-3-amine (10.00 g, 64.9 mmol, 1.00 equivalent) and 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (14.28 g, 71.3 mmol, 1.10 equivalent) in ethanol (200 mL, 0.3243 M) was stirred at 80 °C for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was filtered, washed with methanol, and dried under vacuum to provide 5-[[(5,6-dimethoxy-3-pyridinyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (15.00 g, 81% yield) as a pale brown solid. MS (ES+) m / z, [M+H] + [C 14 H 16 N2O6+H] + Calculated value: 309.11, measured value: 308.90, t R = 1.640 min.

[0340] Synthesis of 6,7-dimethoxy-1,5-naphthidine-4-ol 5-[[(5,6-dimethoxy-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (10.00 g, 32.4 mmol, 1.00 equivalent) was added in portions over 0.5 h to a stirred solution of diphenyl ether (100 mL, 1622 mmol, 50.0 equivalent), and stirring was continued at 270 °C for 3 h. The reaction progress was monitored by LCMS. After cooling, the reaction mixture was treated with heptane (100 mL), and the resulting precipitate was filtered and washed with heptane (100 mL) to provide 6,7-dimethoxy-1,5-naphthyl-4-ol (4.00 g, 38% yield) as a pale yellow solid. MS (ES+) m / z, [M+H] + [C 10 H 10 N2O3+H] + Calculated value: 207.08, measured value: 206.09, t R = 1.130min.

[0341] Synthesis of 8-chloro-2,3-dimethoxy-1,5-naphthidine At room temperature, a catalytic amount of N,N-dimethylformamide (1.8 mL, 23.2 mmol, 1.33 equivalents) was added to a stirred solution of 6,7-dimethoxy-1,5-naphthyl-4-ol (3.60 g, 17.5 mmol, 1.00 equivalents) in thionyl chloride (90 mL, 1241 mmol, 71.1 equivalents). The resulting reaction mixture was heated at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure by LCMS to obtain a crude product. The crude product was milled with ethyl acetate (100 mL) for 10 min. The resulting solid was filtered and dried under vacuum to obtain 8-chloro-2,3-dimethoxy-1,5-naphthylidine (2.20 g, 51% yield) as a pale yellow solid. MS (ES+) m / z, [M+H] + [C 10 H9ClN2O2+H] + Calculated value: 225.05, measured value: 224.80, t R = 1.750 min.

[0342] Synthesis of 4-[(6,7-dimethoxy-1,5-naphthid-4-yl)oxy]-3-fluoroaniline [intermediate 21]: Potassium tert-butoxide (2548 mg, 22.7 mmol, 3.00 equivalents) was added to a stirred solution of 4-amino-2-fluorophenol (1.92 g, 15.1 mmol, 2.00 equivalents) in N,N-dimethylformamide (60 mL, 0.1261 M) at room temperature and stirred for 10 min. Then, 8-chloro-2,3-dimethoxy-1,5-naphthidine (1.70 g, 7.57 mmol, 1.00 equivalents) was added. The reaction mixture was heated to 120 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth pad, and washed with ethyl acetate (300 mL). The filtrate was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by passing through a YMC 40 g column using a combi flash and eluting with heptane containing 60%–100% ethyl acetate to give the desired product. The product was ground with diethyl ether (2 × 50 mL) and n-pentane (2 × 50 mL). The resulting precipitate was filtered and dried under vacuum to provide 4-[(6,7-dimethoxy-1,5-naphthid-4-yl)oxy]-3-fluoroaniline (950 mg, 38% yield) as a brown solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.48 (d,J =5.3 Hz, 1H), 7.62 (s, 1H), 7.04 (t, J = 9.0 Hz, 1H), 6.60 (d, J = 5.3 Hz, 1H), 6.54 (dd, J = 2.3, 13.3 Hz, 1H), 6.45 (dd, J = 2.0, 8.8 Hz, 1H), 5.45 (s, 2H), 4.03 (s, 3H), 3.96 (s, 3H). MS(ES+) m / z,[M+H] + [C 16 H 14 FN3O3+H] + Calculated value: 316.3, measured value: 316.00, t R = 1.35 min.

[0343] Synthesis of 4-((6,7-dimethoxy-1,5-naphthid-4-yl)oxy)-3,5-difluoroaniline [intermediate 22]: Synthesis of 8-(2,6-difluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthidine Cesium carbonate (4.8 g, 2 equivalents, 15 mmol) and 1,2,3-trifluoro-5-nitrobenzene (1.9 g, 1.5 equivalents, 11 mmol) were added to a stirred solution of 6,7-dimethoxy-1,5-naphthyl-4-ol (1.5 g, 7.3 mmol) in acetonitrile (15 mL) at room temperature and stirred for 24 h. According to TLC, after the reaction was complete, the reactants were diluted with EtOAc (50 mL), filtered through a diatomaceous earth bed, washed with ethyl acetate (40 mL), and the organic layer was concentrated to give 2.17 g of crude product as a brown liquid. This crude product was purified by passing it through 100-200 mesh silica. The compound was eluted with heptane containing 21%-23% EtOAc to provide 8-(2,6-difluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthidine (680 mg, 1.823 mmol, 25% yield) as a pale yellow solid. MS (ES+) m / z, [M+H] + [C 16 H 11 F2N3O5+H] + Calculated value: 363.07, Measured value: 334 tR = 1.945 min.

[0344] Synthesis of 4-((6,7-dimethoxy-1,5-naphthid-4-yl)oxy)-3,5-difluoroaniline [intermediate 22]: Iron (638 mg, 5 equivalents, 11.42 mmol) and ammonium chloride (612 mg, 5 equivalents, 11.42 mmol) were added to a stirred solution of 8-(2,6-difluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthidine (830 mg, 2.285 mmol) in ethanol (80 mL) and water (8 mL) at room temperature, and the mixture was stirred at 90 °C for 60 min. The reaction mixture was monitored by TLC. After cooling, the reaction mixture was filtered through a diatomaceous earth bed, the bed was washed with EtOAc (50 mL) and concentrated to a crude product (230 mg), 20 mL of water was added, the mixture was stirred for 10 min and filtered, and dried to provide 4-((6,7-dimethoxy-1,5-naphthidine-4-yl)oxy)-3,5-difluoroaniline (700 mg, 2.058 mmol, 90.09% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) = 8.51 (d, J = 5.2 Hz, 1H), 7.63 (s, 1H), 6.40 (dd, J = 10.8 Hz,1H), 5.78 (brs, 2H), 4.02 (s, 3H), 3.97 (s, 2H). MS(ES+)m / z,[M+H] + [C 16 H 13 F2N3O3+H] + Calculated value: 333.09, Measured value: 334 t R = 1.531 min.

[0345] Synthesis of 3-fluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthid-4-yl)oxy)aniline [intermediate 23]: Synthesis of 7-fluoro-8-(2-fluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthidine DIEA (2.2 mL, 13 mmol, 10 equivalents) and 8-chloro-7-fluoro-2,3-dimethoxy-1,5-naphthidine (1 g, 4.1215 mmol, 1 equivalent) were added to a solution of 2-fluoro-4-nitrophenol (0.971 g, 6.1822 mmol, 1.5 equivalents) in chlorobenzene (10 mL) at room temperature. The resulting mixture was stirred at 150 °C for 72 h. After the reaction was complete, the mixture was evaporated under vacuum to give a crude product, which was purified by combi flash using a 24 g column and eluted with 0%–50% EtOAc / heptane to provide 7-fluoro-8-(2-fluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthidine (200 mg, 0.4349 mmol, 10.55% yield) as a pale yellow solid. MS(ES+) m / z, [M+H] + [C 16 H 11 F2N3O5+H] + Calculated value: 364.08, measured value: 364.0, t R =2.08 min.

[0346] Synthesis of 3-fluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthid-4-yl)oxy)aniline [intermediate 23]: NH4Cl (0.146 g, 2.75 mmol, 5 equivalents) and Fe (0.152 g, 2.75 mmol, 5 equivalents) were added to a solution of 7-fluoro-8-(2-fluoro-4-nitro-phenoxy)-2,3-dimethoxy-1,5-naphthidine (200 mg, 0.5505 mmol) in EtOH:H2O (10 mL) at room temperature under a nitrogen atmosphere. The resulting reaction was stirred at 90 °C for 3 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with ethyl acetate (20 mL), and the filtrate was dried under vacuum to give a crude residue. The crude product was further treated with water and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with a brine solution (10 mL), dried over Na2SO4, filtered, concentrated under vacuum, and then purified by combi flash using a 12 g column and eluted with heptane containing 50%–70% ethyl acetate to provide 3-fluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthid-4-yl)oxy)aniline (0.15 g, 0.35 mmol, 64% yield) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6): 8.83 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 6.84 (t, J = 8.8 Hz, 1H). 6.44 (dd, J = 2.8 Hz, J = 13.6 Hz, 1H), 6.26 (dd J = 2.0 Hz, J = 8.8 Hz, 1H), 5.21 (s, 2H), 3.93 (s, 3H), 3.72 (s, 3H). MS(ES+) m / z,[M+H] + [C 16 H 11 F2N3O5+H] + Calculated value: 364.08, measured value: 364.0, t R =2.08 min.

[0347] Synthesis of 5-fluoro-6-((3-fluoro-6,7-dimethoxy-1,5-naphthidin-4-yl)oxy)pyridine-3-amine [intermediate 24]: Synthesis of 3-fluoro-6,7-dimethoxy-1,5-naphthidine-4-ol K₂CO₃ (2.29 g, 16.5 mmol, 2 equivalents) was added to a solution of 8-chloro-7-fluoro-2,3-dimethoxy-1,5-naphthidine (2 g, 8.2430 mmol, 1 equivalent) in 1,4-dioxane and water (100 mL [1:1]) at room temperature under a nitrogen atmosphere. The reaction was degassed under a nitrogen atmosphere for 10 min, and Trixie Phos (0.492 g, 1.2365 mmol, 0.15 equivalents) and PdCl₂(dppf)DCM (1.35 g, 1.65 mmol, 0.2 equivalents) were added. The resulting mixture was stirred at 100 °C for 16 h and filtered through diatomaceous earth, washed with ethyl acetate (100 mL), and then washed with DCM containing 15% MeOH (2 × 50 mL). The combined organic layers were washed with an aqueous salt solution, dried over Na2SO4, filtered, and concentrated under vacuum to provide 3-fluoro-6,7-dimethoxy-1,5-naphthidine-4-ol (1.4 g, 6.1 mmol, 74% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6): 8.05 (d, J = 5.2 Hz, 1H), 7.23 (s, 1H), 3.88 (s, 3H), 3.78 (s, 3H). MS(ES+) m / z,[M+H] + [C 10 H9FN2O3] + Calculated value: 225.01, measured value: 225.1, t R = 1.23 min.

[0348] Synthesis of 7-fluoro-8-((3-fluoro-5-nitropyridin-2-yl)oxy)-2,3-dimethoxy-1,5-naphthidine Cs₂CO₃ (2.2 g, 6.8 mmol, 1.08 equivalent) and 3-fluoro-6,7-dimethoxy-1,5-naphthyl-4-ol (1.4 g, 6.2 mmol, 1 equivalent) were added to a solution of 2-chloro-3-fluoro-5-nitro-pyridine (1.3 g, 7.4 mmol, 1.18 equivalent) in ACN (70 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was evaporated under vacuum to give a crude product, which was purified by combi flash using a 24 g column and eluted with 40%–50% EtOAc / heptane to provide 7-fluoro-8-[(3-fluoro-5-nitro-2-pyridyl)oxy]-2,3-dimethoxy-1,5-naphthylidine (1.4 g, 2.8 mmol, 44% yield). MS(ES+) m / z, [M+H] + [C 15 H 10 F2N4O5] + Calculated value: 365.06, measured value: 365.2, t R = 2.28 min.

[0349] Synthesis of 5-fluoro-6-((3-fluoro-6,7-dimethoxy-1,5-naphthidin-4-yl)oxy)pyridine-3-amine [intermediate 24]: NH₄Cl (1.0 g, 19 mmol, 15 equivalents) and Fe (1.1 g, 20 mmol, 5 equivalents) were added to a solution of 7-fluoro-8-[(3-fluoro-5-nitro-2-pyridyl)oxy]-2,3-dimethoxy-1,5-naphthidine (1.4 g, 3.8 mmol, 100 wt%) in EtOH and water (50 mL [1:1]) at room temperature under a nitrogen atmosphere. The resulting reaction was stirred at 90 °C for 1 h. After the reaction was complete, the mixture was filtered through diatomaceous earth and washed with ethyl acetate (100 mL), and dried under vacuum to give the residue. The residue was treated with water (50 mL) and stirred for 5 min. The resulting precipitate was filtered and washed with water (30 mL) and dried under vacuum to provide 5-fluoro-6-[(3-fluoro-6,7-dimethoxy-1,5-naphthid-4-yl)oxy]pyridine-3-amine (900 mg, 66% yield). 1 HNMR (400 MHz, DMSO-d6): 8.88 (d, J = 1.6Hz, 1H), 7.67 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H). 7.06 (dd, J = 2.4 Hz, J = 12.4 Hz, 1H), 5.38 (s, 2H), 3.93 (s, 3H), 3.64 (s, 3H). MS(ES+) m / z,[M+H] + [C15H12F2N4O3 +H] + Calculated value: 335.10, Measured value: 335.0 t R = 1.75 min.

[0350] Synthesis of 3,5-difluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthid-4-yl)oxy)aniline [intermediate 25]: Synthesis of 8-(2,6-difluoro-4-nitrophenoxy)-7-fluoro-2,3-dimethoxy-1,5-naphthidine 2,6-Difluoro-4-nitrophenol (541 mg, 1.5 equivalence, 3.09 mmol) was added to a stirred solution of 8-chloro-7-fluoro-2,3-dimethoxy-1,5-naphthidine (500 mg, 2.0608 mmol) in acetonitrile (10 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (3.6 mL, 10 equivalence, 20.61 mmol). The resulting mixture was stirred at 130 °C for 24 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was concentrated and purified by passing it through a Combi flash column using 230-400 mesh silica gel and eluting with heptane containing 30%-40% ethyl acetate to provide 8-(2,6-difluoro-4-nitro-phenoxy)-7-fluoro-2,3-dimethoxy-1,5-naphthidine (450.00 mg, 41.23% yield) as an off-white solid. MS(ES+) m / z, [M+H] + [C 16 H 10 F3N3O5] + Calculated value: 381.3, measured value: 382.0, t R = 2.10 min.

[0351] Synthesis of 3,5-difluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthid-4-yl)oxy)aniline [intermediate 25]: Iron (237 mg, 5 equivalents, 4.249 mmol) was added to a stirred solution of a mixture of two compounds [20% 7-chloro-8-(2,6-difluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthidine and 72% 8-(2,6-difluoro-4-nitrophenoxy)-7-fluoro-2,3-dimethoxy-1,5-naphthidine (450.00 mg, 0.8497 mmol)] in a mixture of ethanol (16 mL, 270 mmol) and water (4 mL) under a nitrogen atmosphere at 0 °C, followed by the addition of ammonium chloride (228 mg, 5 equivalents, 4.249 mmol), and the mixture was stirred at 80 °C for 12 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was filtered through a diatomaceous earth mat, washed with methanol (100 mL), and concentrated to give the residue. The residue was treated with 20% MeOH / DCM (50 mL), filtered, and concentrated to obtain a crude product. The crude product was purified by passing it through a Combi flash column using 230-400 mesh silica gel and eluting with heptane containing 40%-50% ethyl acetate to provide 3,5-difluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthid-4-yl)oxy)aniline (310 mg, 16% yield) as a pale brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J = 2.4 Hz, 1H), 7.64 (s, 1H), 6.26 (d, J=11.2Hz, 2H), 5.55 (s, 2H), 3.93 (s, 3H), 3.71 (s, 3H). MS(ES+) m / z,[M+H] + [C 10 H 10 ClN3O2+H] + Calculated value: 239.66, Measured value: 239.8 t R = 1.63 min.

