Method for treating or preventing tumors

Abstract

Disclosed is a method of treating or preventing a tumor, the method comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound represented by general formula (I): wherein R1, R2, X and Y are as defined in the disclosure, or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Methods for treating or preventing tumors

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the invention patent application with application number 202211329128.3 and invention name “Method for treating or preventing tumors” filed with the State Intellectual Property Office of the People’s Republic of China on October 27, 2022, and incorporates its entire contents into this disclosure by reference.

[0003] field

[0004] The present disclosure relates generally to the field of medicinal chemistry, and more particularly to methods for treating and preventing tumors.

[0005] background

[0006] Cancer incidence is increasing, with approximately 4.2 million deaths worldwide each year. In 2012, China accounted for nearly half of all cancer cases worldwide, ranking first. Cancer treatments primarily include cytotoxic drugs and molecularly targeted drugs. Cytotoxic drugs, also known as traditional chemotherapy agents, primarily inhibit tumor growth by killing rapidly dividing tumor cells. However, cytotoxic drugs can also harm normally rapidly dividing cells, such as those in the bone marrow, gastrointestinal tract, and hair follicles, leading to common chemotherapy side effects such as bone marrow suppression, mucositis, and alopecia. Targeted drug therapies achieve therapeutic effects by interfering with specific protein targets that influence tumor cell proliferation. A well-designed protein or enzyme target possesses mutations or other genetic alterations specific to tumor cells but absent in normal tissue cells, thereby achieving specific cell selectivity. However, targeted drugs often suffer from limitations such as drug resistance and target-molecule-related toxic side effects, resulting in many drug candidates failing in clinical trials despite promising results in animal models. The combined use of targeted inhibitors and cytotoxic drugs can improve drug efficacy through two different mechanisms of action, thereby achieving a better efficacy / toxicity window by reducing the dosage.

[0007] Anaplastic lymphoma kinase (ALK) is a transmembrane protein tyrosine kinase that belongs to the insulin receptor kinase subfamily. It was first discovered in anaplastic large cell lymphoma (ALCL) as a nucleophosmin (NPM)-ALK fusion, a T-cell non-Hodgkin lymphoma often associated with a chromosomal translocation. Since then, many cancers have been associated with different forms of ALK fusions. These include non-small cell lung cancer (NSCLC, EML4-ALK), inflammatory myofibroblastic tumor (IMT, TPM3-ALK), and diffuse large B-cell lymphoma (DLBCL, CLTC-ALK). In addition, amplification of the ALK gene and mutations in the wild-type ALK protein have been reported in various tumors.

[0008] Targeted inhibition of anaplastic lymphoma kinase (ALK) has significantly improved treatment outcomes for ALK-positive cancers, but unfortunately, acquired resistance mutations in ALK have emerged. Therefore, it is crucial to develop a class of highly active and selective pyrimidopyrrole kinase inhibitors that target ALK. Currently available ALK inhibitors are all class I kinase inhibitors that compete with ATP for the binding pocket.

[0009] Overview

[0010] In one aspect, the present disclosure relates to a method for treating or preventing tumors, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0011] in:

[0012] R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;

[0013] R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group; and

[0014] X and Y are each independently selected from O, S or N.

[0015] In another aspect, the present disclosure relates to the use of a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing tumors:

[0016] in:

[0017] R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;

[0018] R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group; and

[0019] X and Y are each independently selected from O, S or N.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG1 shows the interaction pattern between the compound YH-I-001 of the present disclosure and ALK;

[0022] Figure 2 shows the -1 The blood concentration-time curve of the compound YH-I-001 of the present disclosure in ICR mice after intravenous administration of a dose of

[0023] Figure 3 shows the -1 The blood concentration-time curve of the compound YH-I-001 of the present disclosure in ICR mice after intravenous administration of a dose of

[0024] FIG4 shows a graph showing the changes in tumor volume of KELLY tumor-bearing mice; and

[0025] FIG5 shows the weight changes of KELLY tumor-bearing mice.

[0026] Details

[0027] In the following description, certain specific details are included to provide a thorough understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0028] Unless otherwise required by this disclosure, throughout this specification and the claims that follow, the words "include" and "comprising" should be construed in an open, inclusive sense, ie, "including, but not limited to."

