Methods to improve the absorption of quinoxaline type III receptor tyrosine kinase inhibitors

Abstract

A method is provided for improving the pharmacokinetics of a compound of formula (I), its stereoisomers, tautomers, prodrugs, or pharmaceutically acceptable salts. The method comprises administering a pharmaceutical composition comprising a compound of formula (I), its stereoisomers, tautomers, prodrugs, or pharmaceutically acceptable salts to a subject in need in a non-fasting state. Herein, the compound of formula (I) has the following structure. The compound of formula (I) can be used to treat diseases and conditions mediated by CSF-1R, PDGFR, FLT3, or c-KIT kinases. These diseases and conditions may include cancer, autoimmune diseases, bone resorption disorders, etc. JPEG2026525340000060.jpg4591

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This disclosure claims priority based on U.S. Provisional Application No. 63 / 514,214, filed on July 18, 2023, the entire content of which is incorporated herein by reference for all purposes.

[0002] (Technical Field) The present invention relates to a method of administering a quinoxaline compound that can function as a type III receptor tyrosine kinase inhibitor to animals and / or humans.

Background Art

[0003] Receptor tyrosine kinases (RTKs) are a subfamily of protein kinases. Type III RTKs, including colony - stimulating factor - 1 receptor (CSF - 1R), platelet - derived growth factor receptor α (PDGFRα), PDGFRβ, Fms - like tyrosine kinase 3 (FLT3), and c - KIT, are involved in various proliferative diseases, inflammatory diseases, and autoimmune diseases.

[0004] CSF-1R, also known as the macrophage colony-stimulating factor receptor (M-CSFR), is the receptor for macrophage colony-stimulating factor (M-CSF or CSF-1). When M-CSF binds to its receptor, signaling pathways, including the PI3K / Akt pathway and the MAPK pathway, are activated, inducing the proliferation, survival, motility, and differentiation of monocyte / macrophage cells (including microglia). Upregulation of CSF-1R and / or its ligands has been observed in various cancers, and high levels of M-CSF are associated with poor prognosis in certain cancers. M-CSF is one of several cytokines involved in the recruitment of tumor-associated macrophages (TAMs), which contribute to tumor progression to tumor angiogenesis and metastasis. Activation of CSF-1R also promotes the proliferation and differentiation of osteoclast precursor cells and mediates the process of bone resorption. Therefore, inhibition of CSF-1R is effective in treating cancer, particularly cancer invasion, angiogenesis, metastasis, immune tolerance, and bone metastasis. Due to its role in osteoclast biology, CSF-1R is also an important therapeutic target for osteoporosis, inflammatory arthritis, and other inflammatory bone resorption.

[0005] Platelet-derived growth factor receptor (PDGFR) kinase receptor tyrosine kinases are involved in a variety of proliferative disorders, including glioblastoma, sarcoma, chronic myelomonocytic leukemia (CML), and gastrointestinal tumors, and may be potential targets for antitumor therapy.

[0006] FLT3 plays a crucial role in the proliferation and differentiation of hematopoietic stem cells. More than 12 FLT3 inhibitors are under development, some of which have shown promising clinical efficacy against acute myeloid leukemia (AML). The FLT3 receptor is also expressed in dendritic cell progenitor cells, and inhibition of FLT3 reduces dendritic cell (DC)-mediated inflammation and autoimmune responses.

[0007] c-KIT (or stem cell growth factor receptor (SCFR)) is another member of the PDGFR family, and mutations in c-KIT are associated with gastrointestinal stromal tumors (GIST), mast cell / myeloid leukemia, testicular / ovarian germ cell tumors, and melanoma. Gleevec® received FDA approval in 2002 for c-KIT-dependent GIST.

[0008] Although various tyrosine kinase inhibitors have shown to be useful therapeutic agents, there is still a need for type III kinase inhibitors. [Overview of the project] [Means for solving the problem]

[0009] The present invention relates to a method for delivering quinoxaline compounds as inhibitors of kinase activity (e.g., CSF-1R, PDGFR, FLT-3, and / or c-KIT) to animals and / or humans for the treatment of diseases mediated by these kinases (e.g., cancer, autoimmune diseases, bone resorption disorders, neurodegenerative diseases, etc.).

[0010] The present invention provides a method for improving the pharmacokinetics of a compound of formula (I), comprising administering a pharmaceutical composition containing the compound of formula (I), or its stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt, to a subject in need under non-fasting conditions.

[0011] [ka]

[0012] Here, X, U, Z, G, R 1 , R 2 , and R 3 This is as defined herein.

[0013] Preferably, the compound of formula (I) is administered orally.

[0014] Preferably, to improve pharmacokinetics, the peak blood concentration (C) max This includes an increase in ) and / or an increase in bioavailability (AUC).

[0015] Preferably, the pharmaceutical further comprises a carrier, a diluent, or an excipient.

[0016] Preferably, the excipient includes a surfactant, a binder, a disintegrant, and / or a lubricant.

[0017] Efficient delivery of drug compounds into the bodies of animals and / or humans is crucial for their therapeutic applications. Better delivery is expected to lead to greater therapeutic effects from the drug compound in treating the target disease.

[0018] Embodiments of the present invention are based on the unexpected finding that the quinoxaline compound, which is poorly soluble in water but highly soluble in acidic buffers, is more efficiently delivered into the body when administered after or with a meal. [Brief explanation of the drawing]

[0019] [Figure 1] Figure 1 shows the changes in gastric pH before and after meals using the conventional technology.

[0020] [Figure 2] Figure 2 shows the time course of the concentration of DCBCO1701-DS in a blood sample in Example 2 according to an embodiment of the present invention.

[0021] [Figure 3A] Figure 3A shows the pharmacokinetics, specifically Cmax, of EI-1071 tablets in beagle dogs according to an embodiment of the present invention. [Figure 3B] Figure 3B shows the pharmacokinetics, specifically the AUC, of ​​EI-1071 tablets in beagle dogs according to an embodiment of the present invention. [Modes for carrying out the invention]

[0022] While the listed embodiments are described, it should be understood that there is no intention to limit the invention to these embodiments. Rather, the present invention is intended to cover all alternatives, modifications, and equivalents that may fall within the scope of the invention as defined by the claims.

[0023] (definition)

[0024] For convenience, the specific terms used in the context of this specification are summarized here. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that generally understood by a person of ordinary skill in the art to which this invention pertains.

[0025] As used herein, "non-fasting" or "post-feeding" means that an animal, such as a dog, receives a nutritionally balanced daily feed throughout the pre-test period and the entire test period.

[0026] The term "AUC" stands for "Area Under the Curve" and is used in its usual sense. In embodiments, it refers to the area under the plasma concentration-time curve from 0 to 24 hours when the dose form is orally administered to animals such as rats or dogs (beagles) under fasting or non-fasting conditions. The unit of AUC is "concentration × time". After experimental concentration-time data is obtained, AUC can be conveniently calculated, for example, by a computer program or the trapezoidal rule.

[0027] In this specification, "improvement of pharmacokinetics" means the C of the drug. max (maximum blood concentration), T max(Time to reach the maximum plasma concentration), AUC, or the plasma half-life of the drug, or an increase in the drug concentration in blood, liver or other tissues. Non-limiting examples of drugs whose pharmacokinetics can be improved by the compounds of formula (I) are given. Generally, the amount of the compound of formula (I) in the tablet is sufficient to improve the in vivo pharmacokinetics of the co-formulated drug.