[0352] Synthesis of 4-((6,7-dimethoxypyridano[3,2-d]pyrimidin-4-yl)oxy)-3-fluoroaniline [intermediate 26]: Synthesis of (5,6-dimethoxypyridin-3-yl)carbamate tert-butyl ester Tert-butyl carbamate (5.209 g, 44.02 mmol, 1 equivalent), cesium carbonate (18.8 g, 57.6 mmol, 2.09 equivalent), and XPhos (1.59 g, 3.30 mmol, 0.12 equivalent) were added to a stirred solution of 5-bromo-2,3-dimethoxypyridine (6 g, 27.517 mmol, 1 equivalent) in 1,4-dioxane (60 mL) under argon atmosphere. The mixture was degassed with argon for 5 min, and then palladium(II) acetate (309 mg, 1.376 mmol, 0.05 equivalent) was added. The resulting mixture was stirred at 120 °C for 16 h. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by combi flash using a 40 g YMC column and heptane containing 20%–25% ethyl acetate as eluent to provide tert-butyl (5,6-dimethoxypyridin-3-yl)carbamate (4.30 g, 59.8% yield) as a grayish-white solid. MS (ES+) m / z, [M+H] + [C 12 H 18 N2O4 +H] + Calculated value: 255.28, Measured value: 255.1 t R =1.81 min. Method details: Column: X-Select CSH C18, (50 mm) Column temperature: 3.0 mm, 2.5 µm; Mobile phase A: water containing 0.05% formic acid; Mobile phase B: acetonitrile containing 0.05% formic acid; Flow rate: 1.0 mL / min; Column temperature: 40 °C; Gradient program (B%): 0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.

[0353] Synthesis of tert-butyl (2-bromo-5,6-dimethoxypyridin-3-yl)carbamate NBS (6.0568 g, 33.349 mmol, 1.06 equivalent) was added in portions to a stirred solution of {N}-(5,6-dimethoxy-3-pyridyl)carbamate (8 g, 31.461 mmol, 1 equivalent) in MeCN (160 mL) at 25 °C. The resulting reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with a brine solution (100 mL), dried over sodium sulfate, and concentrated under vacuum to give a crude product, which was purified by combi flash using a 40 g YMC column with heptane containing 20%–25% ethyl acetate as eluent to provide tert-butyl (2-bromo-5,6-dimethoxypyridyl-3-yl)carbamate (7.6 g, 69% yield) as a white solid. 1 H NMR (401 MHz, DMSO- d 6) δ ppm 8.65 (s, 1 H)7.39 (s, 1 H) 3.84 (s, 3 H) 3.78 (s, 3 H) 1.45 (s, 9 H). MS(ES+) m / z,[M+H] + [C 12 H 17 BrN2O4+H] + Calculated value: 334.18, Measured value: 332.7 t R = 5.11 min. Method details: TFA 10 MIN, column: Acquity UPLC BEH C18 (2.1 50 mm, 1.7 μm, flow rate: 0.5 mL / min. Mobile phase A: water containing 0.05% TFA, mobile phase B: acetonitrile containing 0.05% TFA, column temperature: 40℃, gradient program, time / B: 0.0 / 3, 1.5 / 3, 6 / 97, 8 / 97, 9.0 / 3, 10 / 3.

[0354] Synthesis of 2-bromo-5,6-dimethoxypyridine-3-amine 4 M HCl (50 mL, 200 mmol, 8.89 equivalents) in dioxane was added to a stirred solution of N-(2-bromo-5,6-dimethoxy-3-pyridyl)carbamate (7.50 g, 22.5 mmol, 1 equivalent) in DCM (73 mL). The reaction mixture was stirred at room temperature for 6 h, and the reaction progress was monitored by TLC. After completion, the reactants were alkalized with saturated K₂CO₃ solution, extracted with DCM (110 mL), and the organic layer was washed with a brine solution (200 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to provide 2-bromo-5,6-dimethoxypyridin-3-amine (5.3 g, 100% yield) as a brown semi-solid. MS (ES+) m / z, [M+H] + [C7H9BrN2O2+H] + Calculated value: 234.06, Measured value: 234.7 t R =1.67 min.

[0355] Method details: Column: X-Select CSH C18, (50 mm) Column temperature: 3.0 mm, 2.5 µm; Mobile phase A: water containing 0.05% formic acid; Mobile phase B: acetonitrile containing 0.05% formic acid; Flow rate: 1.0 mL / min; Column temperature: 40 °C; Gradient program (B%): 0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.

[0356] Synthesis of 3-amino-5,6-dimethoxypyridinecarboxynitrile Zinc cyanide (1.9 g, 16 mmol, 0.7 equivalent) was added to a stirred solution of 2-bromo-5,6-dimethoxy-pyridine-3-amine (5.3 g, 23 mmol, 1 equivalent) in N,N-dimethylformamide (53 mL) under argon atmosphere. Then, 1,1'-bis(diphenylphosphino)ferrocene (650 mg, 0.1154 mmol, 0.05 equivalent) was added, and degassing was continued for 5 min, followed by the addition of tris(dibenzylacetone)dipalladium(0) (640 mg, 0.699 mmol, 0.035 equivalent). The mixture was stirred at 130 °C for 16 h. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give crude 3-amino-5,6-dimethoxypyridinecarboxynitrile (4.1 g, 90% yield) as a pale brown liquid. MS (ES+) m / z, [M+H] + [C8H9N3O2+H] + Calculated value: 180.19, Measured value: 179.9 t R = 1.59 min.

[0357] Method details: Column: X-Select CSH C18, (50 mm) Column temperature: 3.0 mm, 2.5 µm; Mobile phase A: water containing 0.05% formic acid; Mobile phase B: acetonitrile containing 0.05% formic acid; Flow rate: 1.0 mL / min; Column temperature: 40 °C; Gradient program (B%): 0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.

[0358] Synthesis of 3-amino-5,6-dimethoxypyridine carboxamide Hydrogen peroxide in water (23.6 mL, 208 mmol, 9.1 equivalents) was added to 3-amino-5,6-dimethoxy-pyridine-2-carboxynitrile (4.10 g, 22.9 mmol, 1 equivalent) in a mixture of 3-amino-5,6-dimethoxy-pyridine-2-carboxynitrile (157 mL, 1119.97 mmol, 49 equivalents) in an aqueous solution of ammonium hydroxide (157 mL, 1119.97 mmol, 49 equivalents). The reaction mixture was stirred at room temperature for 1 h, and the reaction progress was monitored by TLC and LCMS. After completion, the solid was filtered under vacuum and washed with water (20 mL). The filtrate was collected and extracted with ethyl acetate (200 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to provide 3-amino-5,6-dimethoxy-pyridine-2-carboxamide (3.2 g, 68% yield) as a pale brown solid. MS (ES+) m / z, [M+H] + [C8H11N3O3+H] + Calculated value: 198.19, Measured value: 197.9 t R = 1.36 min.

[0359] Method details: Column: X-Select CSH C18, (50 mm) Column temperature: 3.0 mm, 2.5 µm; Mobile phase A: water containing 0.05% formic acid; Mobile phase B: acetonitrile containing 0.05% formic acid; Flow rate: 1.0 mL / min; Column temperature: 40 °C; Gradient program (B%): 0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.

[0360] Synthesis of 3-amino-5,6-dimethoxypyridine carboxamide Triethyl orthoformate (14 ml, 81.6 mmol, 5.03 equivalents) and p-toluenesulfonic acid (280 mg, 1.46 mmol, 0.09 equivalents) were added to a stirred solution of 3-amino-5,6-dimethoxypyridine-2-carboxamide (3.2 g, 16 mmol, 1 equivalent) in toluene (64 ml) at room temperature. The reaction mixture was stirred at 120 °C for 6 h. The reaction progress was monitored by LCMS and TLC. After the reaction was complete, the mixture was concentrated under vacuum to give a crude product. The crude product was milled with heptane containing 20% ​​ethyl acetate, filtered under vacuum to obtain the solid, and dried to provide 3-amino-5,6-dimethoxypyridinecarboxamide (2.60 g, 70% yield) as a light brown solid. MS (ES+) m / z, [M+H] + [C9H9N3O3+H] +Calculated value: 208.19, Measured value: 207.8 t R =1.26 min.

[0361] Method details: Column: X-Select CSH C18, (50 mm) Column temperature: 3.0 mm, 2.5 µm; Mobile phase A: water containing 0.05% formic acid; Mobile phase B: acetonitrile containing 0.05% formic acid; Flow rate: 1.0 mL / min; Column temperature: 40 °C; Gradient program (B%): 0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.

[0362] Synthesis of 4-chloro-6,7-dimethoxypyrido[3,2-d]pyrimidine A solution of phosphoryl chloride (53 mL, 562.9 mmol, 47 equivalents) in 6,7-dimethoxypyrido[3,2-d]pyrimidine-4-ol (2.5 g, 12 mmol, 1 equivalent) was added at room temperature, followed by stirring at 120 °C for 3 h. The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was dissolved in DCM (200 mL), and a saturated NaHCO3 solution (200 mL) was slowly added while stirring for 5 min, followed by separation of the layers. The organic layer was washed again with a brine solution (300 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to provide 4-chloro-6,7-dimethoxypyrido[3,2-d]pyrimidine (2.3 g, 77% yield) as a brown solid. 1 HNMR (400 MHz, DMSO- d 6) δ ppm 8.93 (s, 1 H) 7.70 (s, 1 H) 4.11 (s, 3 H) 4.04 (s, 3 H). MS(ES+) m / z,[M+H] + [C9H8ClN3O2+H] + Calculated value: 226.63, Measured value: 225.8 t R =1.75 min.

[0363] Method details: Column: X-Select CSH C18, (50 mm) Column temperature: 3.0 mm, 2.5 µm; Mobile phase A: water containing 0.05% formic acid; Mobile phase B: acetonitrile containing 0.05% formic acid; Flow rate: 1.0 mL / min; Column temperature: 40 °C; Gradient program (B%): 0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.

[0364] Synthesis of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxypyrido[3,2-d]pyrimidine 2-fluoro-4-nitrophenol (1.9 g, 12 mmol, 1.1 equivalent) was added to a stirred solution of 4-chloro-6,7-dimethoxy-pyrido[3,2-d]pyrimidine (2.5 g, 11 mmol, 1 equivalent) in o-xylene (62.50 mL, 510 mmol) at room temperature. The resulting mixture was stirred at 130 °C for 16 h, and the reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by combi flash using a 24 g YMC column with heptane containing 50%-60% ethyl acetate as eluent to provide 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxypyrido[3,2-d]pyrimidine (1.4 g, 33% yield) as a white solid. 1 H NMR (401 MHz, DMSO-) d 6) δ ppm: 8.65 (s, 1 H) 8.43 (dd, J =10.21, 2.63 Hz, 1 H) 8.22- 8.28 (m, 1 H) 7.85 (dd, J =8.86, 7.89 Hz, 1 H) 7.70 (s, 1 H) 4.09 (s, 3 H) 4.04 (s, 3 H). MS(ES+) m / z,[M+H] + [C 15 H 11 FN4O5+H] + Calculated value: 347.3, measured value: 347.6, t R : 4.40 min.

[0365] Method details: Column: XSelect CSH-C18 (3.0 × 50 mm, 2.5 µm), Mobile phase A: Water containing 0.05% formic acid, Mobile phase B: MeCN (gradient) containing 0.05% formic acid. T / B%: 0.0 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2. Flow rate: 1 ml / min. Column temperature: 40℃.

[0366] Synthesis of 4-((6,7-dimethoxypyridano[3,2-d]pyrimidin-4-yl)oxy)-3-fluoroaniline [intermediate 26]: Tetrahydroxydiboron (980 mg, 10 mmol, 3 equivalents) and 4,4'-bipyridine (9 mg, 0.052 mmol, 0.015 equivalents) were added to a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxypyridino[3,2-d]pyrimidine (1.3 g, 3.5 mmol, 1 equivalent) in N,N-dimethylformamide (15.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. After stirring, the reaction mixture was poured into cold water, and the precipitated solid was filtered and dried under vacuum. The obtained solid was ground with methanol (10 mL), filtered, and dried under vacuum to provide 4-((6,7-dimethoxypyridino[3,2-d]pyrimidin-4-yl)oxy)-3-fluoroaniline (820 mg, 73% yield) as a light brown solid. 1 HNMR (400 MHz, DMSO- d 6) δ ppm: 8.57 (s, 1 H) 7.62 (s, 1 H) 7.03 (t, J =8.82 Hz, 1 H) 6.50 (dd, J =13.07, 2.19 Hz, 1 H) 6.42 (dd, J =8.76, 1.75 Hz, 1 H) 5.38 (s, 2 H) 4.08 (s, 3 H) 4.01 (s, 3 H). MS(ES+) m / z,[M+H] + [C 15 H 13 FN4 O3+H] + Calculated value: 317.3, measured value: 317.37, t R 3.85 min.

[0367] Method details: FA 10 MIN, column: Acquity UPLC BEH C18 (2.1) 50 mm, 1.7 μm, flow rate: 0.5 mL / min. Mobile phase A: water containing 0.05% formic acid, mobile phase B: acetonitrile containing 0.05% formic acid, column temperature: 45℃, gradient program, time / B%: 0.0 / 3, 1.5 / 3, 6 / 97, 8 / 97, 9.0 / 3, 10 / 3.

[0368] Synthesis of N-[3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)methyl]phenyl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxamide [intermediate 27]: Synthesis of N-[3-fluoro-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)methyl]phenyl]carbamate tert-butyl and [4-(tert-butoxycarbonylamino)-2-fluoro-phenyl]methylboronic acid Tri-tert-butylphosphine palladium (96.88 mg, 189.57 μmol, 0.10 equivalent) and KOH (8 M, 348.34 μL, 1.47 equivalent) were added to a solution of N-(4-bromo-3-fluoro-phenyl)carbamate tert-butyl (550.00 mg, 1.90 mmol, 1.00 equivalent) and 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)methyl]-1,3,2-dioxaborhexacyclopentane (1.52 g, 5.69 mmol, 3.00 equivalent) in dioxane (5.5 mL). The mixture was stirred at 25 °C for 16 h. LC-MS showed ~10% of the starting material remaining and ~60% of the product detected. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was subjected to preparative HPLC (neutral conditions; column: WePure Biotech XP tC18 150). 40 Purification was performed using a mobile phase of [H2O(10 mM NH4HCO3)-MeCN] and a gradient of 50%–80% B for 8.0 min to provide a mixture of N-[3-fluoro-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)methyl]phenyl]carbamate tert-butyl and [4-(tert-butoxycarbonylamino)-2-fluoro-phenyl]methylboronic acid (250 mg, 18.77% yield) as a yellow solid mixture. 1 H NMR (400 MHz, DMSO- d 6) δ ppm 9.29- 9.44 (m, 2 H) 7.64 (s, 2 H) 7.16 - 7.21 (m, 2 H) 7.00 - 7.08 (m, 4 H) 2.03- 2.07 (m, 2 H) 1.94 - 2.08 (m, 1 H) 1.96 (s, 1 H) 1.46 (s, 18 H) 1.16 (s, 12H). MS(ES+) m / z,[MH] + [C 18 H 27 BFNO4+H] + Calculated value: 352.20, Measured value: 350.1 t R = 1.485min.