[0029] Reference throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" means that the particular referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "one embodiment" or "an embodiment" or "another embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0030] It should be understood that the singular article "a", "an" and "the" used in the specification of the present disclosure and the appended claims include plural objects unless the context clearly provides otherwise. Therefore, for example, a pharmaceutical composition comprising "a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes one compound of formula (I) or a pharmaceutically acceptable salt thereof, or two or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0031] definition

[0032] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0033] Certain chemical groups named in this disclosure are preceded by abbreviations indicating the total number of carbon atoms present in the indicated chemical group. For example, C1-C4 alkyl describes an alkyl group as defined below having a total of 1 to 4 carbon atoms, while C3-C4 alkyl describes an alkyl group ... 10 Cycloalkyl describes a cycloalkyl group as defined below having a total of 3 to 10 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0034] In this disclosure, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0035] In this disclosure, the term "hydroxyl" refers to an -OH group.

[0036] In this disclosure, the term "amino" refers to a -NH2 group.

[0037] In this disclosure, the term "cyano" refers to a -CN group.

[0038] In the present disclosure, the term "hydrocarbyl" refers to an aliphatic hydrocarbon group. The hydrocarbyl portion can be a "saturated hydrocarbyl" group, meaning that it does not contain any alkene or alkyne moieties. The hydrocarbyl portion can also be an "unsaturated hydrocarbyl" portion, meaning that it contains at least one alkene or alkyne moiety. The "alkene" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, and connected to the rest of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc., and the "alkyne" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon triple bond, and connected to the rest of the molecule by a single bond. The hydrocarbyl portion, whether saturated or unsaturated, can be branched or straight-chain.

[0039] The hydrocarbyl group can have from 1 to 8 carbon atoms (each occurrence in this disclosure of a numerical range such as "1 to 8" refers to each integer in the given range; e.g., "1 to 8" means that the hydrocarbyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 8 carbon atoms, although this definition also covers occurrences of the term "hydrocarbyl" without specifying a numerical range).

[0040] The hydrocarbyl group may be optionally substituted, i.e., substituted or unsubstituted. When substituted, the substituent groups are individually and independently selected from one or more of the following: cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined herein), or amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Typical hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, propynyl and butynyl. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0041] In certain embodiments, "C1-C4 hydrocarbyl" refers to a hydrocarbyl group as defined above containing one to four carbon atoms. The C1-C4 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0042] In certain embodiments, a "C1-C4 hydrocarbyl" may be a C1-C4 alkyl group. A C1-C4 alkyl group may be optionally substituted as defined for a hydrocarbyl group.

[0043] In certain embodiments, "C1-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing one to six carbon atoms. The C1-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0044] In certain embodiments, a "C1-C6 hydrocarbyl" may be a C1-C6 alkyl group. A C1-C6 alkyl group may be optionally substituted as defined for a hydrocarbyl group.

[0045] In certain embodiments, "C1-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing from one to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0046] In certain embodiments, "C1-C 12 The "hydrocarbon group" can be C1-C 12 Alkyl group. C1-C 12 Alkyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0047] In certain embodiments, "C2-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing two to six carbon atoms. The C2-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0048] In certain embodiments, a "C2-C6 hydrocarbyl" may be a C2-C6 alkyl group. A C2-C6 alkyl group may be optionally substituted as defined for a hydrocarbyl group.

[0049] In certain embodiments, a "C2-C6 alkyl" may be a C2-C6 alkenyl group. A C2-C6 alkenyl group may be optionally substituted as defined for an alkyl group.

[0050] In certain embodiments, a "C2-C6 alkyl" may be a C2-C6 alkynyl group. A C2-C6 alkynyl group may be optionally substituted as defined for an alkyl group.

[0051] In certain embodiments, "C3-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing three to six carbon atoms. A C3-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0052] In certain embodiments, a "C3-C6 hydrocarbyl" may be a C3-C6 alkyl group. A C3-C6 alkyl group may be optionally substituted as defined for a hydrocarbyl group.

[0053] In certain embodiments, a "C3-C6 alkyl" may be a C3-C6 alkenyl group. A C3-C6 alkenyl group may be optionally substituted as defined for an alkyl group.

[0054] In certain embodiments, a "C3-C6 alkyl" may be a C3-C6 alkynyl group. A C3-C6 alkynyl group may be optionally substituted as defined for an alkyl group.