[0028] The term "alkyl", unless otherwise specified, refers to a straight-chain or branched monovalent saturated hydrocarbon containing 1 to 20 carbon atoms. Numerical ranges in this description are to be interpreted as if each individual numerical value within the range were specifically disclosed. For example, an alkyl group having 1 to 20 carbons includes C1, C2, ··· C 20 In addition to C1-C 20 C1-C 15 C1-C 10 C1-C6, C1-C4, etc. are included. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, etc.

[0029] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon containing 2 to 20 carbon atoms (e.g., C2-C 10 ) and having one or more double bonds. Examples of alkenyl include ethenyl, propenyl, allyl, 1,4-butadienyl, etc.

[0030] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon containing 2 to 20 carbon atoms (e.g., C2-C 10 ) and having one or more triple bonds. Examples of alkynyl include ethynyl, 1-propynyl, 1- and 2-butynyl, 1-methyl-2-butynyl, etc.

[0031] The term "alkoxy" refers to an -O-alkyl radical, and the alkyl moiety is the same as defined above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, etc.

[0032] The term "acyloxy" refers to the -OC(O)-R radical, where R may be any of the following as defined herein: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

[0033] The term "amino" refers to NH2. The term "alkylamino" refers to the -N(R)-alkyl radical, where "alkyl" is the same as defined above, and R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

[0034] The term "cycloalkyl" refers to a monovalent saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C6 or C3-C6). 12 This refers to cycloalkyl compounds. Examples of cycloalkyl compounds include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantanil.

[0035] The term "cycloalkenyl" refers to a group of 3 to 30 carbon atoms (e.g., C3-C6 or C3-C6). 12 This refers to a non-aromatic monovalent hydrocarbon ring system that has one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0036] The term "heterocycloalkyl" refers to a monovalent non-aromatic ring system containing one or more heteroatoms (such as O, N, S, and Se), and having a monocyclic ring with 5 to 8 members, a bicyclic ring with 8 to 12 members, or a tricyclic ring with 11 to 14 members. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, piperidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

[0037] The term "heterocycloalkenyl" refers to a monovalent non-aromatic ring system containing one or more heteroatoms (such as O, N, S, and Se) and having one or more double bonds, and having a monoring of 5 to 8 members, a diring of 8 to 12 members, or a triring of 11 to 14 members.

[0038] The term "aryl" refers to monovalent aromatic ring systems consisting of a 6-membered monocycle, a 10-membered dicycle, or a 14-membered tricycle. Examples of aryl groups include phenyl, naphthyl, and anthracenyl.

[0039] The term "aryloxy" refers to -O-aryl, where "aryl" is defined above. The term "arylamino" refers to -N(R)-aryl, where "aryl" is defined above, and R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. The term "heteroaryl" refers to a monovalent aromatic ring system containing one or more heteroatoms (O, N, S, Se, etc.) and having a monocycle of 5-8 members, a dicycle of 8-12 members, or a tricycle of 11-14 members. Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, pyrrolyl, isoquinolinyl, prinyl, oxazolyl, pyrazolyl, and carbazolyl. The "aryl" portion in these terms is defined above.

[0040] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, amino, alkylamino, arylamino, alkoxy, aryloxy, and heteroaryl compounds described above may have substituents or be unsubstituted. Possible substituents for amino, alkylamino, arylamino, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl compounds include C1-C 10 Alkyl, C2-C 10Alkenyl, C2-C 10 Alkinyl, C3-C 20 Cycloalkyl, C3-C 20 Cycloalkenyl, C1-C 20 Heterocycloalkyl, C1-C 20 Heterocycloalkenyl, C1-C 10 Alkoxy, aryl, allyloxy, heteroaryl, heteroallyloxy, amino, C1-C 10 Alkylamino, arylamino, hydroxyl, halooxo(O=), thioxo(S=), thio, C1-C 10 Alkylthio, arylthio, C1-C 10 Alkylsulfonyls, arylsulfonyls, acylaminos, aminoacyls, aminothioacyls, amidinos, mercaptos, amides, thioureidos, thiocyanatos, sulfonamides, guanidines, ureidos, cyanos, nitros, acyls, thioacyls, acyloxys, carbamides, carbamyls (-C(O)NH2), carboxyls (-COOH), and carboxylic acid esters. Possible substituents on alkyl, alkenyl, or alkynyl compounds include all substituents listed above, but C1-C 10 Alkyl groups are excluded. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also condense with each other.

[0041] Embodiments of the present invention relate to a method for improving the pharmacokinetics of a compound of formula (I), comprising administering to a subject in need of such improvement a pharmaceutical product comprising the compound of formula (I), its stereoisomers, tautomers, prodrugs, or pharmaceutically acceptable salts, in a non-fasting state, wherein the compound of formula (I) has the following structure.

[0042] [ka]

[0043] Here, X is CR 4 R 5 , NR 6Selected from the group consisting of O and S; Z is -NR 7 Selected from the group consisting of - and -O-; U is N or CR 8 and; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkene, and alkyne; R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkylamino, C1-C6 alkoxy, C3-C6 cycloalkoxy, aryl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, and is alkylamino, dialkylamino, alkoxy, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, cycloalkylamino, cycloalkoxy, heterocyclyl, aryl, and heteroaryl are optionally substituted with halogens, amino, hydroxyl, cyano, nitro, acyl, acyloxy, C1-C4 alkyl, hydroxy C1-C4 alkyl, alkoxy C1-C4 alkyl, acyloxy C1-C4 alkyl, C1-C4 alkoxy, C1-C4 dialkylamino, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, aryl, and 5-6 membered heteroaryl; R 2 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, and C1-C6 dialkylaminocarbonyl; R 3 The group is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino. R 4 The group is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and aryl; R 5 It is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl; R 6 It is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; R 7 It is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; R 8 The group is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino.

[0044] In some embodiments, G in the compound of formula 1 may be selected from the following:

[0045] [ka]

[0046] Here, R 9 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, carbonyl C1-C6 alkoxy, carbonyl C1-C6 alkylamino, and carbonyl C1-C6 dialkylamino; R 10 It is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; Furthermore, each n is independently 0, 1, 2, or 3.

[0047] In some embodiments, G in the compound of formula 1 may be selected from the following:

[0048] [ka]

[0049] Here, R 11 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro group, cyano group, trifluoromethyl group, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkyl, carboxylic acid, carbonyl C1-C6 alkoxy, carbonyl C1-C6 alkylamino, and carbonyl C1-C6 dialkylami; R 12 This is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; Furthermore, each n is independently 0, 1, 2, or 3.

[0050] In some embodiments, G in the compound of formula 1 may be selected from the following:

[0051] [ka]

[0052] Here, R 13This is selected from the group consisting of hydrogen, deuterium, halogen, nitro group, cyano group, trifluoromethyl group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, and C1-C6 dialkylaminocarbonyl; Furthermore, each n is independently 0, 1, 2, or 3.

[0053] In some embodiments, G in the compound of formula 1 may be selected from the following:

[0054] [ka]

[0055] Here, R 14 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro group, cyano group, trifluoromethyl group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, and C1-C6 dialkylaminocarbonyl. Q is NR 15 , selected from O and S, where R 15 It is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; Furthermore, each n is independently 0, 1, 2, or 3.

[0056] In some embodiments, G in the compound of formula 1 may be selected from the following:

[0057] [ka]

[0058] Here, R16 This is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, 3-membered heterocyclyl, 5-6 membered heteroaryl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, and C1-C6 dialkylaminocarbonyl.

[0059] Those skilled in the art will understand that in formula (I) above, any combination or permutation of different substituents falls within the scope of the present invention. Representative quinoxaline compounds of the present invention are shown in Table 1.