[0369] Synthesis of N-[3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)methyl]phenyl]carbamate tert-butyl ester Cs₂CO₃ (350.57 mg, 1.08 mmol, 2.00 equivalent) and RuPhos Pd G₄ (45.75 mg, 53.80 μmol, 0.10 equivalent) were added to a solution of N-[3-fluoro-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)methyl]phenyl]carbamate, [4-(tert-butoxycarbonylamino)-2-fluorophenyl]methylboronic acid (188.95 mg, 537.98 μmol, 1.00 equivalent) and 4-chloro-3-fluoro-6,7-dimethoxyquinoline (130.00 mg, 537.98 μmol, 1.00 equivalent) in 2-methylbut-2-ol (2 mL) and H₂O (0.5 mL). The mixture was stirred at 80 °C for 12 hours. LCMS showed that both starting materials were completely consumed and a main peak with the desired m / z was detected. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was subjected to preparative HPLC (formic acid conditions; column: Phenomenex luna C18 100). 40 mm 5 μm; mobile phase: [H2O (0.2% formic acid)-MeCN]; gradient: 35%-70% B (for 8.0 min) to purify, providing 35 mg, 13.91% yield as a white solid. MS (ES+) m / z, [M+H) + [C 23 H 24 F2N2O4+H] + Calculated value: 431.17, Measured value: 431.3 t R = 1.974 min.

[0370] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)methyl]aniline [intermediate 27]: HCl / EtOAc (4 M, 2.50 mL) was added to N-[3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)methyl]phenyl]carbamate tert-butyl (25.00 mg, 58.08 μmol, 1.00 equivalent). The mixture was stirred at 25 °C for 1 h. LC-MS showed that the starting material was completely consumed and a main peak with the desired m / z was detected. The mixture was concentrated to provide 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)methyl]aniline (19 mg, crude) as a white solid, which was used directly for amide coupling reaction. MS (ES+) m / z, [M+H] + [C 18 H 16 F2N2O2+H] + Calculated value: 331.11, Measured value: 331.3 t R = 0.539 min.

[0371] Synthesis of N-[1-(3-fluoro-6,7-dimethoxy-4-quinolinyl)indoline-5-yl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxamide [intermediate 28]: Synthesis of 3-fluoro-6,7-dimethoxy-4-(5-nitroindoline-1-yl)quinoline Under N2, 5-nitroindoline (81.52 mg, 496.59 μmol, 1.20 equivalent), Cs2CO3 (404.50 mg, 1.24 mmol, 3.00 equivalent), Xantphos (47.89 mg, 82.77 μmol, 0.20 equivalent), and Pd2(dba)3 (37.89 mg, 41.38 μmol, 0.10 equivalent) were added to a solution of 4-chloro-3-fluoro-6,7-dimethoxyquinoline (100.00 mg, 413.83 μmol, 1.00 equivalent) in dioxane (2 mL), respectively. The mixture was stirred at 100 °C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was poured into H2O (50 mL), and the aqueous phase was then extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (2 × 100 mL), dried over anhydrous Na₂SO₄, and concentrated by filtration and vacuum. The residue was purified by preparative TLC (SiO₂, petroleum ether: EtOAc = 4:1) to provide 3-fluoro-6,7-dimethoxy-4-(5-nitroindoline-1-yl)quinoline (120.00 mg, 78.51% yield) as a yellow solid. MS (ES+) m / z, [M+H] + [C 19 H 16 N3FO4+H] + Calculated value: 370.11, Measured value: 369.8 t R = 0.567 min.

[0372] Synthesis of 1-(3-fluoro-6,7-dimethoxy-4-quinolinyl)indoline-5-amine Pd / C (259.32 mg, 243.67 μmol, 1.00 equivalent) was added to a mixture of 3-fluoro-6,7-dimethoxy-4-(5-nitroindoline-1-yl)quinoline (90.00 mg, 243.67 μmol, 1.00 equivalent) in MeOH (1 mL) and THF (1 mL) under H2. The mixture was stirred at 25 °C for 1 h. LCMS showed no remaining starting material and detected new peaks. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EtOAc (2 × 10 mL). The reaction mixture was poured into water (20 mL), and the aqueous phase was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue as a yellow solid, yielding 1-(3-fluoro-6,7-dimethoxy-4-quinolinyl)indoline-5-amine (70.00 mg, 84.65% yield). 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.62 (d, J=3.75 Hz, 1 H) 7.38 (s, 1 H) 7.17 (s, 1 H) 6.56 (s, 1H) 6.25 (dd, J=8.19, 1.81 Hz, 1 H) 6.00 (dd, J=8.25, 1.50 Hz, 1 H) 4.57 (brs, 2 H) 4.10 (br d, J=4.13 Hz, 1 H) 3.92 (s, 4 H) 3.75 (s, 3 H) 3.08 - 3.20 (m, 2 H). MS(ES+) m / z,[M+H] + [C 19 H 18 N3FO2+H] + Calculated value: 340.14, Measured value: 339.8 t R =0.485 min.

[0373] Synthesis of 1-(6,7-dimethoxy-4-quinolinyl)indole-5-amine [intermediate 29]: Synthesis of 6,7-dimethoxy-4-(5-nitroindol-1-yl)quinoline Add to a mixture of 5-nitro-1H-indole (1.45 g, 8.94 mmol, 1.00 equivalent) and 4-chloro-6,7-dimethoxy-quinoline (2.00 g, 8.94 mmol, 1.00 equivalent) in DMA (20 mL) t -BuOK (3.01 g, 26.83 mmol, 3.00 equivalent) and the mixture was stirred at 120 °C for 15 h. LCMS showed 30% of the starting material remaining and 25% of the product detected. The reaction mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 3 / 1, 0 / 1) to provide 6,7-dimethoxy-4-(5-nitroindol-1-yl)quinoline (1.1 g, 29.33% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J=4.75 Hz, 1 H) 8.75 (d, J=2.25 Hz, 1 H) 8.01 - 8.10 (m, 2 H) 7.57 - 7.59 (m, 1 H) 7.54 - 7.57 (m, 1 H)7.32 (d, J=9.13 Hz, 1 H) 7.15 (d, J=2.75 Hz, 1 H) 6.72 (s, 1 H) 3.99 (s, 3 H)3.64 (s, 3 H) 1.95 (s, 4 H). MS(ES+) m / z,[M+H] + [C19H15N3O4+H] + Calculated value: 350.10, Measured value: 349.8 t R = 0.564 min.

[0374] Synthesis of 1-(6,7-dimethoxy-4-quinolinyl)indole-5-amine [intermediate 29]: Fe (399.65 mg, 7.16 mmol, 5.00 equivalent) was added to a mixture of 6,7-dimethoxy-4-(5-nitroindol-1-yl)quinoline (0.50 g, 1.43 mmol, 1.00 equivalent) in EtOH (10 mL) and saturated NH4Cl (2.5 mL) at 75 °C, and the mixture was stirred at 75 °C for 1 h. LCMS showed that the reaction was complete. The residue was poured into Na2CO3 (100 mL) and EtOAc (50 mL) was added. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to provide 1-(6,7-dimethoxy-4-quinolinyl)indol-5-amine (0.4 g, crude) as a brown solid, which was used directly for amide coupling reactions. MS(ES+) m / z, [M+H] + [C19H17N3O2+H] + Calculated value: 320.13, Measured value: 319.8 t R = 0.463 min.

[0375] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)oxy]aniline [intermediate 30]: Synthesis of 5-fluoro-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine NaH (705.16 mg, 17.63 mmol, 60% purity, 1.20 equivalent) was added fractionally to a mixture of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 14.69 mmol, 1.00 equivalent) in THF (40 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, and then 4-methylbenzenesulfonyl chloride (3.08 g, 16.16 mmol, 1.10 equivalent) was added in THF (10 mL). The mixture was stirred at 25 °C for 1 h. LCMS showed that the reaction was complete. The reaction mixture was poured into 80 mL of saturated NH4Cl. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to provide 5-fluoro-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine (3 g crude) as a yellow solid. MS (ES+) m / z, [M+H + [C14 H 11 FN2O2S+H] + Calculated value: 291.05, Measured value: 291.1 t R = 0.522 min.

[0376] Synthesis of 3-bromo-5-fluoro-1-(p-toluenesulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridine-2-ol NBS (1.69 g, 9.47 mmol, 1.10 equivalent) and H2O (1.55 g, 86.11 mmol, 1.55 mL, 10.00 equivalent) were added in a single step to a mixture of 5-fluoro-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine (2.50 g, 8.61 mmol, 1.55 mL, 10.00 equivalent) in acetone (50 mL) at 25 °C under N2. The mixture was stirred at 25 °C for 4 hours. LCMS showed that the reaction was complete. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, 0%–50% ethyl acetate / petroleum ether gradient eluent, at 80 mL / min) to provide 3-bromo-5-fluoro-1-(p-toluenesulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridine-2-ol (2.5 g, 74.97% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.21 (dd, J=2.75, 1.25 Hz, 1 H) 7.96 (d, J=8.38 Hz, 2 H) 7.89 (dd, J=8.00, 2.75 Hz, 1 H) 7.77 (br d, J=5.00 Hz, 1 H) 7.40 (d, J=8.00 Hz, 2 H) 5.98 (br s, 1 H) 5.32 (s, 1 H) 2.36 (s, 3 H). MS(ES+) m / z,[M+H] + [C 14 H 12 BrFN2O3S+H] + Calculated value: 386.97, measured values: 387.1, 389.1.t R = 1.751 min.

[0377] Synthesis of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-toluenesulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridine-2-ol TEA (2.61 g, 25.82 mmol, 3.59 mL, 5.00 equivalent) was added in a single step to a mixture of 3-bromo-5-fluoro-1-(p-toluenesulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridine-2-ol (2.00 g, 5.16 mmol, 1.00 equivalent) in EtOAc (100 mL) under N2 at 0 °C. The mixture was stirred at 25 °C for 10 min, and then 2-fluoro-4-nitrophenol (1.62 g, 10.33 mmol, 2.00 equivalent) was added. The mixture was stirred at 0 °C for 1 h 50 min. Then it was heated to 50 °C and stirred for 2 h. LCMS showed that the reaction was complete. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash column, 0%–100% ethyl acetate / petroleum ether gradient eluent at 120 mL / min) to provide 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-toluenesulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridine-2-ol (2 g, 83.56% yield) as a brown solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.34 (d, J=1.75 Hz, 1H) 8.16 - 8.31 (m, 2 H) 7.94 - 8.02 (m, 1 H) 7.88 - 8.02 (m, 1 H) 7.91 (dd, J=7.69, 4.44 Hz, 2 H) 7.65 (d, J=8.75 Hz, 1 H) 7.38 (d, J=8.25 Hz, 2 H) 5.88 (d, J=7.38 Hz, 1 H) 5.75 (s, 1 H) 2.37 (s, 3 H). MS(ES+) m / z,[M+H] + [C 20 H15 F2N3O6S+H] + Calculated value: 464.06, Measured value: 463.9 t R = 1.286 min.

[0378] Synthesis of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine BF3·Et2O (1.53 g, 10.79 mmol, 1.33 mL, 5.00 equivalent) was added in portions to a mixture of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-toluenesulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridine-2-ol (1.00 g, 2.16 mmol, 1.00 equivalent) in EtOAc (60 mL) under N2 conditions. The mixture was stirred at 80 °C for 2 h. LCMS showed that the reaction was complete. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, 0%–50% ethyl acetate / petroleum ether gradient eluent, at 80 mL / min) to provide 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine (460 mg, 47.86% yield) as a red solid. MS (ES+) m / z, [M+H] + [C 20 H 13 F2N3O5S +H] + Calculated value: 446.05, Measured value: 445.9 t R = 0.663 min.

[0379] Synthesis of 3-fluoro-4-[5-fluoro-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]oxy-aniline Saturated NNH4Cl (2 mL) was added to a mixture of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine (460.00 mg, 1.03 mmol, 1.00 equivalent) in EtOH (8 mL) at 70 °C, followed by the addition of Fe (288.38 mg, 5.16 mmol, 5.00 equivalent). The mixture was stirred at 70 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAC (2 × 20 mL). The filtrate was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether: EtOAC = 2:1) to provide 3-fluoro-4-[5-fluoro-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]oxy-aniline as a brown oil (256 mg, 59.67% yield). MS (ES+) m / z, [M+H] + [C 20 H 15 F2N3O3S +H] + Calculated value: 416.08, Measured value: 415.9 t R = 0.606 min.

[0380] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)oxy]aniline [intermediate 30]: NaOH (57.77 mg, 1.44 mmol, 4.00 equivalent) was added in a single addition to a mixture of 3-fluoro-4-[5-fluoro-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]oxy-aniline (150.00 mg, 361.09 μmol, 1.00 equivalent) in H₂O (0.6 mL) and MeOH (1.8 mL) under N₂. The mixture was stirred at 50 °C for 1 h. LCMS showed that the reaction was complete. The residue was poured into water (50 mL). The aqueous phase was extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was milled with DCM (5 mL) at 25 °C for 0.5 h. The filter cake contained the desired product, 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)oxy]aniline (50 mg, 53.01% yield), as a white solid. MS (ES+) m / z, [M+H] + [C 13 H9F2N3O +H] + Calculated value: 261.07, Measured value: 261.8 t R = 0.461 min.

[0381] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyridin-3-yloxy-aniline [intermediate 31]: Synthesis of pyrazolo[1,5-a]pyridine-3-ol NaOH (1 M, 7.09 mL, 2.22 equivalents) and H₂O₂ (836.73 mg, 7.38 mmol, 709.09 μL, 30% purity, 2.31 equivalents) were added to a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (780.00 mg, 3.20 mmol, 1.00 equivalents) in THF (35 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed no starting material remaining and ~69% of the desired compound was detected. The reaction mixture was poured into ice water (60 mL) and the pH was adjusted to 2 with 6 N HCl. The aqueous phase was extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, 0%~100% ethyl acetate / petroleum ether gradient eluent, at 100 mL / min) to provide pyrazolo[1,5-a]pyridine-3-ol as a yellow oil (150.00 mg, 35.00% yield). 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.83 (s, 1 H) 8.36 (d, J=7.13 Hz, 1 H) 7.56 (s, 1 H) 7.51 (d, J=9.01 Hz, 1 H) 6.92 (ddd, J=8.97,6.53, 0.75 Hz, 1 H) 6.60 - 6.69 (m, 1H). MS(ES+) m / z,[M+H] + [C7H6N2O+H] + Calculated value: 135.05, Measured value: 135.2 t R = 0.215 min.