[0055] In certain embodiments, "C3-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing three to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0056] In certain embodiments, "C3-C 12 The hydrocarbon group can be C3-C 12 Alkyl group. C3-C 12 Alkyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0057] In certain embodiments, "C3-C 12The hydrocarbon group can be C3-C 12 Alkenyl group. C3-C 12 Alkenyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0058] In certain embodiments, "C3-C 12 The hydrocarbon group can be C3-C 12 Alkynyl group. C3-C 12 Alkynyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0059] In certain embodiments, "C6-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing six to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0060] In certain embodiments, "C6-C 12 The hydrocarbon group can be C6-C 12 Alkyl group. C6-C 12 Alkyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0061] In certain embodiments, "C6-C 12 The hydrocarbon group can be C6-C 12 Alkenyl group. C6-C 12 Alkenyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0062] In certain embodiments, "C6-C 12 The hydrocarbon group can be C6-C 12 Alkynyl group. C6-C 12 Alkynyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0063] In certain embodiments, "C7-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing seven to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0064] In certain embodiments, "C7-C 12 The hydrocarbon group can be C7-C 12 Alkyl group. C7-C 12 Alkyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0065] In certain embodiments, "C7-C 12 The hydrocarbon group can be C7-C 12 Alkenyl group. C7-C12 Alkenyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0066] In certain embodiments, "C7-C 12 The hydrocarbon group can be C7-C 12 Alkynyl group. C7-C 12 Alkynyl groups may be optionally substituted as defined for hydrocarbyl groups.

[0067] In the present disclosure, the term "alkyloxy" refers to the general formula -O-alkyl, wherein alkyl is as defined in the present disclosure. Illustrative examples of alkyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and tert-pentoxy.

[0068] In the present disclosure, the term "aryl" refers to a carbocyclic ring (all carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a completely delocalized pi electron system. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Aryl groups can, for example, have five to twelve carbon atoms. The aryl groups of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0069] In the present disclosure, the term "heteroaryl" refers to a 5- to 18-membered aromatic ring group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Illustrative examples of heteroaryl groups include, but are not limited to, azaquinolyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, diphenyl The heteroaryl groups of the present disclosure may be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0070] In the present disclosure, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, in certain embodiments from three to twelve carbon atoms, and which is saturated or unsaturated and is attached to the rest of the molecule by a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, and the like. Unless otherwise expressly stated in the present disclosure, the term "cycloalkyl" is intended to include cycloalkyl as defined above optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfinylamino, N-sulfinylamino, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl as defined in the present disclosure), or amino including mono- and di-substituted amino groups, and protected derivatives thereof.

[0071] In certain embodiments, "C3-C6 cycloalkyl" refers to a cycloalkyl group as defined above having three to six carbon atoms. The C3-C6 cycloalkyl group may be optionally substituted as defined above for cycloalkyl.

[0072] In certain embodiments, "C3-C 10 "Cycloalkyl" refers to a cycloalkyl group as defined above having three to ten carbon atoms. 10 The cycloalkyl group may be optionally substituted as defined above for a cycloalkyl group.

[0073] In certain embodiments, "C3-C 12 "Cycloalkyl" refers to a cycloalkyl group as defined above having three to twelve carbon atoms. 12 The cycloalkyl group may be optionally substituted as defined above for a cycloalkyl group.

[0074] In the present disclosure, the term "heterocycloalkyl" refers to a stable three- to twelve-membered non-aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of such heterocyclyl groups include, but are not limited to, dioxolane, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0075] In the present disclosure, the term "compound of the present disclosure or a pharmaceutically acceptable salt thereof" refers to the compound represented by the general formula (I) of the present disclosure and a pharmaceutically acceptable salt thereof, as well as any specific compound falling within the general formula (I) and a pharmaceutically acceptable salt thereof.

[0076] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.

[0077] In this disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In certain embodiments, the patient is a mammal, including males and females. In certain embodiments, the patient is a human.

[0078] In this disclosure, the term "pharmaceutically acceptable" refers to carriers, vehicles, diluents, excipients and / or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0079] In this disclosure, the terms “optional” or “optionally” mean that the subsequently described event or circumstance can or cannot occur, and the description includes instances where the event or circumstance occurs and instances where it does not.

[0080] In the present disclosure, the term "pharmaceutically acceptable excipients" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0081] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

[0082] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0083] In this disclosure, the term "acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, Glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0084] In this disclosure, the term "acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acids, and the base addition salts are biologically or otherwise suitable. These salts are prepared by adding inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0085] As used herein, the term "pharmaceutical composition" refers to a formulation of a compound described herein and a medium generally accepted in the art for delivering the bioactive compound to mammals, such as humans. Such a medium includes any pharmaceutically acceptable carrier, diluent, or excipient.