[0060] [Table 1-1]

[0061] [Table 1-2]

[0062] [Table 1-3]

[0063] [Table 1-4]

[0064] [Table 1-5]

[0065] [Table 1-6]

[0066] [Table 1-7]

[0067] Table 1-8

[0068] Table 1-9

[0069] Table 1-10

[0070] Table 1-11

[0071] Table 1-12

[0072] Table 1-13

[0073] Table 1-14

[0074] Table 1-15

[0075] Table 1-16

[0076] Table 1-17

[0077] Table 1-18

[0078] Table 1-19

[0079] Table 1-20

[0080] Table 1-21

[0081] Table 1-22

[0082] Table 1-23

[0083] Table 1-24

[0084] Table 1-25

[0085] [Table 1-26]

[0086] [Table 1-27]

[0087] [Table 1-28]

[0088] [Table 1-29]

[0089] [Table 1-30]

[0090] This specification describes compounds and their pharmaceutical compositions that are useful for the treatment or prevention of diseases, conditions and / or disorders regulated or mediated (or associated with) protein tyrosine kinases such as CSF-1R, PDGFR, FLT-3 and / or c-KIT.

[0091] In one embodiment, the compound of formula (I) described above is administered orally. The pharmaceutical is in the form of a tablet containing 150 mg of the compound of formula (I). The compound of formula (I) shows that in dogs under non-fasting conditions, the dose-adjusted AUC of the compound of formula (I) is at least 170 kg·ng·hr / mL / mg. The compound of formula (I) shows that in dogs under non-fasting conditions, the dose-adjusted C max This indicates that the concentration is at least 20 kg·ng / mL / mg. To improve pharmacokinetics, the maximum blood concentration (C) vbThis includes an increase in blood concentration-time curve area (AUC) and / or an increase in blood concentration-time curve area (AUC).

[0092] In one embodiment, the pharmaceutical further includes a carrier, a diluent, or an excipient. The excipient may include a surfactant, a binder, a disintegrant, and / or a lubricant.

[0093] Surfactants include, but are not limited to, betaine, quaternary ammonium salts, polysorbates, sorbitan esters, poloxamers, and povidone® K-90. In one embodiment, the surfactant is povidone K-90.

[0094] Binders include, but are not limited to, starches such as potato, wheat, or corn starch, microcrystalline cellulose O, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, and polyvinylpyrrolidone (e.g., povidone® K-90). In one embodiment, polyvinylpyrrolidone, preferably povidone® K-90, is used.

[0095] Disintegrants include, but are not limited to, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, and sodium starch glycolate (e.g., sodium starch glycolate type A). In one embodiment, sodium starch glycolate, for example sodium starch glycolate type A, is used.

[0096] Lubricants include, but are not limited to, magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, and hydrogenated vegetable oils. In one embodiment, magnesium stearate is used.

[0097] In one embodiment, the compound of formula (I) is formed as an amorphous solid dispersion (ASD) with povidone®, polymethacrylate derivatives, hydroxypropyl methylcellulose (HPMC), and hydroxypropyl methylcellulose acetate succinate derivatives, among others. In one embodiment, the compound of formula (I) is formed as an ASD with hydroxypropyl methylcellulose acetate succinate (HPMCAS) (hereinafter referred to as "DCBCO1701-SP01").

[0098] In one embodiment, the compound of formula (I) is used to manufacture a pharmaceutical tablet using HPMCAS, povidone K-90, sodium starch glycolate type A and / or magnesium stearate (hereinafter referred to as "EI-1071 tablet").

[0099] Enhanced absorption of quinoxaline type III receptor tyrosine kinase inhibitors

[0100] The effect of food on drug compound delivery

[0101] Certain drugs that are highly soluble in a low pH environment reach their maximum blood concentration (C) after a meal. max ) and the area under the blood concentration curve (AUC) may decrease. This phenomenon occurs because, in a fasted state, the gastric environment of a healthy individual is normally around pH 1. However, after food intake, gastric pH temporarily rises to pH 4.5-4.98 and remains high for up to approximately 4.5 hours. As shown in Figure 1[1], the change in gastric pH before and after a meal is shown. At baseline, the median gastric pH is approximately 1, rises to above pH 4.5 after food intake, and then returns to approximately pH 1 about 3-4 hours after the start of the meal. Therefore, drugs that are highly soluble in an acidic environment are expected to have reduced solubility when administered after a meal, which may reduce drug absorption. Furthermore, compared to a fasted state, oral drug administration after a meal can significantly affect systemic bioavailability because changes in gastrointestinal physiology affect drug transit time, solubility in the lumen, and permeability.

[0102] Known examples in the prior art [2]:

[0103] Repaglinide: Highly soluble under low pH conditions. When administered with food, average T max While the mean C remains unchanged, max The AUC decreases by 20% and 12.4%, respectively. [3]

[0104] Telmisartan: Highly soluble under low pH conditions. When administered to a non-fasted state, average C125 is high. max Both the metric and AUC decrease. [4]

[0105] The compound of formula (I) is administered to subjects requiring it in a non-fasting state. Non-fasting (or post-meal state) means, in particular, that the patient is not fasting. In particular, this means that the active ingredient is administered with or after a meal (e.g., breakfast, lunch, and / or dinner). More specifically, it is administered with or after breakfast and / or dinner. In particular, the compound of formula (I) (and, if necessary, the orally available active ingredient) is administered within 5 hours after a meal, more specifically within 4 hours, even more specifically within 3 hours, even more specifically within 2.5 hours, even more specifically within 2 hours, even more specifically within 60 minutes, and even more specifically within 30 minutes. In particular after a meal (more specifically a light meal, especially a light breakfast and / or dinner). Examples of a physician's recommendation for a light meal include small to moderate amounts of one or two of the following: fruit, yogurt, cereal, toast, croissant, bread, cold cuts, cheese, or salad, plus coffee, tea, juice, milk, or an equivalent amount of food. These typically correspond to approximately 150-300 kcal. However, in actual treatment situations, patients often receive treatment on an outpatient basis, and the content of their meals is determined by the patients themselves, so the types and quantities of food may vary to some extent.

[0106] When the compound of formula (I) is administered twice a day, the first dose may be given within the time frame associated with the aforementioned breakfast or light breakfast, particularly within 30 minutes after the breakfast or light breakfast. The second dose may be given within the time frame associated with the aforementioned dinner or light dinner, particularly within 30 minutes after the dinner or light dinner. For clarification, "food intake," "meals," etc., logically refers to the food intake, meals, etc., of the patient receiving the compound.

[0107] Experimental materials and methods

[0108] Compound "DCBCO1701-DS"

[0109] Chemical name: 6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoxaline-5-carbonitrine

[0110] CAS index name: 5-Quinoxaline Carbonitride, 6-[[3-Methoxy-4-[(6-methyl-3-pyridinyl)methoxy]phenyl]amino]-3-(4-morpholinyl)-;

[0111] CAS RN:2222689-47-4

[0112] structure:

[0113] [ka]

[0114] ASD "DCBCO1701-SP01"

[0115] It is a yellow powder containing 20-40% (w / w) DCBCO1701-DS and 60-80% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0116] Pharmaceutical product "EI-1071 Tablets"

[0117] Each EI-1071 tablet (750 mg / tablet) contains 60-70% (w / w) DCBCO1701-SP01, 4-8% (w / w) povidone K-90, 25-30% (w / w) sodium starch glycolate type A, and 0.2-1% (w / w) magnesium stearate.