[0382] Synthesis of 3-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyridine K₂CO₃ (154.56 mg, 1.12 mmol, 1.00 equivalent) was added to a solution of pyrazolo[1,5-a]pyridin-3-ol (150.00 mg, 1.12 mmol, 1.00 equivalent) in DMF (3 mL), and 1,2-difluoro-4-nitrobenzene (177.91 mg, 1.12 mmol, 123.80 μL, 1.00 equivalent) was added. The mixture was stirred at 25 °C for 12 h. LCMS showed no starting material remaining and ~65% of the desired compound was detected. The reaction mixture was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1) to provide 3-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyridine as a yellow solid (170.00 mg, 55.64% yield). 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.71 (d, J=7.00 Hz, 1 H) 8.35 (dd, J=10.88,2.75 Hz, 1 H) 8.20 (s, 1 H) 7.99 - 8.06 (m, 1 H) 7.52 (d, J=9.01 Hz, 1 H)7.21 - 7.29 (m, 1 H) 7.07 (t, J=8.82 Hz, 1 H) 6.92 - 7.01 (m, 1 H). MS(ES+) m / z,[M+H] + [C 13 H8FN3O3+H] + Calculated value: 274.05, Measured value: 274.1 t R = 0.492 min.

[0383] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyridin-3-yloxy-aniline [intermediate 31]: Fe (153.30 mg, 2.75 mmol, 5.00 equivalent) was added to a solution of 3-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyridine (150.00 mg, 549.01 μmol, 1.00 equivalent) in EtOH (2.4 mL) and saturated NH4Cl (0.60 g, 0.6 mL). The mixture was stirred at 80 °C for 1 hour. LCMS showed no starting material remaining and ~89% of the desired compound was detected. The reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (2 × 20 mL). The resulting filtrate was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed successively with water (2 × 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1) to provide 3-fluoro-4-pyrazolo[1,5-a]pyridin-3-yloxyaniline as a yellow oil (120.00 mg, 89.86% yield). 1 H NMR (400 MHz, DMSO- d 6 ): δ8.55 (d, J=7.13 Hz, 1 H) 7.85 (s, 1 H) 7.41 (d, J=9.01 Hz, 1 H) 7.09 - 7.16 (m, 1 H) 6.79 - 6.89 (m, 2 H) 6.46 (dd, J=13.51, 2.50 Hz, 1 H) 6.28 (dt, J=8.69, 1.22 Hz, 1 H) 5.20 (s, 2 H). MS(ES+) m / z,[M+H] + [C 13 H 10 FN3O+H] + Calculated value: 244.08, Measured value: 244.2 t R = 0.330 min.

[0384] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline [intermediate 32]: Synthesis of 2-[(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane NaH (2.34 g, 58.63 mmol, 60% purity, 5.00 equivalent) was added to a solution of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 11.73 mmol, 1.00 equivalent) in DMF (40 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, and then SEM-Cl (2.35 g, 14.07 mmol, 2.49 mL, 1.20 equivalent) was added at 0 °C. The resulting mixture was stirred at 25 °C for 1.5 h. LCMS showed ~95% detection of the desired compound. The reaction mixture was poured into saturated NH4Cl (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with brine (2 × 90 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to provide 2-[(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (3.30 g, 90.75% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO) -d 6 ) δ 8.40 (d, J=2.00 Hz, 1 H) 7.87 (d, J=3.63 Hz, 1 H) 6.62 (d, J=3.63Hz, 1 H) 5.62 (s, 2 H) 3.50 (t, J=8.00 Hz, 2 H) 0.80 (t, J=8.00 Hz, 2 H) -0.12 (s, 9 H). MS(ES+) m / z,[M+H] + [C 13 H 18 ClFN2OSi+H] + Calculated value: 301.09, Measured value: 301.1 t R = 0.669 min.

[0385] Synthesis of 5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-4-ol 2-[(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethylsilane (1.50 g, 4.99 mmol, 1.00 equivalent) was added to a solution of NaOMe (60 mL, 30% solution in MeOH). The mixture was stirred at 95 °C for 12 hours. LCMS showed ~75% detection of the desired compound. The reaction mixture was poured into water (150 mL). The aqueous phase was then adjusted to pH 5-6 with 6 N HCl solution. The aqueous phase was extracted with ethyl acetate (3 × 90 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to provide 5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-4-ol as a white solid (1.00 g, 71.02% yield). 1 H NMR (400 MHz, DMSO -d 6 ) δ 11.20 (br s, 1 H) 8.10 (br d, J=3.50 Hz, 1 H) 7.46 (br d, J=2.88 Hz, 1 H) 6.65 (br d, J=3.25 Hz, 1H) 5.52 (s, 2 H) 3.47 (t, J=8.00 Hz, 2 H) 0.76 - 0.82 (m, 2 H) -0.11 (s, 9H). MS(ES+) m / z,[M+H] + [C 13 H 19 FN2O2Si+H] + Calculated value: 283.12, Measured value: 283.1 t R = 0.459min.

[0386] Synthesis of 2-[[5-fluoro-4-(2-fluoro-4-nitro-phenoxy)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane] To a solution of 5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-ol (1.20 g, 4.25 mmol, 1.00 equivalent) in DMSO (12 mL), K₂CO₃ (2.35 g, 17.00 mmol, 4.00 equivalent) and 1,2-difluoro-4-nitrobenzene (1.28 g, 8.07 mmol, 893.88 μL, 1.90 equivalent) were added. The mixture was stirred at 25 °C for 12 h. LCMS showed ~60% detection of the desired compound. The reaction mixture was poured into water (90 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (2 × 70 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to provide 2-[[5-fluoro-4-(2-fluoro-4-nitro-phenoxy)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (1.50 g, 83.75% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO -d 6 ) δ 8.47 (d,J=3.13 Hz, 1 H) 8.39 (dd, J=10.69, 2.44 Hz, 1 H) 8.08 (br dd, J=9.13, 1.25Hz, 1 H) 7.73 (d, J=3.63 Hz, 1 H) 7.31 (t, J=8.63 Hz, 1 H) 6.20 (d, J=3.50Hz, 1 H) 5.62 (s, 2 H) 3.53 (br t, J=7.94 Hz, 2 H) 0.82 (br t, J=7.94 Hz, 2H) -0.10 (s, 9 H). MS(ES+) m / z,[M+H] + [C 19 H 21 F2N3O4Si+H] + Calculated value: 422.13, Measured value: 422.2 t R = 0.655 min.

[0387] Synthesis of 3-fluoro-4-[5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxy-aniline Fe (927.51 mg, 16.61 mmol, 10.00 equivalent) was added to a solution of 2-[[5-fluoro-4-(2-fluoro-4-nitro-phenoxy)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (700.00 mg, 1.66 mmol, 1.00 equivalent) in EtOH (4 mL) and saturated NH4Cl (2 mL) at 80 °C. The mixture was stirred at 80 °C for 1 hour. LCMS showed ~94% detection of the desired compound. The mixture was filtered under vacuum. The filtrate mixture was poured into water (80 mL). The aqueous phase was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with brine (2 × 90 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to provide 3-fluoro-4-[5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxy-aniline (600.00 mg, crude) as a yellow solid. 1 HNMR (400 MHz, DMSO - d 6 ) δ 8.30 (d, J=3.75 Hz, 1 H) 7.48 (d, J=3.63 Hz, 1 H)7.08 (t, J=9.13 Hz, 1 H) 6.50 (dd, J=13.38, 2.50 Hz, 1 H) 6.42 (dt, J=8.69,1.22 Hz, 1 H) 5.52 - 5.54 (m, 1 H) 5.53 (s, 1 H) 5.48 (s, 2 H) 5.44 (d, J=3.75 Hz, 1 H) 3.47 (t, J=8.00 Hz, 2 H) 0.71 - 0.83 (m, 2 H) -0.13 - -0.10 (m,9 H). MS(ES+) m / z, [M+H] + [C 19 H 23 F2N3O2Si+H] + Calculated value: 392.15, Measured value: 391.6 t R =0.577 min.

[0388] Synthesis of [4-(4-amino-2-fluoro-phenoxy)-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl]methanol 3-fluoro-4-[5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxy-aniline (300.00 mg, 766.31 μmol, 1.00 equivalent) was added to a solution of DCM (5.4 mL) and TFA (1.8 mL). The mixture was stirred at 25 °C for 2 hours. LCMS showed ~76% detection of the desired compound. The reaction mixture was poured into water (40 mL) and the pH was adjusted to 11-12 with saturated Na₂CO₃. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to provide [4-(4-amino-2-fluoro-phenoxy)-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl]methanol (290.00 mg, crude) as a yellow oil. MS(ES+) m / z, [M+H] + [C 14 H 11 F2N3O2+H] + Calculated value: 292.08, Measured value: 292.1 t R =0.350 min.

[0389] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline [intermediate 32]: Add [4-(4-amino-2-fluoro-phenoxy)-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl]methanol (280.00 mg, 663.34 μmol, 1.00 equivalent) to a solution of THF (2 mL) and NaOH (4 M, 1.82 mL, 11.00 equivalent). Stir the mixture at 25 °C for 2 hours. LC-MS showed ~72% detection of the desired compound. Pour the reaction mixture into water (50 mL). Extract the aqueous phase with ethyl acetate (3 × 30 mL). Wash the combined organic phases with brine (2 × 60 mL), dry with anhydrous Na₂SO₄, filter, and concentrate under vacuum to provide 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline (200.00 mg, crude) as a yellow solid. MS (ES+) m / z, [M+H] + [C 13 H9F2N3O+H] + Calculated value: 262.07, Measured value: 262.1 t R= 0.356 min.

[0390] Synthesis of N1-(6,7-dimethoxyquinazoline-4-yl)-2,6-difluoro-phenyl-1,4-diamine [intermediate 33]: Synthesis of N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazolin-4-amine Cs₂CO₃ (2.18 g, 6.68 mmol, 3.00 equivalent) was added to a solution of 4-chloro-6,7-dimethoxy-quinazoline (500.00 mg, 2.23 mmol, 1.00 equivalent) and 2,6-difluoro-4-nitro-aniline (426.27 mg, 2.45 mmol, 1.10 equivalent) in DMF (5 mL). The mixture was stirred at 90 °C for 3 hours. LC-MS showed ~75% detection of the desired compound. The reaction mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazoline-4-amine (750 mg, 78% purity) as a yellow solid, which was further purified by preparative TLC (SiO2, petroleum ether: EtOAc = 1:1) to give N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazoline-4-amine (570.00 mg, 70.69% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO -d 6 ) δ 9.92 (brs, 1 H) 8.42 (br s, 1 H) 8.23 ​​(br d, J=7.25 Hz, 2 H) 7.86 (br s, 1 H) 7.26 (br s, 1 H) 3.95 (br s, 6 H) 2.89 (s, 1 H). MS(ES+) m / z,[M+H] + [C 16 H 12 F2N4O4+H] + Calculated value: 363.08, Measured value: 362.8 t R = 0.520 min.

[0391] Synthesis of N1-(6,7-dimethoxyquinazoline-4-yl)-2,6-difluoro-phenyl-1,4-diamine [intermediate 33]: Fe (462.44 mg, 8.28 mmol, 10.00 equivalent) was added to a solution of N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazoline-4-amine (300.00 mg, 828.07 μmol, 1.00 equivalent) in EtOH (4 mL) and saturated NH4Cl (2 mL). The mixture was stirred at 80 °C for 1 hour. LC-MS showed ~99% detection of the desired compound. The reaction mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to provide N1-(6,7-dimethoxyquinazoline-4-yl)-2,6-difluoro-phenyl-1,4-diamine (270.00 mg, crude) as a white solid. 1 H NMR (400 MHz, DMSO) -d 6 ) δ 9.02 (s, 1 H) 8.28 (s, 1 H) 7.78 (s, 1 H) 7.16 (s, 1 H)6.31 (d, J=10.38 Hz, 2 H) 5.73 (s, 2 H) 3.92 (d, J=3.00 Hz, 6 H) 1.99 (s, 4H). MS(ES+) m / z,[M+H] + [C 16 H 14 F2N4O2+H] + Calculated value: 333.11, Measured value: 332.9 t R = 0.442min.

[0392] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenyl)thioalkyl-6,7-dimethoxy-quinoline [intermediate 34]: NaH (98.81 mg, 2.47 mmol, 60% purity, 1.10 equivalents) was added to DMSO (10 mL) at 25 °C, and the reaction mixture was stirred at 25 °C for 10 min. Then, 4-amino-2-fluorophenol (314.04 mg, 2.47 mmol, 1.10 equivalents) was added, and the mixture was stirred for 10 min. Next, 4-chloro-7,8-dihydro-[1,4]dioxane-[2,3-g]quinazoline (0.50 g, 2.25 mmol, 1.00 equivalents) was added, and the mixture was then stirred at 25 °C for 1 h. LCMS showed the reaction was complete. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to provide 3-fluoro-4-(2-fluoro-4-nitro-phenyl)thioalkyl-6,7-dimethoxy-quinoline (0.53 g, crude) as a brown solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.50 (s, 1 H)7.63 (s, 1 H) 7.37 (s, 1 H) 7.02 (t, J=8.82 Hz, 1 H) 6.38 - 6.52 (m, 2 H)5.40 (s, 2 H) 4.43 (br dd, J=12.88, 5.13 Hz, 4 H). MS(ES+) m / z,[M+H] + [C16H12FN3O3 +H] + Calculated value: 314.09, measured value: 314.0, t R = 1.038 min.

[0393] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)thioalkyl]aniline [intermediate 35]: Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenyl)thioalkyl-6,7-dimethoxy-quinoline 2-fluoro-4-nitro-benzenethiol (107.49 mg, 620.74 μmol, 1.50 equivalent) was added to a solution of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (0.10 g, 413.83 μmol, 1.00 equivalent) in chlorobenzene (4.00 mL), and the mixture was then stirred at 130 °C under N2 for 16 h. LCMS showed very little of the starting material remaining and ~70% of the desired compound was detected. The mixture was concentrated to remove chlorobenzene. 4 mL of MeOH was added to the residue and the mixture was stirred for 1 h. The precipitated solid was collected by filtration. The filter cake was collected and dried under vacuum to provide 3-fluoro-4-(2-fluoro-4-nitro-phenyl)thioalkyl-6,7-dimethoxy-quinoline (0.11 g, 63.23% yield) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6 ): δ 8.90 (s, 1 H) 8.24 (dd, J=9.88, 2.38 Hz, 1 H) 7.92 (dd, J=8.76, 2.13 Hz, 1 H) 7.55 (s, 1 H) 7.42 (s, 1 H) 7.12 (t, J=8.25 Hz, 1 H) 3.96 (s, 3 H) 3.85 (s, 3 H). MS(ES+) m / z,[M+H] + [C17H12F2N2O4S +H] + Calculated value: 379.05, measured value: 378.9, t R = 1.367 min.