[0086] In the present disclosure, the term "therapeutically effective amount" refers to an amount of a compound or combination of compounds that ameliorates, reduces, or eliminates a particular disease or condition and symptoms of a particular disease or condition, or prevents or delays the onset of a particular disease or condition or symptoms of a particular disease or condition. The amount of a compound described in the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, but the amount of a compound described in the present disclosure can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0087] As used herein, "treating" or "treatment" encompasses treating a relevant disease or condition in a mammal, such as a human, suffering from the relevant disease or condition, and includes:

[0088] (i) preventing a disease or disease state from occurring in a mammal, particularly where the mammal is susceptible to said disease state but has not yet been diagnosed with such disease state;

[0089] (ii) inhibiting the disease or disease state, i.e., preventing its occurrence; or

[0090] (iii) ameliorating the disease or condition, even if the disease or condition regresses or does not progress.

[0091] In this disclosure, the term "prevent" or "preventing" refers to preventing the onset, recurrence, or spread of a disease or disease state, or one or more symptoms thereof.

[0092] In this disclosure, the term "prophylactically effective amount" refers to an amount of a compound or combination of compounds sufficient to prevent a disease or disease state, or to prevent its recurrence or spread. The amount of a compound described in this disclosure that constitutes a "prophylactically effective amount" will vary depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, but the amount of a compound described in this disclosure can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0093] As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be distinct in that a particular disease or disease state may have no known causative agent (and therefore cannot be explained etiologically) and therefore is not recognized as a disease, but rather is considered an undesirable disease state or condition in which clinicians have identified a more or less specific constellation of symptoms.

[0094] In this disclosure, the term "topoisomerase" refers to an enzyme that corrects the number of DNA strands by severing the phosphodiester bonds in one or both strands of DNA, followed by rewinding and sealing. DETAILED DESCRIPTION

[0095] In one aspect, the present disclosure relates to a method for treating or preventing tumors, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound represented by formula (I), and a pharmaceutically acceptable salt thereof:

[0096] in:

[0097] R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;

[0098] R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group; and

[0099] X and Y are each independently selected from O, S or N.

[0100] In certain embodiments, R1 is selected from halogen, unsubstituted aryl, optionally substituted alkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, optionally substituted amino-substituted aryl, sulfonamido-substituted aryl, unsubstituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted amino-substituted heteroaryl, or heterocycloalkyl-substituted heteroaryl.

[0101] In certain embodiments, R1 is selected from halogen, unsubstituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted heterocycloalkyl-substituted optionally substituted alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, optionally substituted amino-substituted phenyl, sulfonamido-substituted phenyl, unsubstituted pyridyl, unsubstituted thienyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, optionally substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocycloalkyl-substituted amino-substituted pyrazolyl, or heterocycloalkyl-substituted pyrazolyl.

[0102] In certain embodiments, R1 is selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-substituted alkyl-substituted aryl, alkyl-substituted heterocycloalkyl-substituted alkyl-substituted aryl, alkyl-substituted heterocycloalkyl-substituted oxoalkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, alkyl-substituted amino-substituted aryl, optionally substituted heterocycloalkyl-substituted amino-substituted aryl, sulfonamido-substituted phenyl, unsubstituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocycloalkyl-substituted amino-substituted heteroaryl, or heterocycloalkyl-substituted heteroaryl.

[0103] In certain embodiments, R1 is selected from iodo, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4-(4-methylpiperazin-1-yl)methylphenyl, 4-(4-methylpiperazin-1-yl)oxymethylphenyl, methoxyphenyl, isopropyloxyphenyl, bromophenyl, cyano-substituted phenyl, dimethylaminophenyl, 2-methyl-4-piperidinyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methylpiperidinyl)-amino-substituted phenyl, 2-methyl-4-tetrahydropyrrolyl-substituted amino-substituted phenyl, 2-methyl-4-sulfonyl-substituted phenyl, amido-substituted phenyl, pyridyl, thienyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

[0104] In certain embodiments, R1 is selected from:

[0105] In certain embodiments, R2 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted aryl-heterocycloalkyl.

[0106] In certain embodiments, R2 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted benzoheterocycloalkyl.

[0107] In certain embodiments, R2 is selected from unsubstituted alkyl, halogen-substituted aryl, optionally substituted alkyl-substituted aryl, optionally substituted alkoxy-substituted aryl, unsubstituted cycloalkyl, unsubstituted benzoheterocycloalkyl, or halogen-substituted benzoheterocycloalkyl.

[0108] In certain embodiments, R2 is selected from unsubstituted alkyl, halogen-substituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkoxy-substituted phenyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted thienyl, unsubstituted cycloalkyl, unsubstituted benzo[1,3]dioxolanyl, or halogen-substituted benzo[1,3]dioxolanyl.

[0109] In certain embodiments, R2 is selected from hexyl, 3,4-dichlorophenyl, 4-chlorophenyl, 4-isopropylphenyl, 3,5-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, cyclopentyl or cyclohexyl.