[0118] Chemical properties of the quinoxaline compound DCBCO1701-DS

[0119] Solubility of DCBCO1701-DS and DCBCO1701-SP01 in water and various pH buffers

[0120] As shown in Table 2, the solubility of DCBCO1701-DS was measured in pure water and buffers under various pH conditions (pH 1.2, pH 4.0, pH 6.8, and pH 7.4). DCBCO1701-DS was almost insoluble in pure water, with a solubility of <1 μg / mL. However, its solubility in pH 1.2 buffer was measured at 493.33 ± 125.70 μg / mL, decreased significantly at pH 4.0 to 1.86 ± 0.11 μg / mL, and became almost undetectable at pH 6.8 and pH 7.4 (<1 μg / mL). Solubility was significantly higher in the acidic pH 1.2 buffer.

[0121] [Table 2]

[0122] As shown in Table 3, the solubility of DCBCO1701-SP01 was measured in pure water and buffers under various pH conditions (pH 1.2, pH 4.0, pH 6.8). DCBCO1701-SP01 was almost insoluble in pure water, with a solubility of 4.38 ± 0.05 μg / mL. The solubility of DCBCO1701-SP01 was measured at 441.46 ± 76.06 μg / mL at pH 1.2, which was comparable to the solubility of DCBCO1701-DS at pH 1.2. The solubility decreased significantly to 2.08 ± 0.70 μg / mL at pH 4.5, almost at the detection limit, and to 7.52 ± 2.08 μg / mL at pH 6.8, which was similar to the solubility in pure water and the solubility of DCBCO1701-DS under similar pH conditions.

[0123] Table 3. Solubility of DCBCO1701-SP01

[0124] [Table 3]

[0125] HPMCAS-based ASDs (solid dispersions) are widely established in commercially available products and are widely used as solubility enhancers to improve the solubility of poorly soluble pharmaceuticals, or as precipitation inhibitors and stabilizers to achieve supersaturation of pharmaceuticals in the intestinal tract and suppress crystallization. However, the results showed that the solubility of DCBCO1701-DS in pure water and under various pH conditions was not significantly affected by HPMCAS, another component of DCBCO1701-SP01.

[0126] Dietary influence on the absorption of DCBCO1701-DS compounds in animals

[0127] Research 1

[0128] The pharmacokinetics (PK) and bioavailability of DCBCO1701-DS in healthy Sprague Dawley male rats were investigated using two formulations: DCBCO1701-DS and DCBCO1701-SP01. Each formulation was suspended in 0.5% methylcellulose (0.5% MC) and administered orally (per os, PO) to rats fasted for at least 10 hours, and frequently monitored. The dose was 10 mg / kg for DCBCO1701-DS and an equivalent dose for DCBCO1701-SP01, administered as a single dose via jugular vein garbage collection. Blood samples were collected at selected post-administration time points: before administration, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours. The concentration of DCBCO1701-DS in each blood sample was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS). max The PK parameters, including AUC, were calculated using the method shown in Table 4.

[0129] [Table 4]

[0130] 1. EQ DCBCO1701-DS: Equivalent amount of DCBCO1701-DS 2.C max : Maximum concentration observed 3. AUC(0-∞): Area under the concentration-time curve from time point 0 after administration to the last measurable concentration. 4. Per os (by mouth): Oral administration

[0131] The results showed that absorption of DCBCO1701-DS in rats was significantly higher in the DCBCO1701-SP01 form than in the DCBCO1701-DS form (e.g., AUC / Dose values: SP01 vs DS = 169.2 vs 45.2).

[0132] DCBCO1701 shows high solubility at low pH but is almost insoluble under other pH conditions. Therefore, like other drugs with similar physicochemical properties, it is soluble after food intake.max And AUC may decrease. To comprehensively understand the effect of diet on the PK profile of DCBCO1701-DS, two PK studies (Study 2 and Study 3) were conducted using beagle dogs. The results are summarized in Table 5 (Study 2), Table 6, and Table 7 (Study 3) below.

[0133] All AUC data in this study have been corrected to the 1 mg dose level. The AUC is determined within a range where it increases proportionally with dose. A 150 mg dose of compound (I) of formula (I), e.g., EI-1071 tablets administered to dogs, is considered suitable for determining the AUC values ​​used in this study. The protocol and AUC calculation method for the oral bioavailability study in beagle dogs are described in U.S. Patent Application Publication No. 20050084529, which is incorporated herein by reference in its entirety.

[0134] Research 2

[0135] In fasted or non-fasted (post-meal) dogs, a single dose of EI-1071 tablets was administered orally (PO) at a dose equivalent to 55 mg / kg in terms of DCBCO1701-DS. Blood samples were collected at selected time points after administration: before administration, 0.5, 1, 2, 4, 8, 12, and 24 hours. The DCBCO1701-DS concentration in each sample was measured by LC-MS / MS. PK parameters were calculated using the method shown in Table 5 below.

[0136] [Table 5]

[0137] 1. EQ DCBCO1701-DS: Equivalent amount of DCBCO1701-DS 2.C max Observed maximum blood concentration 3.AUC: Area under the blood concentration-time curve 4. Per os: Oral administration

[0138] The results in Table 5 show that when EI-1071 tablets were administered under non-fasting conditions, the absorption of DCBCO1701-DS in animals was significantly higher. This is indicated by the AUC / Dose values ​​of 175.7 under non-fasting conditions and 117.5 under fasting conditions, as well as the time course of DCBCO1701-DS concentration in blood samples (Figure 2).

[0139] Research 3

[0140] Study 3 was similar to Study 2, but investigated a larger number of doses. The results are summarized in Tables 6 and 7, and Figures 3A and 3B. When EI-1071 tablets were administered under non-fasting (or post-meal) conditions, the absorption of DCBCO1701-DS in animals was significantly higher at all doses (75 mg / 10 kg, 150 mg / 10 kg, and 300 mg / 10 kg). This can be confirmed by the AUC / Dose values ​​for fasting and post-meal conditions shown in Figure 3B.

[0141] [Table 6]

[0142] #EQ DCBCO1701-DS: Equivalent amount of DCBCO1701-DS

[0143] [Table 7]

[0144] #EQ DCBCO1701-DS: Equivalent amount of DCBCO1701-DS

[0145] Based on the results of trials 2 and 3, it was concluded that, unlike the aforementioned drugs such as repaglinide, nevirapine, and telmisartan, dietary intake prior to administration of EI-1071 tablets significantly increased the absorption of DCBCO1701-DS in dogs.

[0146] conclusion

[0147] This invention provides the unexpected finding that the quinoxaline compound of the present invention, which has low solubility in water but high solubility in acidic buffers, can be efficiently delivered into the body by administration after or with food intake, thereby improving the therapeutic effect of kinase-mediated diseases such as cancer, autoimmune diseases, bone resorption diseases, and neurodegenerative diseases.

[0148] Unless otherwise defined, all technical and scientific terms and abbreviations used herein shall have the same meaning as that commonly understood by those skilled in the art in the field of the invention. Similar or equivalent compositions, methods, kits, and means of communication described herein may be used to carry out the invention, but the compositions, methods, kits, and means of communication described herein are recommended.