[0394] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)thioalkyl]aniline [intermediate 35]: Fe (81.18 mg, 1.45 mmol, 5.00 equivalent) was added in portions to a mixture of 3-fluoro-4-(2-fluoro-4-nitro-phenyl)thioalkyl-6,7-dimethoxy-quinoline (0.11 g, 290.74 μmol, 1.00 equivalent) in EtOH (4.50 mL) and saturated NH4Cl (1.50 mL) at 70 °C, and the mixture was then stirred at 70 °C for 1 hour. LCMS showed that the reaction was complete. The mixture was filtered through diatomaceous earth and washed with EtOAc (50 mL). The filtrate was diluted with H2O (20 mL), the organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 15 mL). The organic layer was washed with brine (20 mL) and dried over Na2SO4 to provide 0.075 g of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolinyl)thioalkyl]aniline as a yellow solid. MS (ES+) m / z, [M+H] + [C17H14F2N2O2S+H] + Calculated value: 349.07, measured value: 348.9, t R = 1.201 min Synthesis of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline [intermediate 36]: Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine K₂CO₃ (8.24 g, 59.64 mmol, 4.00 equivalent) was added to a mixture of 1H-pyrrolo[2,3-b]pyridin-4-ol (2.00 g, 14.91 mmol, 1.00 equivalent) and 1,2-difluoro-4-nitrobenzene (2.61 g, 16.40 mmol, 1.82 mL, 1.10 equivalent) in DMSO (20 mL) at 25 °C, and the mixture was stirred at 25 °C for 1 h. TLC (petroleum ether:EtOAc = 1:1, SM₂ / R) was performed. f =0.41, TM / R f=0.27) indicates the reaction is complete. The residue was poured into H2O (100 mL). A large amount of solids formed, which were then filtered and collected. The aqueous phase was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with brine (3 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The solids were washed with MeOH (2 × 10 mL) and concentrated under vacuum to provide 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine (1 g, 24.36% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6): δ 11.05 -12.69 (m, 1 H) 8.41 (dd, J =10.57, 2.69 Hz, 1 H) 8.20 (d, J =5.38 Hz, 1 H) 8.09- 8.15 (m, 1 H) 7.36 - 7.49 (m, 2 H) 6.72 (d, J =5.38 Hz, 1 H) 6.24 (d, J =3.50Hz, 1H). MS(ES+) m / z,[M+H] + [C13H8FN3O3+H] + Calculated value: 274.05, Measured value: 274.0 t R =1.155 min.

[0395] Synthesis of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline [Intermediate 36] Fe (1.02 g, 18.30 mmol, 5.00 equivalent) was added to a mixture of 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 3.66 mmol, 1.00 equivalent) in EtOH (10 mL) and saturated NH4Cl (2.5 mL) at 75 °C, and the mixture was stirred at 75 °C for 1 h. TLC (petroleum ether: EtOAC = 2:1, SM2 / R) f =0.42, TM / R f=0.28) indicates the reaction is complete. The reaction mixture was poured into saturated Na2CO3 (100 mL) and EtOAc (50 mL) was added. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to provide 0.8 g of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.68 (brs, 1 H) 8.02 (d, J=5.50 Hz, 1 H) 7.26 - 7.35 (m, 1 H) 7.02 (t, J=9.01 Hz, 1H) 6.51 (dd, J=13.20, 2.44 Hz, 1 H) 6.43 (dd, J=8.69, 2.19 Hz, 1 H) 6.26 -6.32 (m, 1 H) 6.19 - 6.25 (m, 1 H) 5.31 - 5.49 (m, 2 H).

[0396] Synthesis of 4-(4-amino-2-fluoro-phenoxy)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one [intermediate 37]: Synthesis of 3,3-dibromo-4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridin-2-one BLAH; pyridine-1-onium (2.05 g, 6.41 mmol, 3.50 equivalent) was added to a solution of 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine (500.00 mg, 1.83 mmol, 1.00 equivalent) in t-BuOH (32.5 mL). The mixture was stirred at 25 °C for 12 hours. TLC (petroleum ether: EtOAc = 1:1, S M / R f =0.44, T M / R f=0.57) indicates that the starting material has been completely consumed and a new spot has formed. Pour the reaction mixture into H2O (50 mL). Extract the aqueous phase with ethyl acetate (3 × 25 mL). Wash the combined organic phases with brine (20 mL), dry with anhydrous Na2SO4, filter and concentrate under vacuum. Grind the crude product with DCM:MeOH = 10:1 (10 mL) at 25 °C for 20 min, filter to provide 3,3-dibromo-4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridin-2-one (450 mg, 55.01% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 12.19 (s, 1 H) 8.48 (dd, J=10.38, 2.63 Hz, 1 H) 8.14 - 8.27 (m, 2 H) 7.70 (t, J=8.50 Hz, 1 H)6.69 (d, J=6.13 Hz, 1 H).

[0397] Synthesis of 4-(4-amino-2-fluoro-phenoxy)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one [intermediate 37]: Pd / C (1 g, 939.67 μmol, 10% purity, 2.10 equivalents) was added to a solution of 3,3-dibromo-4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridin-2-one (200.00 mg, 447.42 μmol, 1.00 equivalents) in MeOH (15 mL). The mixture was stirred at 25 °C under H2 for 1 h. LCMS showed the consumption of starting material and detected ~57% of the desired compound. The reaction solution was filtered through diatomaceous earth. The diatomaceous earth pad was washed with MeOH (100 mL) and concentrated under vacuum to give the crude product. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1) to provide 4-(4-amino-2-fluoro-phenoxy)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (25 mg, 21.55% yield) as a yellow solid. 1 H NMR (400 MHz, methanol-) d 4): δ 7.92 (d, J=6.13 Hz, 1 H)6.97 (t, J=8.82 Hz, 1 H) 6.56 (dd, J=12.63, 2.50 Hz, 1 H) 6.49 - 6.53 (m, 1H) 6.41 (d, J=6.25 Hz, 1 H) 3.42 (s, 2 H). MS(ES+) m / z,[M+H] + [C 13 H 10 FN3O2+H] + Calculated value: 260.08, Measured value: 260.0 t R = 0.837 min.

[0398] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyrazin-4-yloxy-aniline [intermediate 38]: Synthesis of 4-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyrazine To a solution of 4-chloropyrazolo[1,5-a]pyrazine (200.00 mg, 1.30 mmol, 1.00 equivalent) in chlorobenzene (2 mL), 2-fluoro-4-nitro-phenol (204.60 mg, 1.30 mmol, 1.00 equivalent) was added. The mixture was stirred at 140 °C for 8 hours. LCMS showed the reaction was complete. The reaction mixture was poured into H2O (50 mL), and the aqueous phase was extracted with EtOAC (3 × 20 mL). The combined organic phases were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether: EtOAC = 4:1) to provide 4-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyrazine (100 mg, 28.00% yield) as a yellow solid. MS(ES+) m / z, [M+H] + [C 12 H7FO3N4+H] + Calculated value: 275.05, measured value: 274.6, t R = 0.534 min.

[0399] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyrazin-4-yloxy-aniline [intermediate 38]: Saturated NH4Cl (0.5 mL) was added to a mixture of 4-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyrazine (100.00 mg, 364.69 μmol, 1.00 equivalent) in EtOH (2 mL) at 80 °C, followed by the addition of Fe (101.84 mg, 1.82 mmol, 5.00 equivalent). The mixture was stirred at 80 °C for 1 h. LCMS showed no starting material remaining and 90% of the product was detected. The reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (2 × 50 mL). The reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (2 × 50 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to provide 3-fluoro-4-pyrazolo[1,5-a]pyrazin-4-yloxy-aniline (100.00 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.49 (dd, J=4.75, 0.63 Hz, 1 H) 8.17 (d, J=2.25 Hz, 1 H) 7.35 (d,J=4.75 Hz, 1 H) 7.07 (d, J=1.63 Hz, 1 H) 7.03 (t, J=8.88 Hz, 1 H) 6.49 (dd, J=13.07, 2.44 Hz, 1 H) 6.41 (dd, J=8.63, 1.88 Hz, 1 H) 5.40 (s, 2 H). MS(ES+)m / z,[M+H] + [C 12 H9FN4O+H] + Calculated value: 245.07, measured value: 244.9, t R = 0.534 min.

[0400] Partial B synthesis: Synthesis of 6-cyclopropyl-1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxylic acid [intermediate 7]: Synthesis of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one

[34] : Cyclopropylformyl chloride (13 mL, 143 mmol, 1.00 equivalent) and aluminum chloride (22.95 g, 172 mmol, 1.20 equivalent) were added to a stirred solution of trimethyl(2-trimethylsilylethynyl)silane (31 mL, 143 mmol, 1.00 equivalent) in DCM (300 mL, 0.4783 M) at 0 °C, and stirring was continued for 2 h. Stirring was continued for another 6 h, and then the reaction mixture was poured into a solution of 10% HCl (300 mL) in ice water and stirred for another 20 min. After separation of the two phases, the aqueous phase was extracted with DCM (3 × 200 mL) and separated. The combined organic layers were evaporated under reduced pressure to provide 22 g of the title compound in 92.19% yield as a brown oily product, which was used directly in the next reaction. 1 H NMR (400 MHz, DMSO-) d 6): δ 2.10 - 2.01 (m, 1H), 1.14 - 1.04 (m, 4H), 0.23 (s, 9H); MS(ES) + m / z, [M+H] + [C9H 14 OSi+H] + Calculated value: 167.29, Measured value: 167.0 t R = 2.07 min, [method N].

[0401] Synthesis of (E)-1-cyclopropyl-3-methoxy-prop-2-en-1-one

[35] : At rt, 1,4-diazabicyclo[2.2.2]octane (22.26 g, 198 mmol, 1.50 equivalent) was slowly added to a stirred solution of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one (22.00 g, 132 mmol, 1.00 equivalent) in methanol (300 mL, 0.441 M), and the resulting reaction mixture was stirred at room temperature for 5 h and concentrated. The crude product was diluted with ethyl acetate (300 mL), washed with saturated brine (2 × 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was further purified by elution with a YMC 80 g column using a combi flash with 0%–20% ethyl acetate / heptane to provide 7 g of the title compound as a brown liquid in 36.81% yield. 1 H NMR (400 MHz, DMSO-d 6): δ 7.75 (d, J = 12.7 Hz, 1H), 5.78 (d, J = 12.7 Hz, 1H), 3.72 (s, 3H), 2.21 - 2.10 (m, 1H), 0.85 - 0.79 (m,4H); MS(ES) + m / z, [M+H] + [C7H 10 O2+H] + Calculated value: 127.07, Measured value: 127.0 t R = 1.43 min, [method N].

[0402] Synthesis of ethyl 3-(4-fluoroaniline)-3-oxo-propionate

[36] : A stirred solution of 4-fluoroaniline (4.4 mL, 45.0 mmol, 1.00 equivalent) in THF (50 mL, 0.8999 M) and triethylamine (19 mL, 135 mmol, 3.00 equivalent) was cooled to 0 °C, and ethyl 3-chloro-3-oxo-propionate (8.1 mL, 54.0 mmol, 1.20 equivalent) was added. The mixture was stirred at rt for 2 hours. The resulting mixture was then filtered and washed with heptane (50 mL) to obtain a crude product, which was purified by combi flash using a YMC 40 g column eluting with 0%–70% ethyl acetate / heptane to provide 5.5 g of the title compound as a pale yellow solid in 42.12% yield. 1 H NMR (400 MHz, DMSO- d 6): δ 10.21 (br s, 1H), 7.61 - 7.55 (m, 2H), 7.20- 7.11 (m, 2H), 4.15 - 4.08 (m, 2H), 3.44 (s, 2H), 1.20 (t, J = 7.0 Hz, 3H); MS(ES) + m / z, [M+H] + [C 11 H 12 FNO3+H] + Calculated value: 226.05, Measured value: 226.0 t R = 1.62 min, [method N].

[0403] Synthesis of 6-cyclopropyl-1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxylic acid [intermediate 7]: At rt, add ( E 1-Cyclopropyl-3-methoxy-prop-2-en-1-one (1.512 g, 12.0 mmol, 1.50 equivalent) and 20% sodium ethoxide in ethanol (9.3 mL, 24.0 mmol, 3.00 equivalent). The reaction mixture was stirred at 90 °C for 16 h, and the mixture was concentrated to dryness and diluted with water (10 mL), and then cooled to 0 °C and the pH was adjusted to 1–2 using 2 N HCl (5 mL). The reaction mixture was extracted with EtOAc (100 mL), and the combined organic layers were washed with water (20 mL) and saturated brine (20 mL). The combined organic layers were then separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by combi flash using a YMC 24 g column eluted with 0%–70% ethyl acetate / heptane to provide 550 mg of the title compound as a pale yellow solid in 24.92% yield. 1 H NMR (400 MHz, DMSO- d 6): δ 14.21 (br s, 1H), 8.36 (d, J = 7.8Hz, 1H), 7.59 - 7.53 (m, 2H), 7.47 - 7.41 (m, 2H), 6.53 (d, J = 7.8 Hz, 1H),1.40 - 1.32 (m, 1H), 0.99 - 0.91 (m, 2H), 0.90 - 0.83 (m, 2H), MS(ES) + m / z, [M+H] + [C 15 H 12 FNO3+H] + Calculated value: 274.08, Measured value: 274.0 t R = 1.16 min, [method N].

[0404] Synthesis of 1-(4-methoxy-2-methylphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid [a mixture of intermediates 8A and 8B]: Synthesis of ethyl 3-(4-methoxy-2-methyl-aniline)-3-oxo-propionate

[38] : A stirred solution of 4-methoxy-2-methyl-aniline hydrochloride (17 mL, 115 mmol, 1.00 equivalent) in THF (250 mL, 0.4607 M) was cooled to 0 °C, and then triethylamine (48 mL, 346 mmol, 3.00 equivalent) was added and stirred at 0 °C for 10 min. Ethyl 3-chloro-3-oxo-propionate (22 mL, 173 mmol, 1.50 equivalent) was then added at 0 °C, and the resulting reaction mixture was stirred at rt for 1 h. The mixture was diluted with 100 mL of Na₂CO₃ solution and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with 100 mL of brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a 10%–15% ethyl acetate-hexane gradient to provide 17.00 g of the title compound as a pale brown solid in 53.15% yield. MS (ES) + m / z, [M+H] + [C 13 H 17 NO4+H] + Calculated value: 252.01, Measured value: 262.1 t R = 1.639 min, [method N].

[0405] ( E Synthesis of ethyl 6,6,6-trifluoro-2-[(4-methoxy-2-methyl-phenyl)carbamoyl]-5-oxo-hex-3-enoate

[40] : Ethyl 3-(4-methoxy-2-methyl-aniline)-3-oxo-propionate (2.00 g, 7.16 mmol, 1.00 equivalent) and cesium carbonate (3.27 g, 10.0 mmol, 1.40 equivalent) were added dropwise to a stirred solution of 3-(4-methoxy-2-methyl-aniline)-3-oxo-propionate (20 mL, 0.3582 M) in MeCN (20 mL, 0.3582 M). E1,4-ethoxy-1,1,1-trifluorobut-3-en-2-one (1.2 mL, 8.60 mmol, 1.20 equivalents) was prepared, and the reaction mixture was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure to provide 2.00 g of the title compound as a brown solid in 53.85% yield. (No further purification was performed.) MS (ES) + ) m / z, [M+H] + [C 17 H 18 F3NO5+H] + Calculated value: 373.0, Measured value: 372.0 t R = 1.825 min and t R = 1.92 min, [method N].

[0406] Synthesis of 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [a mixture of intermediates 8A and 8B]: Will( E Ethyl 6,6,6-trifluoro-2-[(4-methoxy-2-methyl-phenyl)carbamoyl]-5-oxo-hex-3-enoate (8.00 g, 17.1 mmol, 1.00 equivalent) in trifluoroethanol (80 mL, 1113 mmol, 64.9 equivalent) and triethylamine (7.2 mL, 51.4 mmol, 3.00 equivalent) under stirring was heated at 90 °C for 16 h. After the starting material was consumed, the reaction was concentrated under reduced pressure to obtain a crude residue. The crude residue was dissolved in water and washed with ethyl acetate, and the aqueous layer was acidified to pH 2–3 with 2 N HCl and extracted and separated with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to provide 1.60 g of the title compound as a pale brown solid in 27.95% yield. 1 H NMR (400 MHz, DMSO- d 6): δ 13.65 (s, 1H), 8.44 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 3.0 Hz, 1H), 6.91 (dd, J= 2.8,8.8 Hz, 1H), 3.81 (s, 3H), 1.98 (s, 3H); MS(ES) + m / z, [M+H] + [C 15 H 12 F3NO4+H] + Calculated value: 328.01, Measured value: 327.9 t R = 1.917 min, [method N].

[0407] Purification of 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [a mixture of intermediates 8A and 8B]: A mixture of intermediates 8A and 8B (1.66 g) was separated by a chiral SFC (instrument name: Waters-2767, prep-SFC 100) method to provide a yield of 670 mg of title compound 8A as a brown solid. SFC purification method: Number of injections: 30 injections (50 mg / injection), Column: Chiral pack IC (30 × 250 mm, 5 μm), Mobile phase A: hexane containing 0.10% TFA, Mobile phase B: ethanol:methanol (1:1), Eluent A:B: 80-20, Total flow rate (mL / min): 46, Diluent: MP+DCM-MEOH, Mobile phase detection: 330 nm.

[0408] 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [intermediate 8A]: Chiral separation yielded 670 mg of pure intermediate 8A. 1 H NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 2.8, 8.8 Hz, 1H), 3.81 (s, 3H), 1.98 (s, 3H); MS(ES + ) m / z, [M+H] + [C 15 H 12 F3NO4+H] + Calculated value: 328.1, Measured value: 327.9t R = 4.35 min, [Method W]. Chiral HPLC purity: 99.67%, t R =9.86 min, ee = 99.40%. Specific rotation (SOR): 127.68, method: light source WI, monitor wavelength: 589 nm, DIT: 5 seconds, number of cycles: 5, cycle interval: 5 seconds, temperature monitor: stand, temperature correction factor: none, pore size (S): 8.0 mm, pore size (L): automatic mode, specific OR path length: 50 mm, concentration: 0.05 w / v.

[0409] 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [intermediate 8B]: Chiral separation yielded 760 mg of intermediate 8B. 1 H NMR (400 MHz, DMSO- d 6): δ 8.44 (d, J =7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 2.8 Hz, 1H), 6.91 (dd, J = 2.8, 8.8 Hz, 1H), 3.81 (s, 3H), 1.98 (s, 3H); MS(ES + ) m / z, [M+H] + [C 15 H 12 F3NO4+H] + Calculated value: 328.1, Measured value: 328.2 t R = 3.50 min, [Method V]. Chiral HPLC purity: 97.27%. t R =11.37, ee = 94.54%. Specific rotation (SOR): -91.32, Method: Light source WI, Monitor wavelength: 589 nm, DIT: 5 seconds, Number of cycles: 5, Cycle interval: 5 seconds, Temperature monitor: Stand, Temperature correction factor: None, Aperture (S): 8.0 mm, Aperture (L): Auto mode, Specific OR path length: 50 mm, Concentration: 0.05 w / v.

[0410] Synthesis of 1-(4-fluorophenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [intermediate 9]: Synthesis of ethyl 3-(4-fluoroaniline)-3-oxo-propionate

[36] : A stirred solution of 4-fluoroaniline (43 mL, 450 mmol, 1.00 equivalent) in THF (550 mL, 0.8181 M) was cooled to 0 °C, and triethylamine (188 mL, 1350 mmol, 3.00 equivalent) was added. The mixture was stirred at 0 °C for 10 min, followed by the addition of ethyl 3-chloro-3-oxo-propionate (69 mL, 540 mmol, 1.20 equivalent). The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate and separated. The combined organic layers were washed with aqueous brine and separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a 10%–15% ethyl acetate-hexane gradient to provide 23.00 g of the title compound as a pale yellow solid in 15.66% yield. MS (ES) + m / z, [M+H] + [C 11 H 12 FNO3+H] + Calculated value: 226.22, Measured value: 226.0 t R = 1.66 min, [method N].

[0411] Synthesis of 1-(4-fluorophenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [intermediate 9]: At rt, to a stirred solution of ethyl 3-(4-fluoroaniline)-3-oxo-propionate (12.00 g, 36.8 mmol, 1.00 equivalent) in ethanol (120 mL, 0.3064 M), add ( E4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (7.9 mL, 55.1 mmol, 1.50 equivalent) was added, followed by the addition of 20% sodium ethoxide (43 mL, 110 mmol, 3.00 equivalent), and the reaction mixture was then stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 2–3 using 2 NHCl, followed by extraction with ethyl acetate (2 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was then recrystallized from 2-propanol (2 × 50 mL) to provide 4.10 g of the title compound as a grayish-white solid in 35.44% yield. 1 H NMR (400 MHz, DMSO- d 6):δ 13.60 (br s, 1H), 8.41 (d, J = 7.5 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.45 -7.37 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H); MS(ES) + m / z, [M+H] + [C 13 H7F4NO3+H] + Calculated value: 302.04, Measured value: 301.9 t R = 1.84 min, [method N].

[0412] Synthesis of 1-(2-chloro-4-fluorophenyl)-6-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid [a mixture of intermediates 10A and 10B]: Synthesis of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one

[34] : A stirred solution of trimethyl(2-trimethylsilylethynyl)silane (62 mL, 287 mmol, 1.20 equivalent) in DCM (500 mL, 0.4783 M) was cooled to 0 °C, and cyclopropionic acid chloride (22 mL, 239 mmol, 1.00 equivalent) and aluminum chloride (38.26 g, 287 mmol, 1.20 equivalent) were added and stirred at 0 °C for 2 h. The temperature was then allowed to rise to rt, and stirring was continued for another 16 h. The reaction mixture was poured into a solution of 10% hydrochloric acid in ice water (300 mL) and stirred for 20 min. The aqueous phase was extracted with dichloromethane (2 × 200 mL) and separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 35 g of the title compound as a brown oil in 83.86% yield. MS (ES) + m / z, [M+H] + [C9H 14 OSi+H] + Calculated value: 167.29, Measured value: 167.0 t R = 2.08min, [method N].

[0413] ( E Synthesis of 1-cyclopropyl-3-methoxy-prop-2-en-1-one

[35] : At rt, 1,4-diazabicyclo[2.2.2]octane (35.41 g, 316 mmol, 1.50 equivalent) was slowly added to a stirred solution of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one (35.00 g, 210 mmol, 1.00 equivalent) in methanol (350 mL, 0.6014 M) and stirred at rt for 16 h. After completion, the reaction mixture was concentrated and diluted with ethyl acetate (300 mL), washed with saturated brine (2 × 100 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude compound was purified by combi flash using a YMC 80 g column eluted with 0%–20% ethyl acetate / heptane to provide 16.00 g of the title compound as a brown liquid in 57.00% yield. 1 H NMR (400MHz, DMSO- d 6): δ 7.59 (d, J = 12.6 Hz, 1H), 5.62 (d, J= 12.6 Hz, 1H), 3.56(s, 3H), 2.03 - 1.96 (m, 1H), 0.69 - 0.63 (m, 4H); MS(ES) + m / z, [M+H] + [C7H 10 O2+H] + Calculated value: 127.07, Measured value: 127.0 t R = 1.46 min, [method N].

[0414] Synthesis of ethyl 3-(2-chloro-4-fluoro-aniline)-3-oxo-propionate

[41] : A stirred solution of 2-chloro-4-fluoroaniline (15 mL, 124 mmol, 1.00 equivalent) in THF (150 mL, 0.8244 M) was cooled to 0 °C, and then triethylamine (52 mL, 371 mmol, 3.00 equivalent) was added and stirred at 0 °C for 10 min. Ethyl 3-chloro-3-oxopropionate (24 mL, 185 mmol, 1.50 equivalent) was then added at 0 °C, and the resulting reaction mixture was stirred at rt for 1 h. After the reaction was complete, the mixture was diluted with a solution of Na₂CO₃ (100 mL) and extracted with ethyl acetate (2 × 100 L). The combined organic layers were washed with brine (100 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography with elution of 5%–10% ethyl acetate-hexane to provide 15.00 g of the title compound as a pale yellow solid in 43.68% yield. 1 HNMR (400 MHz, DMSO- d 6): δ 9.83 (s, 1H), 7.73 (dd, J = 5.5, 9.0 Hz, 1H), 7.51(dd, J = 3.0, 8.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 4.17 - 4.07 (m, 2H), 3.54 (s,2H), 1.21 (t, J = 7.3 Hz, 3H); MS(ES) + m / z, [M+H] + [C 11 H 11 ClFNO3] +Calculated value: 259.6, Measured value: 259.9 t R = 1.80 min, [method N].

[0415] Synthesis of 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 10A and 10B]: At rt, ethyl 3-(2-chloro-4-fluoro-aniline)-3-oxo-propionate (13.00 g, 50.1 mmol, 1.00 equivalent) was added to a stirred solution of ethanol (130 mL, 0.3851 M). E 1-Cyclopropyl-3-methoxy-prop-2-en-1-one (9.47 g, 75.1 mmol, 1.50 equivalent) and 20% sodium ethoxide in ethanol (97 mL, 250 mmol, 5.00 equivalent) were added, and the reaction mixture was stirred at 50 °C for 48 h. The reaction mixture was cooled to 0 °C and acidified to pH 1-2 with 2 N HCl (100 mL). The resulting precipitate was filtered, washed with water (20 mL), and then dried under reduced pressure to obtain a crude product. The crude compound was washed with IPA (2 × 30 mL) to provide a mixture of intermediates 10A and 10B as off-white solids in a yield of 8.50 g, 52.04%. 1 H NMR (400 MHz, DMSO-d6): δ 13.83 (s,1H), 8.41 (d, J = 7.5 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.81 - 7.78 (m, 1H), 7.54- 7.49 (m, J = 8.5, 8.5 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 1.38 - 1.30 (m,1H), 0.95 - 0.85 (m, 4H); MS (ES) + m / z, [M+H] + [C 15 H 11 ClFNO3+H] + Calculated value: 308.04, Measured value: 307.9 t R = 4.20 min, [method W].

[0416] Purification of 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 10A and 10B]: A mixture of intermediates 10A and 10B (8.5 g) was separated by a chiral SFC (instrument name: Waters-2767, prep-SFC 100) method to provide 2.95 g of intermediate 10A as a grayish-white solid and 3.1 g of intermediate 10B. SFC purification method: Number of injections: 85 injections (100 mg / injection); Column: Chiral pack IC (30 × 250 mm, 5 μm); Mobile phase A: n-hexane; Mobile phase B: ETOH:MEOH (1:1); Eluent A:B: 50-50; Total flow rate (mL / min): 45; Diluent DCM:MEOH (1:1); Detection: 330 nm.

[0417] 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [intermediate 10A]: 1 H NMR (400MHz, DMSO- d 6): δ 8.41 (d, J = 8.0 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.55 - 7.49(m, J = 8.5, 8.5 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 1.40 - 1.28 (m, 1H), 0.97- 0.85 (m, 4H); MS(ES + ) m / z, [M+H] + [C 15 H 11 ClFNO3+H] + Calculated value: 308.81, Measured value: 307.9 t R = 4.20, [Method O]. Chiral HPLC purity: 99.51%. t R= 10.96 min, ee = 99.02%. Specific rotation (SOR): 156.96, method: light source WI, monitor wavelength: 589 nm, DIT: 5 seconds, number of cycles: 5, cycle interval: 5 seconds, temperature monitor: stand, temperature correction factor: none, pore size (S): 8.0 mm, pore size (L): automatic mode, specific OR path length: 50 mm, concentration: 0.05 w / v.

[0418] 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [intermediate 10B]: 1 H NMR (400MHz, DMSO- d 6): δ 8.41 (d, J = 8.0 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.55 - 7.49(m, J = 8.6, 8.6 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 1.38 - 1.29 (m, 1H), 0.98- 0.83 (m, 4H); MS(ES + ) m / z, [M+H] + [C 15 H 11 ClFNO3+H] + Calculated value: 308.04, Measured value: 307.9 t R = 4.20 min, [Method O]. Chiral HPLC purity: 99.95%. t R = 14.721 min, ee = 99.90%. Specific rotation (SOR): -136.800, method: source WI, monitor wavelength: 589 nm, DIT: 5 seconds, number of cycles: 5, cycle interval: 5 seconds, temperature monitor: stand, temperature correction factor: none, pore size (S): 8.0 mm, pore size (L): automatic mode, SpecificO.R. path length: 50 mm, concentration: 0.05 w / v.

[0419] Synthesis of 6-cyclopropyl-1-(4,5-difluoro-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [a mixture of intermediates 11A and 11B]: Synthesis of ethyl 3-(4,5-difluoro-2-methyl-aniline)-3-oxo-propionate

[43] : A stirred solution of 4,5-difluoro-2-methylaniline (4.4 mL, 34.9 mmol, 1.00 equivalent) in THF (50 mL, 0.6986 M) was cooled to 0 °C and triethylamine (15 mL, 105 mmol, 3.00 equivalent) was added, followed by ethyl 3-chloro-3-oxopropionate (6.3 mL, 41.9 mmol, 1.20 equivalent). The reaction mixture was allowed to heat to rt and stirred for 2 h. The resulting mixture was poured into ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (100 mL) and water (2 × 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude compound was purified by elution with a YMC 40 g column using a Combi flash with 0%–70% ethyl acetate / heptane to give a pure product, which was further washed with diethyl ether (50 mL) to provide 5.00 g of the title compound as an off-white solid in 55.38% yield. 1 H NMR (400 MHz, chloroform-) d ): δ 9.43 (br s, 1H), 7.98 (dd, J = 7.9, 12.0Hz, 1H), 7.01 - 6.92 (m, 1H), 4.32 - 4.22 (m, 2H), 3.49 (s, 2H), 2.27 (s,3H), 1.33 (t, J = 7.0 Hz, 3H); MS(ES) + m / z, [M+H] + [C 12 H 13 F2NO3+H] + Calculated value: 258.15.05, Measured value: 257.9 t R = 1.62 min, [method N].

[0420] Synthesis of 6-cyclopropyl-1-(4,5-difluoro-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 11A and 11B]: In rt, towards ( EEthyl 3-(4,5-difluoro-2-methyl-aniline)-3-oxo-propionate (4.00 g, 15.5 mmol, 1.00 equivalent) and 20% sodium ethoxide in ethanol (40 mL, 2.2214 M) were added to a stirred solution, followed by heating to 90 °C and maintaining the temperature at 90 °C for 72 h. The reaction mixture was allowed to cool to rt, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was dissolved in water (100 mL), and the aqueous layer was washed with diethyl ether (3 × 20 mL). The combined organic layers were washed with water (10 mL), and the combined aqueous layers were acidified to pH 1–2 using 1 N HCl solution (25 mL). The product was extracted with ethyl acetate (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by combi-flash column chromatography using a 40 g SEPA-flash column and eluting in heptane containing 75% ethyl acetate to give a pure product as a yellow solid. This pure product was washed with acetonitrile (10 mL) to provide a mixture of intermediates 11A and 11B as a yellow solid, in a yield of 3.30 g (68.36%). MS (ES) + m / z, [M+H] + [C 16 H 13 F2NO3+H] + Calculated value: 306.18, Measured value: 306.0 t R = 1.80 min, [method N].