[0149] References 1. Gardner, JD, Ciociola, AA & Robinson, M. (2002).Measurement of meal-stimulated gastric acid secretion by in vivo gastric autotitration.Journal of Applied Physiolog,92(2),427-434.92,427-434(2002). 2. Sieger, P., Cui, Y., & Scheuerer, S. (2017).pH-dependent solubility and permeability profiles: A useful tool for prediction of oral bioavailability.European Journal of Pharmaceutical Sciences,105,82-90. 3. US FDA drug label(Reference ID 4052550). 4. Burrell, LM, & Johnston, CI (1997). Angiotensin II receptor antagonists. Potential in elderly patients with cardiovascular disease. Drugs Aging, 10(6), 421-434.

[0150] [Note 1] A method for improving the pharmacokinetics of a compound of formula (I), comprising administering to a subject in need thereof, in a non-fasting state, a pharmacopoeia comprising the compound of formula (I), its stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof. Here, the compound of formula (I) has the following structure,

[0151] [ka]

[0152] Here, X is CR 4 R 5 , NR 6 Selected from O and S; Z is -NR 7 Selected from the group consisting of - and -O-; U is N or CR 8 and; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyne; R 1The group consists of hydrogen, deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkylamino, C1-C6 alkoxy, C3-C6 cycloalkoxy, aryl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, and includes alkylamino, dialkylamino, alkoxy, alkyl, alkenyl, and alkynyl. Cycloalkyl, cycloalkenyl, cycloalkylamino, cycloalkoxy, heterocyclyl, aryl, and heteroaryl are optionally substituted with halogens, amino, hydroxyl, cyano, nitro, acyl, acyloxy, C1-C4 alkyl, hydroxyl C1-C4 alkyl, alkoxy C1-C4 alkyl, acyloxy C1-C4 alkyl, C1-C4 alkoxy, C1-C4 dialkylamino, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, aryl, and 5-6 membered heteroaryl; R 2 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, and C1-C6 dialkylaminocarbonyl; R 3 This is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino and C1-C6 dialkylamino; R 4 This is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and aryl; R 5 This is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl; R 6This is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; R 7 This is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; R 8 The group is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino.

[0153] [Note 2] The method described in Appendix 1, in which G is selected from the following.

[0154] [ka]

[0155] Here, R 9 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, carbonyl C1-C6 alkoxy, carbonyl C1-C6 alkylamino, and carbonyl C1-C6 dialkylamino; R 10 This is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; Furthermore, each n is independently 0, 1, 2, or 3.

[0156] [Note 3] The method described in Appendix 1, in which G is selected from the following.

[0157] [ka]

[0158] Here, R 11 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkyl, carboxylic acid, carbonyl C1-C6 alkoxy, carbonyl C1-C6 alkylamino, and carbonyl C1-C6 dialkylamino; R 12 This is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; Furthermore, each n is independently 0, 1, 2, or 3.

[0159] [Note 4] The method described in Appendix 1, in which G is selected from the following.

[0160] [ka]

[0161] Here, R 13 This is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, and C1-C6 dialkylaminocarbonyl; Furthermore, each n is independently 0, 1, 2, or 3.

[0162] [Note 5] The method described in Appendix 1, in which G is selected from the following.

[0163] [ka]

[0164] Here, R 14 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, carboxylic acid, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl and C1-C6 dialkylaminocarbonyl; Q is NR 15 , O and S, where R 15 is selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl; and each n is independently 0, 1, 2, or 3.

[0165] [Appendix 6] The method according to Appendix 1 where G is as follows.

[0166] [Chemical formula]

[0167] Here, R 16 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl and C1-C6 dialkylaminocarbonyl.

[0168] [Appendix 7] The method according to Appendix 1 where X is NH.

[0169] [Appendix 8] The method according to Appendix 1 where Z is -O-.