[0421] Purification of 6-cyclopropyl-1-(4,5-difluoro-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 11A and 11B]: A mixture of 3.3 g of intermediates 11A and 11B was separated by a preparative normal-phase chiral purification method, SFC. The SFC purification method was as follows: number of injections: 40 injections (25 mg / injection); column: chiralpak IK (30 × 250 mm, 5 μm); mobile phase A: EtOH:MeOH (1:1); mobile phase B: ACN; eluent A: B-80-20; total flow rate (mL / min): 42; diluent: MP; detection: 335 nm; properties: off-white solid, providing 1.10 g of intermediate 11A as an off-white solid and 1.2 g of intermediate 11B as an off-white solid.

[0422] 6-Cyclopropyl-1-(4,5-Difluoro-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 11A]: 1 HNMR (400 MHz, DMSO- d 6): δ 13.99 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 7.8, 11.0 Hz, 1H), 7.64 (dd, J = 8.6, 11.4 Hz, 1H), 6.54 (d, J = 7.8 Hz,1H), 2.00 (s, 3H), 1.40 - 1.30 (m, 1H), 1.02 - 0.87 (m, 4H); MS (ES + ) m / z, [M+H] + [C 16 H 13 F2NO3+H] + Calculated value: 306.09, Measured value: 305.9 t R= 4.23 min, [Method W]. Chiral HPLC: ee: 100%, Method file: Chiral_met-VIB_B 1mL.lcm, Column: CHIRALPAK IK (250 × 4.6 mm, 5 µm), Mobile phase A: EtOH:MeOH, Mobile phase B: ACN, A / B: 80:20, Flow rate: 1.5 mL / min. Specific rotation (SOR): 64.08, Method: Source WI, Monitor wavelength: 589 nm, DIT: 5 seconds, Cycles: 5, Cycle interval: 5 seconds, Temperature monitor: Stand, Temperature correction factor: None, Pore size (S): 8.0 mm, Pore size (L): Auto mode, Specific OR path length: 50 mm, Concentration: 0.1 w / v.

[0423] 6-Cyclopropyl-1-(4,5-Difluoro-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 11B]: 1 HNMR (400 MHz, DMSO- d 6): δ 13.99 (br s, 1H), 8.39 (d, J = 7.5 Hz, 1H), 7.75 (dd, J = 7.5, 11.0 Hz, 1H), 7.64 (dd, J = 9.0, 11.5 Hz, 1H), 6.54 (d, J = 7.5Hz, 1H), 1.99 (s, 3H), 1.43 - 1.31 (m, 1H), 0.99 - 0.86 (m, 4H); MS(ES + ) m / z, [M+H] + [C 16 H 13 F2NO3+H] + Calculated value: 306.09, Measured value: 305.9 t R = 1.80 min, [Method N]. Specific rotation (SOR): -78.68, Method: Source WI, Monitor wavelength: 589 nm, DIT: 5 seconds, Cycle count: 5, Cycle interval: 5 seconds, Temperature monitor: Stand, Temperature correction factor: None, Aperture (S): 8.0 mm, Aperture (L): Auto mode, SpecificO.R. path length: 50 mm, Concentration: 0.1 w / v.

[0424] Synthesis of 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 12A and 12B]: Synthesis of ethyl 3-(2-chloro-4-methoxy-aniline)-3-oxo-propionate

[45] : A stirred solution of 2-chloro-4-methoxyaniline (3.9 mL, 31.7 mmol, 1.00 equivalent) in THF (50 mL, 0.6345 M) was cooled to 0 °C, and triethylamine (13 mL, 95.2 mmol, 3.00 equivalent) was added and stirred at 0 °C for 10 min. Ethyl 3-chloro-3-oxopropionate (4.9 mL, 38.1 mmol, 1.20 equivalent) was then added at 0 °C, and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a 10%–15% ethyl acetate-hexane gradient to provide 3.40 g of the title compound as a brown solid in 38.82% yield. MS(ES) + m / z, [M+H] + [C 12 H 14 ClNO4+H] + Calculated value: 272.1, Measured value: 271.9 t R = 1.719 min, [method N].

[0425] Synthesis of 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 12A and 12B]: Ethyl 3-(2-chloro-4-methoxy-aniline)-3-oxo-propionic acid (2 g, 7.21 mmol, 1 equivalent) in ethanol (20 mL, 0.3607 M) was added to a sealed tube. E1-Cyclopropyl-3-methoxy-prop-2-en-1-one (1.11 g, 8.66 mmol, 1.20 equivalents) and 20% sodium ethoxide in ethanol (14 mL, 36.1 mmol, 5.00 equivalents). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was then concentrated and diluted with water (20 mL), and extracted and separated with ethyl acetate (2 × 40 mL). The aqueous layer was acidified to pH ~3 with 2 N HCl, and the precipitated solid was filtered to give the crude product. The crude product was milled with diethyl ether (3 × 20 mL) to provide 1.1 g, 45.38% yield of the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6): δ 14.01 (br s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.15(dd, J = 2.8, 9.0 Hz, 1H), 6.53 (d, J = 7.8 Hz, 1H), 3.87 (s, 3H), 1.39 -1.31 (m, 1H), 1.01 - 0.83 (m, 4H); MS(ES + ) m / z, [M+H] + [C 16 H 14 ClNO4+H] + Calculated value: 320.01, Measured value: 320.4 t R = 3.256 min, [Method AC].

[0426] Note: The obtained 1.1 g product was further prepared and purified for the separation of the transtransfer isomer.

[0427] Purification of 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 12A and 12B]: 1.1 g of the racemic compound was separated by a chiral SFC (instrument name: Waters-2767, PREP-SFC 100). SFC purification method: number of injections: 16 injections (68 mg / injection, 12 min), column: Chiral pack IK (20 × 250 mm, 5 μm), mobile phase A: n-hexane containing 0.1% TFA, mobile phase B: EtOH:MeOH (1:1), eluent A:B: -20-80, total flow rate (mL / min): 50, diluent: mobile MP+DCM, phase detection: 340 nm, to provide 530 mg of intermediate 12A as a brown colloidal semi-solid and 525 mg of intermediate 12B as a brown colloidal semi-solid.

[0428] 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [intermediate 12A]: 1 H NMR (400 MHz, DMSO-) d 6): δ 13.97 (br s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 2.8, 8.8 Hz, 1H), 6.53(d, J = 7.5 Hz, 1H), 3.87 (s, 3H), 1.39 - 1.31 (m, 1H), 0.98 - 0.85 (m, 4H); MS(ES + ) m / z, [M+H] + [C 16 H 14 ClNO4+H] + Calculated value: 320.01, Measured value: 319.9 t R = 4.28 min, [Method W]. Chiral HPLC purity: 99.99%. t R= 9.88 min, ee = 99.99%. Specific rotation (SOR): 62.64, method: light source WI, monitor wavelength: 589 nm, DIT: 5 seconds, number of cycles: 5, cycle interval: 5 seconds, temperature monitor: stand, temperature correction factor: 0 at 20°C, pore size (S): 8.0 mm, pore size (L): automatic mode, specific OR path length: 50 mm, concentration: 0.1 w / v.

[0429] 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [intermediate 12B]: 1 H NMR (400 MHz, DMSO-) d 6): δ 13.93 (br s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 2.8, 8.8 Hz, 1H), 6.54(d, J = 7.5 Hz, 1H), 3.87 (s, 3H), 1.38 - 1.33 (m, 1H), 1.00 - 0.83 (m, 4H); MS(ES + ) m / z, [M+H] + [C 16 H 14 ClNO4+H] + Calculated value: 320.01, Measured value: 319.9 t R = 4.24 min, [Method W]. Chiral HPLC - Purity: 99.96%, t R = 14.82 min, ee = 95.96%. Specific rotation (SOR): -102.96, method: light source WI, monitor wavelength: 589 nm, DIT: 5 seconds, number of cycles: 5, cycle interval: 5 seconds, temperature monitor: stand, temperature correction factor: 0 at 20°C, pore size (S): 8.0 mm, pore size (L): automatic mode, specific OR path length: 50 mm, concentration: 0.1 w / v.

[0430] Synthesis of 1-(4-fluoro-2-methylphenyl)-6-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [mixture of Intermediate 13A and Intermediate 13B]: Synthesis of 1-methylcyclopropanecarbonyl chloride

[47] : A suspension of 1-methylcyclopropanecarboxylic acid (10.00 g, 99.9 mmol, 1.00 equivalent) and DMF (1 mL, 0.9889 M) in DCM (100 mL, 0.9889 M) was cooled to 0 °C and oxalyl chloride (10 mL, 120 mmol, 1.20 equivalents) was added dropwise. The resulting mixture was stirred at rt for 2 h. Excess oxalyl chloride and the solvent were removed under reduced pressure (<rt), giving 11.00 g of the title compound as an oily compound in 92.89% yield, which was used in the next step without further purification.

[0431] Synthesis of 1-(1-methylcyclopropyl)-3-trimethylsilyl-prop-2-yn-1-one

[48] : A solution of trimethyl(2-trimethylsilylethynyl)silane (25 mL, 111 mmol, 1.20 equivalents) in DCM (20 mL, 4.639 M) was cooled to 0 °C, and 1-methylcyclopropanecarbonyl chloride (11.00 g, 92.8 mmol, 1.00 equivalent) was added, followed by slow addition of aluminum chloride (14.84 g, 111 mmol, 1.20 equivalents). The reaction mixture was stirred at 0 °C for 2 h, then allowed to warm to rt and stirred for an additional 16 h. The reaction mixture was poured into a 10% HCl solution (300 mL) in ice water and stirred for 10 min. After separating the two phases, the aqueous phase was extracted three times with DCM (500 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford 16.00 g of the title compound as a brown oily product in 87.03% yield, which was used directly in the next reaction step. MS(ES) + m / z, [M+H] + [C 10 H 16 OSi+H] + Calculated value: 180.32, found value: 181.1, [Method N].

[0432] ( ESynthesis of 3-methoxy-1-(1-methylcyclopropyl)prop-2-en-1-one

[49] : A solution of 1-(1-methylcyclopropyl)-3-trimethylsilyl-prop-2-yn-1-one (17.58 g, 88.7 mmol, 1.00 equivalent) in methanol (160 mL, 0.5546 M) was cooled to 0 °C, and then DABCO (14.93 g, 133 mmol, 1.50 equivalent) was slowly added, with the reaction mixture stirred for 2 h. After 2 h, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by combi flash using a YMC 40 g column eluted with 0%–10% ethyl acetate / heptane to provide 4.70 g of the title compound as a brown liquid in 34.01% yield. 1 H NMR (400 MHz, DMSO- d 6): δ 7.50 (d, J = 12.0 Hz, 1H), 5.76 (d, J = 12.0 Hz, 1H), 3.70 (s, 3H), 1.25 (s, 3H), 1.16 - 1.12 (m, 2H), 0.76 - 0.70 (m, 2H); MS (ES) + m / z, [M+H] + [C8H 12 O2+H] + Calculated value: 140.18, Measured value: 141.1 t R = 1.60 min, [method N].

[0433] Synthesis of ethyl 3-(4-fluoro-2-methyl-aniline)-3-oxo-propionate

[50] : A stirred solution of 4-fluoro-2-methylaniline (22 mL, 200 mmol, 1.00 equivalent) in DCM (500 mL, 0.3995 M) was cooled to 0 °C, and then triethylamine (83 mL, 599 mmol, 3.00 equivalent) was added. After 10 min, ethyl 3-chloro-3-oxopropionate (30 mL, 240 mmol, 1.20 equivalent) was added to the reaction mixture, and the mixture was stirred at rt for 3 h. The reaction mixture was poured into ice water (400 mL), extracted with DCM (2 × 500 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by elution with heptane containing 30%–40% ethyl acetate using a 120 g column via a combi flash to provide 22.00 g of the title compound as a grayish-white solid in 45.94% yield. 1 H NMR (400 MHz, DMSO- d 6): δ 9.55 (s, 1H), 7.37 -7.33 (m, 1H), 7.10 - 7.07 (m, 1H), 7.02 - 6.97 (m, 1H), 4.12 (q, J = 7.0 Hz,2H), 3.46 (s, 2H), 2.20 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); MS(ES) + m / z, [M+H] + [C 12 H 14 FNO3] + Calculated value: 239.2, Measured value: 240.0 t R = 3.78 min, [method W].

[0434] Synthesis of 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 13A and 13B]: Ethyl 3-(4-fluoro-2-methylaniline)-3-oxo-propionate (1.70 g, 7.11 mmol, 1.00 equivalent) was added to a stirred solution of 3-(4-fluoro-2-methylaniline)-3-oxo-propionate in ethanol (5 mL, 1.42 M) and the mixture was stirred at 120 °C for 90 h. The reaction solution was concentrated under reduced pressure, and the crude product was diluted with water (200 mL) and cooled to 0 °C, then acidified to pH 4–5 with 1 N HCl (20 mL). The aqueous layer was extracted with ethyl acetate (3 × 100 mL) and separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by elution with heptane containing 50%-60% ethyl acetate using a 40 g column via Combi flash, yielding 600 mg of a mixture of intermediates 13A and 13B as a grayish-white solid in 27.45% yield. 1 HNMR (400 MHz, DMSO- d 6): δ 14.18 (br s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.58 (dd, J = 5.3, 8.8 Hz, 1H), 7.34 (dd, J = 3.0, 9.5 Hz, 1H), 7.28 - 7.23 (m,1H), 6.87 (d, J = 7.5 Hz, 1H), 1.99 (s, 3H), 1.08 - 1.05 (m, 1H), 0.97 - 0.92(m, 4H), 0.54 - 0.52 (m, 2H); MS(ES) + m / z, [M+H] + [C 17 H 16 FNO3+H] + Calculated value: 301.32, Measured value: 301.9 t R = 1.86 min, [method N].

[0435] Chiral separation of 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo-pyridine-3-carboxylic acid [a mixture of intermediates 13A and 13B]: A mixture of 2.0 g of intermediates 13A and 13B was separated by a chiral preparative SFC method. SFC purification method: Number of injections: 32 injections (60 mg / injection); Column: Chiral Pak IK (30 × 250 mm, 5 μm); Mobile phase A: n-hexane containing 0.1% TFA; Mobile phase B: EtOH:MeOH (1:1); Total flow rate: 1.0 mL / min; Detection: 340 nm; 560 mg of intermediate 13A and 880 mg of intermediate 13B were obtained as pale yellow solids; P1 recovery = 560 mg.