[0170] [Appendix 9] The method according to Appendix 1 where the compound of formula (I) is any of the following. 3-Methoxy-6-((6-(((6-((((trifluoromethyl)pyridine-3-yl)methyl)amino)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; N 5 -(3-methoxyquinoxaline-6-yl)-N 2 -((6-(trifluoromethyl)pyridine-3-yl)methyl)pyridine-2,5-diamine; 3-Methoxy-6-((3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-((6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-N-(3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)quinoxaline-6-amine; 3-Methoxy-6-((6-(pyridine-3-yl)methoxy)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; 3-(dimethylamino)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-((3-Methoxy-4-(pyridine-3-ylmethoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-((6-((4-methoxybenzyl)oxy)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-(3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyloxy)quinoxaline-5-carbonitrile; 6-((3,4-dimethylphenyl)amino)-3-methoxyquinoxaline-5-carbonitrile; 6-((3-methoxy-4-(4-methoxybenzyloxy)phenyl)amino)-3-(methylamino)quinoxaline-5-carbonitrile; 3-(2-(dimethylamino)ethoxy)-6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)-quinoxaline-5-carbonitrile; 3-Methoxy-6-(3-Methoxy-4-(4-Methoxybenzylamino)phenylamino)quinoxaline-5-carbonitrile; 3-Methoxy-6-(4-(4-methoxybenzyloxy)phenylamino)quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 3-(isopropylamino)-6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)quinoxaline-5-carbonitrile; 6-(2-fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-methoxyquinoxaline-5-carbonitrile; 3-(dimethylamino)-6-(3-methoxy-4-(4-methoxybenzyloxy)phenyloxy)quinoxaline-5-carbonitrile; 6-(4-(4-ethoxybenzyloxy)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; 3-Methoxy-6-(3-Methoxy-4-(4-(trifluoromethoxy)benzyloxy)phenylamino)quinoxaline-5-carbonitrile; 6-(3-fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-methoxyquinoxaline-5-carbonitrile; 6-(4-(benzyloxy)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; N-(3-methoxy-4-(4-methoxybenzyloxy)phenyl)-3-morpholinoquinoxaline-6-amine; N 7 -(3-methoxy-4-(4-methoxybenzyloxy)phenyl)-N 2 -methylquinoxaline-2,7-diamine; 3-Methoxy-6-(3-Methoxy-4-(4-Methoxybenzyloxy)phenoxy)quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzyloxy)phenoxy)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-chlorobenzyloxy)-3-methoxyphenoxy)-3-methoxyquinoxaline-carbonitrile; 6-(4-(4-isopropylbenzylamino)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; 6-(3-ethoxy-4-(4-methoxybenzyloxy)phenoxy)-3-methoxyquinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)-3-(4-methylpiperazine-1-yl)quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-(trifluoromethoxy)benzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-ethylbenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-fluorobenzyloxy)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; 6-(4-(4-ethoxybenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(cyclopropylmethoxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(5-methoxy-6-(4-methoxybenzyloxy)pyridine-3-ylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-methoxybenzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzylamino)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-fluorobenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-Methoxy-4-((3-methyloxetan-3-yl)methoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((1-methylpiperidine-4-yl)methoxy)phenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(pyridine-3-ylmethoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(cyclopentylmethoxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-((2,3-dihydrobenzofuran-5-yl)methoxy)-3-methoxyphenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(pyridine-4-ylmethoxy)phenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-ethoxy-4-(pyridine-4-ylmethoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((1-methyl-1H-imidazole-2-yl)methoxy)phenylamino)-3-morpholi-quinoxaline-5-carbonitrile; 6-(4-(4-chlorobenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(pyrazine-2-ylmethoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(6-(4-Methoxybenzyloxy)pyridin-3-ylamino)-3-morpholinokynoxaline-5-carbonitrile; 6-(2-Fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-morpholinokynoxaline-5-carbonitrile; 6-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)amino)-3-morpholinokynoxaline-5-carbonitrile; 6-(3-Methoxy-4-((1-methyl-1H-imidazol-5-yl)methoxy)phenylamino)-3-morpholino-kynoxaline-5-carbonitrile; 6-(3-Fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-morpholinokynoxaline-5-carbonitrile; 6-(3-Methoxy-4-(pyridin-2-ylmethoxy)phenylamino)-3-morpholinokynoxaline-5-carbonitrile; 6-(4-(3,4-Dimethoxybenzyloxy)-3-methoxyphenylamino)-3-morpholinokynoxaline-5-carbonitrile; 6-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenylamino)-3-(piperazin-1-yl)kynoxaline-5-carbonitrile; 6-(3-Methoxy-4-((4-methoxybenzyl)oxy)phenyl)(methyl)amino)-3-morpholino-kynoxaline-5-carbonitrile; 6-(3-Methoxy-4-((5-methylisoxazol-3-yl)methoxy)phenyl))amino)-3-morpholino-kynoxaline-5-carbonitrile; 6-(3-Methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)-3-(pyrrolidin-1-yl)kynoxaline-5-carbonitrile; 6-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)amino)-3-morpholinokynoxaline-5-carbonitrile;<F 6-(4-((4-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 3-(4-(2-hydroxyethyl)piperazin-1-yl)-6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-(piperazine-1-yl)quinoxaline-5-carbonitrile; 1-(8-cyano-7-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-2-yl)piperidine-4-yl acetate; 6-((3-Methoxy-4-((6-Methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-methylpiperidine-1-yl)quinoxaline-5-carbonitrile; 3-(1H-imidazole-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; (1-(8-cyano-7-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-2-yl)piperidine-4-yl)methyl acetate; 3-(4-acetylpiperazine-1-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-(trifluoromethyl)pyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 2-(4-(8-cyano-7-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-2-yl)piperazine-1-yl)ethyl acetate; 3-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)amino)-3-((2-Morpholinoethyl)amino)quinoxaline-5-carbonitrile; 3-((1-benzylpiperidine-4-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-(4-methylpiperazine-1-yl)quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(pyrrolidine-1-yl)quinoxaline-5-carbonitrile; 3-(4-isopropylpiperazine-1-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-(benzo[d][1,3]dioxol-5-ylmethoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 3-(4-(dimethylamino)piperidine-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(azetidine-1-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-(4-(dimethylamino)piperidine-1-yl)quinoxaline-5-carbonitrile; 3-(4-(dimethylamino)piperidine-1-yl)-6-((4-((3-fluoro-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)quinoxaline-5-carbonitrile; 3-(azetidine-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(azetidine-1-yl)-6-((4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)quinoxaline-5-carbonitrile; 6-((4-(benzyloxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 3-(4-(dimethylamino)piperidine-1-yl)-6-((4-((3-fluorobenzyl)oxy)-3-methoxyphenyl)amino)quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)amino)-3-(piperazine-1-yl)quinoxaline-5-carbonitrile; 6-((4-((3-fluorobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-Methoxy-4-(prop-2-in-1-yloxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-((3-fluoro-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((2-fluoro-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-Methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-methylpiperazine-1-yl)quinoxaline-5-carbonitrile; 6-((4-((3-cyano-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-Methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-(2-Methoxyethyl)piperazine-1-yl)quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-Propylpyridine-3-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((3,4-difluorobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-(4-(2-methoxyethyl)piperazine-1-yl)quinoxaline-5-carbonitrile; 6-((4-((6-ethylpyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-Methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-morpholino-piperidine-1-yl)quinoxaline-5-carbonitrile; 6-((4-((6-isopropylpyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((6-(dimethylamino)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((1-methyl-1H-pyrazole-4-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; N-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3-(prop-1-en-2-yl)quinoxaline-6-amine; 6-((3-Methoxy-4-((6-(Methoxymethyl)pyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)amino)-3-(prop-1-en-2-yl)quinoxaline-5-carbonitrile; 3-Isopropyl-6-((3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((6-(fluoromethyl)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((6-(difluoromethyl)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-((6-ethoxypyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 3-(3,6-dihydro-2H-pyran-4-yl)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-(tetrahydro-2H-pyran-4-yl)quinoxaline-5-carbonitrile; 6-((4-((6-((dimethylaminomethyl)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((1-ethyl-1H-pyrazole-4-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((1-Propyl-1H-Pyrazole-4-yl)methoxy)phenyl)amino)-3-Morpholino-Quinoxaline-5-Carbonitrile; 3-(4-cyclopropylpiperazine-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Isopropoxy-6-((3-Methoxy-4-((6-Methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((6-cyclopropylpyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-(furan-3-ylmethoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-(furan-2-ylmethoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((tetrahydrofuran-2-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((5-methylthiophen-2-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((5-(Methoxymethyl)pyridine-2-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-(thiophen-3-ylmethoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-Methoxy-4-(thiophen-2-ylmethoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile 6-((3-Methoxy-4-((2-methylpyrimidine-5-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)(methyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((6-cyclopropylpyridine-3-yl)methoxy)-3-methoxyphenyl)(methyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-((1-(2-fluoroethyl)-1H-pyrazole-4-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((5-methoxypyridine-2-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 3-(dimethylamino)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((1-cyclopropyl-1H-pyrazole-4-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-Methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carboamide; 3-(3-(dimethylamino)azetidine-1-yl)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(dimethylamino)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(3-methoxy-3-methylazetidine-1-yl)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((3-cyano-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-(dimethylamino)quinoxaline-5-carbonitrile; 6-((4-((3-cyano-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-methoxyquinoxaline-5-carbonitrile; 6-((4-((1-(cyclopropylmethyl)-1H-pyrazole-4-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 3-Morpholino-6-((6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; 6-((5-Methoxy-6-((6-methylpyridine-3-yl)methoxy)pyridine-3-yl)amino)-3-morpholinoquinoxaline-5-carbonitrine; 6-((5-Methoxy-6-((6-Methoxypyridine-3-yl)methoxy)pyridine-3-yl)amino)-3-morpholinoquinoxaline-5-carbonitrine; 3-((2S,6R)-2,6-dimethylmorpholino)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; or, 6-((3-Methoxy-4-((6-methyl-1-(λ1-oxidanail)-1λ4-pyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile;

[0171] [Note 10] The method described in Appendix 1, wherein the compound of formula (I) is one of the following compounds.

[0172] [ka]

[0173] [Note 11] The method described in Appendix 1, wherein the compound of formula (I) is administered orally.

[0174] [Note 12] Improving pharmacokinetics leads to the peak blood concentration (C max The method according to Appendix 1, comprising increasing the area under the blood concentration-time curve (AUC) and / or the blood concentration-time curve.

[0175] [Note 13] The method according to Appendix 1, wherein the pharmaceutical further comprises a carrier, a diluent, or an excipient.

[0176] [Note 14] The method according to Appendix 13, wherein the excipient comprises a surfactant, a binder, a disintegrant, and / or a lubricant.

Claims

1. A method for improving the pharmacokinetics of a compound of formula (I), comprising administering to a subject in need thereof, in a non-fasting state, a pharmacopoeia comprising the compound of formula (I), its stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof. Here, the compound of formula (I) has the following structure, 【Chemistry 1】 Here, X is CR ４ R ５ , NR ６ Selected from O and S; Z is -NR ７ Selected from the group consisting of - and -O-; U is N or CR ８ And; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyne; R １ is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ５ -C ６ cycloalkenyl, C １ -C ６ alkylamino, C １ -C ６ dialkylamino, C ３ -C ６ cycloalkylamino, C<00几千0023>-C ６ alkoxy, C ３ -C[[ID=四十一]] ６ cycloalkoxy, aryl, 3-6 member heterocyclic, 5-6 member heteroaryl, and alkylamino, dialkylamino, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylamino, cycloalkoxy, heterocyclic, aryl and heteroaryl are optionally substituted with halogen, amino, hydroxyl, cyano, nitro, acyl, acyloxy, C １ -C ４ alkyl, hydroxyl C １ -C ４ alkyl, alkoxy C １ -C ４ alkyl, acyloxy C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ dialkylamino, C ３ -C ６ cycloalkyl, 3-6 member heterocyclic, aryl and 5-6 member heteroaryl, and is optionally substituted; R ２ These are hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, and C １ -C ６ Alkylamino, C １ -C ６ Dialkylamino, C １ -C ６ Alkoxy, carboxylic acid, C １ -C ６ Alkylcarbonyl, C ２ -C ６ Alkenylcarbonyl, C １ -C ６ Alkoxycarbonyl, aminocarbonyl, C １ -C ６ Alkylaminocarbonyl and C １ -C ６ Selected from the group consisting of dialkylaminocarbonyl; R ３ These are hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, and C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylamino and C １ -C ６ Selected from the group consisting of dialkylaminos; R ４ is hydrogen, deuterium, halogen, hydroxyl, amino, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Selected from the group consisting of alkoxys and aryls; R ５ is hydrogen, deuterium, C １ -C ６ Alkyl and C １ -C ６ Selected from the group consisting of haloalkyls; R ６ is hydrogen, C １ -C ６ Alkyl and C １ -C ６ Selected from the group consisting of haloalkyls; R ７ is hydrogen, C １ -C ６ Alkyl and C １ -C ６ Selected from the group consisting of haloalkyls; R ８ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, C1-C ６ -alkylamino and C １ -C ６ -dialkylamino.

2. The method according to claim 1, wherein G is selected from the following. 【Chemistry 2】 Here, R ９ is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkylamino C １ -C ６ -alkyl, C １ -C ６ -dialkylamino C １ -C ６ -alkyl, C １ -C ６ -alkylamino, C １ -C ６ -alkoxy C １ -C ６ -alkyl, C １ -C ６ -dialkylamino, C １ -C ６ -alkoxy, carboxylic acid, carbonyl C １ -C ６ -alkoxy, carbonyl C １ -C ６ -alkylamino and carbonyl C １ -C ６ -dialkylamino; R １０ is hydrogen, C １ -C ６ Alkyl and C １ -C ６ Selected from the group consisting of haloalkyls; Furthermore, each n is independently 0, 1, 2, or 3.

3. The method according to claim 1, wherein G is selected from the following. 【Transformation 3】 Here, R １１ These are hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkyl C １ -C ６ Alkyl, C １ -C ６ Alkylamino, C １ -C ６ Dialkylamino, C １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkyl, carboxylic acid, carbonyl C １ -C ６ Alkoxy, Carbonyl C １ -C ６ Alkylamino and Carbonyl C １ -C ６ Selected from the group consisting of dialkylaminos; R １２ is hydrogen, C １ -C ６ Alkyl and C １ -C ６ Selected from haloalkyls; Furthermore, each n is independently 0, 1, 2, or 3.

4. The method according to claim 1, wherein G is selected from the following. 【Chemistry 4】 Here, R １３ These are hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkylamino, C １ -C ６ Dialkylamino, C １ -C ６ Alkoxy, carboxylic acid, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkylaminocarbonyl and C １ -C ６ Selected from the group consisting of dialkylaminocarbonyl; Furthermore, each n is independently 0, 1, 2, or 3.

5. The method according to claim 1, wherein G is selected from the following. 【Transformation 5】 Here, R １４ These are hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkylamino, C １ -C ６ Dialkylamino, C １ -C ６ Alkoxy, carboxylic acid, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkylaminocarbonyl and C １ -C ６ Selected from the group consisting of dialkylaminocarbonyl; Q is NR １５ , selected from O and S, where R １５ is hydrogen, C １ -C ６ Alkyl and C １ -C ６ Selected from the group consisting of haloalkyls; Furthermore, each n is independently 0, 1, 2, or 3.

6. The method according to claim 1, wherein G is as follows. 【Transformation 6】 Here, R １６ is hydrogen, deuterium, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkylaminocarbonyl and C １ -C ６ Selected from the group consisting of dialkylaminocarbonyl.