[0436] 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo-pyridine-3-carboxylic acid [intermediate 13A]: 1 H NMR (400 MHz, DMSO- d 6): δ 14.18 (br s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.58 (dd, J = 5.5, 8.8 Hz, 1H), 7.34 (dd, J = 2.8, 9.5 Hz, 1H), 7.31 - 7.21 (m,1H), 6.87 (d, J = 7.8 Hz, 1H), 1.99 (s, 3H), 1.10 - 1.00 (m, 1H), 0.96 (s,3H), 0.95 - 0.90 (m, 1H), 0.57 - 0.48 (m, 2H); MS(ES + ) m / z, [M+H] + [C 17 H 16 FNO 3+ H] + Calculated value: 301.32, Measured value: 301.9 t R = 4.389, [Method W]. Chiral HPLC - Purity: 99.6%, t R= 9.06 min, ee = 99.2%. Specific rotation (SOR): 141.6800, method: light source WI, monitor wavelength: 589 nm, DIT: 5 seconds, number of cycles: 5, cycle interval: 5 seconds, temperature monitor: stand, temperature correction factor: 0 at 20°C, pore size (S): 8.0 mm, pore size (L): automatic mode, specific OR path length: 50 mm, concentration: 0.1 w / v.

[0437] 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo-pyridine-3-carboxylic acid [intermediate 13B]: 1 H NMR (400 MHz, DMSO- d 6): δ 14.18 (br s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 5.5, 8.8 Hz, 1H), 7.34 (dd, J = 2.8, 9.5 Hz, 1H), 7.29 - 7.23 (m,1H), 6.87 (d, J = 7.5 Hz, 1H), 1.99 (s, 3H), 1.09 - 1.03 (m, 1H), 0.96 (s,3H), 0.95 - 0.90 (m, 1H), 0.57 - 0.49 (m, 2H); MS(ES + ) m / z, [M+H] + [C 17 H 16 FNO3+H] + Calculated value: 301.32, Measured value: 301.9 t R = ...

Claims

1. A compound of formula A: ； Or its pharmaceutically acceptable salt, wherein E is Or a bicyclic heterocyclic system comprising a 5-membered ring fused to a 6-membered ring, wherein the bicyclic heterocyclic system is optionally substituted with one to three groups independently selected from halogens, oxo- and (C1-C4) alkyl groups; R 1 and R 2 Each independently is -OR a or -NR b R c Or R 1 and R 2 With R 1 and R 2 The combined carbon atoms together form 5- to 7-membered heterocyclic groups; R a The group is selected from (C1-C4)alkyl, 4- to 6-membered heterocyclic groups, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH) and -(C1-C4)alkyl [4- to 6-membered heterocyclic groups], wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic groups are each optionally substituted by one or two groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy; R b and R c Each is independently selected from hydrogen and (C1-C4) alkyl groups, or R b and R c With R b and R c The attached nitrogen atoms together form 4- to 6-membered heterocyclic groups; R 3 It is a hydrogen or (C1-C4)alkoxy group; R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl or 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups independently selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano and -NH(C1-C4)alkyl; Ring M is a 6-membered aryl or a 6-membered heteroaryl; R 5 and R 7 Each of these can be independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, hydroxyl, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl]; R 6 It is a halogen, hydroxyl, cyano, (C2-C4) acyl, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, (C3-C6) cycloalkyl, -O(C3-C6) cycloalkyl, or deuterated(C1-C4) alkoxy; R 8 and R 9 Each is either hydrogen or halogen; J is O, NR 11 , S or CH2; R 10 It is a halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl; and R 11 It is hydrogen; or R 10 and R 11 With R 10 and R 11 The atoms that are bonded together form a 5-membered heterocyclic group; Q 1 and Q 2 Each of them is independently CH or N; Q 3 It is CR 8 Or N; Q 4 Is it N, CH or R? 9 Attached carbon atoms; X is N, CH, or related to R. 3 Attached carbon atoms; and Y is -NHC(O)- or -C(O)NH-; The condition is: (i) if R 4 If it is CH3, then: (a) R 5 Not hydrogen or (b) Q 3 It is CR 8 , where R 8 It is a halogen; and (ii) if Q 1 N, Q 2 It is CH, Q 3 It is CR 8 And R 4 If it is CH3 or CH2OH, then R 8 It is halogen.

2. The compound according to claim 1, wherein the compound has the formula AI: (A-I); Or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein... yes Z 1 Z 2 and Z 3 Each independently is N, CH, or R 5 R 6 and R 7 One of the carbon atoms in the bond.

4. The compound according to claim 3, wherein the compound has the formula A-II: (A-II)? Or its pharmaceutically acceptable salt.

5. The compound according to claim 3 or claim 4, or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 3 Each independently is CH or R 5 and R 7 One of the carbon atoms in the bond.

6. The compound of claim 3 or claim 4, or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 3 Each is N.

7. The compound according to claim 3 or claim 4, or a pharmaceutically acceptable salt thereof, wherein Z 1 Is it CH or R? 7 The bonded carbon atoms, and Z 3 It is N.

8. The compound according to claim 3 or claim 4, or a pharmaceutically acceptable salt thereof, wherein Z 1 It is N and Z 3 Is it CH or R? 5 The bonded carbon atoms.

9. The compound according to claim 3, wherein the compound has the formula A-III: (A-III); Or its pharmaceutically acceptable salt.

10. The compound according to claim 3, wherein the compound has formula A-IV: (A-IV); Or its pharmaceutically acceptable salt.

11. The compound according to claim 3, wherein the compound has the formula AV: (AV); Or its pharmaceutically acceptable salt.

12. The compound according to claim 3, wherein the compound has formula A-VI: (A-VI); Or its pharmaceutically acceptable salt.

13. The compound according to claim 3, wherein the compound has the formula A-VI-1: (A-VI-1); Or its pharmaceutically acceptable salt.

14. The compound according to claim 3, wherein the compound has the formula A-VI-2: (A-VI-2); Or its pharmaceutically acceptable salt.

15. The compound according to claim 3, wherein the compound has formula A-VII: (A-VII); Or its pharmaceutically acceptable salt.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 15, wherein Z 3 It is N.

17. The compound according to claim 3, wherein the compound has the formula A-VIII: (A-VIII)? Or its pharmaceutically acceptable salt.

18. The compound according to any one of claims 3 and 17, or a pharmaceutically acceptable salt thereof, wherein Z 2 It is N.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 17 and 18, wherein Q 1 and Q 2 Each is CH, and Q 3 It is CR 8 .

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 17 and 18, wherein Q 1 and Q 2 Each is CH, and Q 3 It is N.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 17 and 18, wherein Q 1 It is N, Q 2 It is CH and Q 3 It is CR 8 .

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 17 and 18, wherein Q 1 It's CH, Q 2 It is N and Q 3 It is CR 8 .

23. The compound according to claim 1, wherein the compound has the formula A-IX: (A-IX)? Or its pharmaceutically acceptable salt.

24. The compound according to claim 1, wherein the compound has the formula AX: (A-X); Or its pharmaceutically acceptable salt.

25. The compound according to claim 1, wherein the compound has the formula A-XI: (A-XI); Or its pharmaceutically acceptable salt.

26. The compound according to claim 1, wherein the compound has the formula A-XII: (A-XII); Or its pharmaceutically acceptable salt.

27. The compound according to claim 1, wherein the compound has the formula A-XIII-1: (A-XIII-1)? Or its pharmaceutically acceptable salt.

28. The compound according to claim 1, wherein the compound has the formula A-XIII-2: (A-XIII-2)? Or its pharmaceutically acceptable salt.

29. The compound according to claim 1, wherein the compound has the formula A-XIV: (A-XIV); Or its pharmaceutically acceptable salt.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein J is O.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein J is S.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein J is CH2.

33. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein J is NR. 11 .

34. The compound according to any one of claims 1 to 3, wherein the compound has the formula A-XV: (A-XV); Or its pharmaceutically acceptable salt.

35. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 10 It is halogen.

36. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 10 It's fluorine.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, 23 to 29 and 34, wherein Q 1 It is N.

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, 23 to 29 and 34, wherein Q 1 It is CH.

39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein Q 4 It is N.

40. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein Q 4 Is with R 9 The bonded carbon atoms.

41. The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 9 It is hydrogen.

42. The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 9 It's fluorine.

43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, cyano, hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl or halogen.

44. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 5 It is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halogen.

45. The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH3, CF3, cyano, hydroxyl, fluorine, chlorine, or bromine.

46. ​​The compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein X is CH.

47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45, wherein X is N.

48. The compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

49. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, 21 to 29, 34, 37 and 38, wherein R 8 It's fluorine.

50. The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein each R a The group is independently selected from (C1-C4)alkyl, oxetyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrrolidinyl], -(C1-C4)alkyl[piperazinyl] and -(C1-C4)alkyl[morpholinyl], wherein the cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl and oxetyl are each optionally substituted by one or two groups selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy.

51. The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently selected from OCH3, , , , , , , , , , , and .

52. The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein E is .

53. The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein E is .

54. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein E is pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, each optionally substituted with one to three groups independently selected from halogens and (C1-C4) alkyl groups.

55. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein E is... , , , , , or .

56. The compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a (C1-C4)alkyl, a halo(C1-C4)alkyl, a hydroxy(C1-C4)alkyl, a halo(C1-C4)alkoxy, a (C3-C6)cycloalkyl, a -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

57. The compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl] or oxetane, wherein the (C3-C6)cycloalkyl is optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl and halo(C1-C4)alkyl.

58. The compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 4 yes , CF3, CH3 OCHF2 CH2CF3 , , , , , , or .

59. The compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a (C2-C4)alkyl, a halo(C1-C4)alkyl, a hydroxy(C2-C4)alkyl, a halo(C1-C4)alkoxy, a (C3-C6)cycloalkyl, a -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

60. The compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 4 It is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl] or oxetane, wherein the cyclopropyl is optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl and halo(C1-C4)alkyl.

61. The compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 4 yes , CF3 OCHF2 CH2CF3 , , , , , , or .

62. The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 7 It is hydrogen, halogen, -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl] or cyano.

63. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 61, wherein R 7 It is hydrogen, fluorine, bromine, chlorine, Or cyano.

64. The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 7 It is hydrogen, cyano, hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl or halogen.

65. The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 7 It is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halogen.

66. The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 7 It is CH3, CF3, cyano, hydroxyl, fluorine, chlorine, or bromine.

67. The compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein R 6 It can be halogen, hydroxyl, cyano, (C2-C4) acyl, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, -O(C3-C6) cycloalkyl or deuterated(C1-C4) alkoxy.

68. The compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein R 6 It contains cyano, CHF2, hydroxyl, acetyl, OCH3, OEt, fluorine, OCHF2, OCF3, Or OCD3.

69. The compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein R 6 It's fluorine.

70. The compound according to claim 1, wherein the compound has formula I: (I)； Or its pharmaceutically acceptable salt, wherein R 1 and R 2 Each independently is -OR a or -NR b R c ; R 5 and R 7 Each of these can be independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl]; R 6 It is a halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl or deuterated(C1-C4)alkoxy; R 8 and R 9 Each is either hydrogen or fluorine; The condition is if R 4 If it is CH3, then R 5 It's not hydrogen.

71. The compound according to claim 70, wherein the compound has formula II: (II); Or its pharmaceutically acceptable salt.

72. The compound according to claim 70 or claim 71, wherein the compound has formula III: (III); Or its pharmaceutically acceptable salt.

73. The compound according to any one of claims 70 to 72, wherein the compound has formula IV: (IV); Or its pharmaceutically acceptable salt.

74. The compound according to any one of claims 70 to 73, wherein the compound has formula V: (V)； Or its pharmaceutically acceptable salt.

75. The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt thereof, wherein R 10 It is halogen.

76. The compound according to any one of claims 70 to 75, or a pharmaceutically acceptable salt thereof, wherein R 10 It's fluorine.

77. The compound according to any one of claims 70 to 76, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl or halogen.

78. The compound according to any one of claims 70 to 77, or a pharmaceutically acceptable salt thereof, wherein R 5 It is (C1-C4)alkyl, halo(C1-C4)alkyl or halogen.

79. The compound according to any one of claims 70 to 78, or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH3, CF3, or chlorine.

80. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 70 to 79, wherein X is CH.

81. The compound according to any one of claims 70 to 80, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

82. The compound according to any one of claims 70 to 81, or a pharmaceutically acceptable salt thereof, wherein R 9 It is hydrogen.

83. The compound according to any one of claims 70 to 82, or a pharmaceutically acceptable salt thereof, wherein R 8 It's fluorine.

84. The compound according to any one of claims 70 to 83, or a pharmaceutically acceptable salt thereof, wherein each R a The group is independently selected from (C1-C4)alkyl, oxetyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrrolidinyl], -(C1-C4)alkyl[piperazinyl] and -(C1-C4)alkyl[morpholinyl], wherein the cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl and oxetyl are each optionally substituted by one or two groups selected from (C1-C4)alkyl, (C1-C4)alkoxy and -(C1-C4)alkyl(C1-C4)alkoxy.

85. The compound according to any one of claims 70 to 84, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently selected from OCH3, , , , , , , , , , , and .

86. The compound according to any one of claims 70 to 85, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a (C1-C4)alkyl, a halo(C1-C4)alkyl, a hydroxy(C1-C4)alkyl, a halo(C1-C4)alkoxy, a (C3-C6)cycloalkyl, a -(C1-C4)alkyl(C3-C6)cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the (C3-C6)cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

87. The compound according to any one of claims 70 to 86, or a pharmaceutically acceptable salt thereof, wherein R 4 It is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl] or oxetane, wherein the cyclopropyl is optionally substituted by one to three groups selected from halogen, NH(C1-C4)alkyl and halo(C1-C4)alkyl.

88. The compound according to any one of claims 70 to 87, or a pharmaceutically acceptable salt thereof, wherein R 4 yes , CF3, CH3 OCHF2 CH2CF3 , , , , , , or .

89. The compound according to any one of claims 70 to 88, or a pharmaceutically acceptable salt thereof, wherein R 7 It is hydrogen, halogen, -(C1-C4)alkoxy [hydroxy(C1-C4)alkyl] or cyano.

90. The compound according to any one of claims 70 to 89, or a pharmaceutically acceptable salt thereof, wherein R 7 It is hydrogen, fluorine, bromine, chlorine, Or cyano.

91. The compound according to any one of claims 70 to 90, or a pharmaceutically acceptable salt thereof, wherein R 6 It is OCH3, fluorine, OCHF2, OCF3, 、OCD3.

92. The compound according to any one of claims 70 to 91, or a pharmaceutically acceptable salt thereof, wherein R 6 It's fluorine.

93. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the compounds in Table 1.

94. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the compounds in Table 2.

95. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 92, wherein the compound is a single transisomer.

96. The compound of claim 95 or a pharmaceutically acceptable salt thereof, wherein the single transisomer has a negative specific rotation.

97. The compound of claim 95 or a pharmaceutically acceptable salt thereof, wherein the single transisomer has a positive specific rotation.

98. A pharmaceutical composition comprising the compound of any one of claims 1 to 97 or a pharmaceutically acceptable salt thereof.

99. A pharmaceutical composition comprising a group of molecules having the structure of a compound according to any one of claims 1 to 94, wherein at least about 97% of the molecules in the group have the same transisomer configuration.

100. The pharmaceutical composition of claim 99 further comprises a pharmaceutically acceptable carrier.

101. A method of treating a condition, comprising administering to a subject in need a therapeutically effective amount of the compound of any one of claims 1 to 97 or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of any one of claims 98 to 100.

102. The method of claim 101, wherein the condition is responsive to the adjustment of PLK4.

103. The method of claim 101, wherein the condition is cancer.

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