7. The method according to claim 1, wherein X is NH.

8. The method according to claim 1, wherein Z is -O-.

9. The method according to claim 1, wherein the compound of formula (I) is any of the following. 3-Methoxy-6-((6-(((6-(trifluoromethyl)pyridine-3-yl)methyl)amino)pyridine-3-yl)amino)quinoxaline-5-carbonitriel; N ５ -(3-methoxyquinoxaline-6-yl)-N ２ -((6-(trifluoromethyl)pyridine-3-yl)methyl)pyridine-2,5-diamine; 3-Methoxy-6-((3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-((6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-N-(3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)quinoxaline-6-amine; 3-Methoxy-6-((6-(pyridine-3-yl)methoxy)pyridine-3-yl)amino)quinoxaline-5-carbonitriel; 3-(dimethylamino)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-((3-Methoxy-4-(pyridine-3-ylmethoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-((6-((4-Methoxybenzyl)oxy)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; 3-Methoxy-6-(3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyloxy)quinoxaline-5-carbonitrile; 6-((3,4-dimethylphenyl)amino)-3-methoxyquinoxaline-5-carbonitrile; 6-((3-methoxy-4-(4-methoxybenzyloxy)phenyl)amino)-3-(methylamino)quinoxaline-5-carbonitrile; 3-(2-(dimethylamino)ethoxy)-6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)-quinoxaline-5-carbonitrile; 3-Methoxy-6-(3-Methoxy-4-(4-Methoxybenzylamino)phenylamino)quinoxaline-5-carbonitrile; 3-Methoxy-6-(4-(4-methoxybenzyloxy)phenylamino)quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 3-(isopropylamino)-6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)quinoxaline-5-carbonitrile; 6-(2-fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-methoxyquinoxaline-5-carbonitrile; 3-(dimethylamino)-6-(3-methoxy-4-(4-methoxybenzyloxy)phenyloxy)quinoxaline-5-carbonitrile; 6-(4-(4-ethoxybenzyloxy)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; 3-Methoxy-6-(3-Methoxy-4-(4-(trifluoromethoxy)benzyloxy)phenylamino)quinoxaline-5-carbonitrile; 6-(3-fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-methoxyquinoxaline-5-carbonitrile; 6-(4-(benzyloxy)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; N-(3-methoxy-4-(4-methoxybenzyloxy)phenyl)-3-morpholinoquinoxaline-6-amine; N ７ -(3-methoxy-4-(4-methoxybenzyloxy)phenyl)-N ２ -Methylquinoxaline-2,7-diamine; 3-Methoxy-6-(3-Methoxy-4-(4-Methoxybenzyloxy)phenoxy)quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzyloxy)phenoxy)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-chlorobenzyloxy)-3-methoxyphenoxy)-3-methoxyquinoxaline-carbonitrile; 6-(4-(4-isopropylbenzylamino)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; 6-(3-ethoxy-4-(4-methoxybenzyloxy)phenoxy)-3-methoxyquinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzyloxy)phenylamino)-3-(4-methylpiperazine-1-yl)quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-(trifluoromethoxy)benzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-ethylbenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-fluorobenzyloxy)-3-methoxyphenylamino)-3-methoxyquinoxaline-5-carbonitrile; 6-(4-(4-ethoxybenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(cyclopropylmethoxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(5-methoxy-6-(4-methoxybenzyloxy)pyridine-3-ylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-methoxybenzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-(4-methoxybenzylamino)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(4-fluorobenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((3-methyloxetan-3-yl)methoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((1-methylpiperidine-4-yl)methoxy)phenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(pyridine-3-ylmethoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(cyclopentylmethoxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-((2,3-dihydrobenzofuran-5-yl)methoxy)-3-methoxyphenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(pyridine-4-ylmethoxy)phenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-ethoxy-4-(pyridine-4-ylmethoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((1-methyl-1H-imidazole-2-yl)methoxy)phenylamino)-3-morpholi-quinoxaline-5-carbonitrile; 6-(4-(4-chlorobenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-(pyrazine-2-ylmethoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(6-(4-methoxybenzyloxy)pyridine-3-ylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(2-fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((1-methyl-1H-imidazole-5-yl)methoxy)phenylamino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-fluoro-4-(4-methoxybenzyloxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-(pyridine-2-ylmethoxy)phenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-(3,4-dimethoxybenzyloxy)-3-methoxyphenylamino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenylamino)-3-(piperazine-1-yl)quinoxaline-5-carbonitrile; 6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)(methyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-((5-methylisoxazole-3-yl)methoxy)phenyl))amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)-3-(pyrrolidine-1-yl)quinoxaline-5-carbonitrile; 6-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-((4-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-(4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 3-(4-(2-hydroxyethyl)piperazine-1-yl)-6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-(piperazine-1-yl)quinoxaline-5-carbonitrile; 1-(8-cyano-7-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-2-yl)piperidine-4-yl acetate; 6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-methylpiperidine-1-yl)quinoxaline-5-carbonitrile; 3-(1H-imidazole-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; (1-(8-cyano-7-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-2-yl)piperidine-4-yl)methyl acetate; 3-(4-acetylpiperazine-1-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-(trifluoromethyl)pyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 2-(4-(8-cyano-7-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-2-yl)piperazine-1-yl)ethyl acetate; 3-(4-(2-hydroxyethyl)piperazine-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)-3-((2-morpholinoethyl)amino)quinoxaline-5-carbonitrile; 3-((1-benzylpiperidine-4-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-(4-methylpiperazine-1-yl)quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(pyrrolidine-1-yl)quinoxaline-5-carbonitrile; 3-(4-isopropylpiperazine-1-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-(benzo[d][1,3]dioxol-5-ylmethoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 3-(4-(dimethylamino)piperidine-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(azetidine-1-yl)-6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)-3-(4-(dimethylamino)piperidine-1-yl)quinoxaline-5-carbonitrile; 3-(4-(dimethylamino)piperidine-1-yl)-6-((4-((3-fluoro-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)quinoxaline-5-carbonitrile; 3-(azetidine-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(azetidine-1-yl)-6-((4-((3-cyanobenzyl)oxy)-3-methoxyphenyl)amino)quinoxaline-5-carbonitrile; 6-((4-(benzyloxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 3-(4-(dimethylamino)piperidine-1-yl)-6-((4-((3-fluorobenzyl)oxy)-3-methoxyphenyl)amino)quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)-3-(piperazine-1-yl)quinoxaline-5-carbonitrile; 6-((4-((3-fluorobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-(prop-2-in-1-yloxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-((3-fluoro-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((2-fluoro-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-methylpiperazine-1-yl)quinoxaline-5-carbonitrile; 6-((4-((3-cyano-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-(2-methoxyethyl)piperazine-1-yl)quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-propylpyridine-3-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((3,4-difluorobenzyl)oxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-(4-(2-methoxyethyl)piperazine-1-yl)quinoxaline-5-carbonitriel; 6-((4-((6-ethylpyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)-3-(4-morpholino-piperidine-1-yl)quinoxaline-5-carbonitrile; 6-((4-((6-isopropylpyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((6-(dimethylamino)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((1-methyl-1H-pyrazole-4-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; N-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3-(prop-1-en-2-yl)quinoxaline-6-amine; 6-((3-methoxy-4-((6-(methoxymethyl)pyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)amino)-3-(prop-1-en-2-yl)quinoxaline-5-carbonitrile; 3-Isopropyl-6-((3-Methoxy-4-((4-Methoxybenzyl)oxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((6-(fluoromethyl)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((6-(difluoromethyl)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-((6-ethoxypyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 3-(3,6-dihydro-2H-pyran-4-yl)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitriel; 6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-(tetrahydro-2H-pyran-4-yl)quinoxaline-5-carbonitriel; 6-((4-((6-((dimethylaminomethyl)pyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((1-ethyl-1H-pyrazole-4-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((1-propyl-1H-pyrazole-4-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 3-(4-cyclopropylpiperazine-1-yl)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-Isopropoxy-6-((3-Methoxy-4-((6-Methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((6-cyclopropylpyridine-3-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-(furan-3-ylmethoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-(furan-2-ylmethoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((tetrahydrofuran-2-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((5-methylthiophen-2-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((5-(methoxymethyl)pyridine-2-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-(thiophen-3-ylmethoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-(thiophen-2-ylmethoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile 6-((3-methoxy-4-((2-methylpyrimidine-5-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)(methyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 6-((4-((6-cyclopropylpyridine-3-yl)methoxy)-3-methoxyphenyl)(methyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((4-((1-(2-fluoroethyl)-1H-pyrazole-4-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((5-methoxypyridine-2-yl)methoxy)phenyl)amino)-3-morpholino-quinoxaline-5-carbonitrile; 3-(dimethylamino)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitriel; 6-((4-((1-cyclopropyl-1H-pyrazole-4-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carboamide; 3-(3-(dimethylamino)azetidine-1-yl)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(dimethylamino)-6-((3-methoxy-4-((6-methoxypyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 3-(3-methoxy-3-methylazetidine-1-yl)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; 6-((4-((3-cyano-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-(dimethylamino)quinoxaline-5-carbonitrile; 6-((4-((3-cyano-4-methoxybenzyl)oxy)-3-methoxyphenyl)amino)-3-methoxyquinoxaline-5-carbonitrile; 6-((4-((1-(cyclopropylmethyl)-1H-pyrazole-4-yl)methoxy)-3-methoxyphenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 3-Morpholino-6-((6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-yl)amino)quinoxaline-5-carbonitrile; 6-((5-methoxy-6-((6-methylpyridine-3-yl)methoxy)pyridine-3-yl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 6-((5-methoxy-6-((6-methoxypyridine-3-yl)methoxy)pyridine-3-yl)amino)-3-morpholinoquinoxaline-5-carbonitrile; 3-((2S,6R)-2,6-dimethylmorpholino)-6-((3-methoxy-4-((6-methylpyridine-3-yl)methoxy)phenyl)amino)quinoxaline-5-carbonitrile; Or, 6-((3-methoxy-4-((6-methyl-1-(λ1-oxidanail)-1λ4-pyridine-3-yl)methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile;

10. The method according to claim 1, wherein the compound of formula (I) is one of the following compounds. 【Transformation 7】

11. The method according to claim 1, wherein the compound of formula (I) is administered orally.

12. Improving pharmacokinetics leads to the peak blood concentration (C ｍａｘ The method according to claim 1, comprising increasing ) and / or increasing the area under the blood concentration-time curve (AUC).

13. The method according to claim 1, further comprising a carrier, diluent, or excipient.

14. The method according to claim 13, wherein the excipient comprises a surfactant, a binder, a disintegrant and / or a lubricant.

Images