[0110] In certain embodiments, R2 is selected from:

[0111] In certain embodiments, X is N and Y is O.

[0112] In certain embodiments, X is N and Y is S.

[0113] In certain embodiments, X is O and Y is N.

[0114] In certain embodiments, X is O and Y is S.

[0115] In another aspect, the present disclosure relates to compounds, and pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0116] N-(4-chlorophenyl)-5-((6-(2-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0117] N-(4-chlorophenyl)-5-((6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0118] N-(4-chlorophenyl)-5-((6-(p-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0119] N-(4-chlorophenyl)-5-((6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0120] 5-((6-(4-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-chlorophenyl)benzo[d]oxazol-2-amine;

[0121] N-(4-chlorophenyl)-5-((6-(thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0122] N-(4-chlorophenyl)-5-((6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0123] N-(4-chlorophenyl)-5-((6-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0124] N-(4-chlorophenyl)-5-((6-(pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0125] N-(4-chlorophenyl)-5-((6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0126] N-(4-chlorophenyl)-5-((6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0127] 4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzonitrile;

[0128] N-(4-chlorophenyl)-5-((6-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0129] N-(4-chlorophenyl)-5-((6-(2-isopropylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0130] N-(4-chlorophenyl)-5-((6-(4-(dimethylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0131] N-(4-chlorophenyl)-5-((6-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0132] N-(4-chlorophenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0133] N-(3,5-bis(trifluoromethyl)phenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0134] N-(3,4-dichlorophenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0135] 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0136] 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-2-amine;

[0137] N-(4-isopropylphenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0138] N-cyclopentyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0139] N-cyclohexyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0140] N-hexyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0141] N-(4-chlorophenyl)-5-((6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0142] 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-phenylbenzo[d]oxazol-2-amine;

[0143] 5-((6-(2-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0144] 5-((6-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0145] 5-((6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0146] 5-((6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0147] 5-((6-(2-methyl-4-(pyrrolidin-3-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0148] 5-((6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0149] N-(4-chlorophenyl)-5-((6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0150] 5-((6-(4-(4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-amine;

[0151] (4-methylpiperazin-1-yl)(4-(4-((4-(trifluoromethyl)phenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methanone;

[0152] N-(4-chlorophenyl)-5-((6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0153] 5-((6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine;

[0154] N-(4-chlorophenyl)-5-((6-(1,3-dimethyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine;

[0155] 2-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethan-1-ol;

[0156] 1-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol; and

[0157] 1-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol.

[0158] In certain embodiments, the compounds of the present disclosure have potent inhibitory activity against ALK.

[0159] In certain embodiments, the compounds of the present disclosure are resistant to drug resistance of ALK mutants.

[0160] In certain embodiments, the compounds of the present disclosure possess excellent stability.

[0161] In certain embodiments, the compounds of the present disclosure have excellent pharmaceutical efficacy.

[0162] In certain embodiments, the methods of treating or preventing tumors disclosed herein further comprise administering another active agent to the individual.

[0163] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the other active agent are administered to the subject simultaneously, sequentially, overlappingly, concomitantly, intermittently, continuously, synchronously, or any combination thereof.

[0164] In certain embodiments, illustrative examples of other active agents that can be used in the present disclosure include, but are not limited to, topoisomerase inhibitors.

[0165] In certain embodiments, illustrative examples of topoisomerase inhibitors that can be used in the present disclosure include, but are not limited to, topoisomerase I inhibitors and topoisomerase II inhibitors.

[0166] In certain embodiments, illustrative examples of topoisomerase inhibitors that can be used in the present disclosure include, but are not limited to, topotecan, irinotecan, belotecan, aclarubicin, doxorubicin, epirubicin, idarubicin, etoposide, and mitoxantrone.

[0167] In certain embodiments, the tumor that can be used in the methods of treating or preventing tumors disclosed herein is mediated by tyrosine kinase (TK).

[0168] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0169] Pharmaceutical composition

[0170] In certain embodiments, the pharmaceutical composition comprises a compound represented by formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0171] In certain embodiments, the compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof, or the compound of the present invention or a pharmaceutically acceptable salt thereof for treating or preventing a disease or disease state mediated by tyrosine kinase (TK) can be administered to a mammal by an enteral or parenteral route.

[0172] In certain embodiments, the compound of the present invention represented by general formula (I) or its pharmaceutically acceptable salt, or the compound of the present invention or its pharmaceutically acceptable salt for tyrosine kinase (TK)-mediated diseases or disease states when administered to a mammal can be administered orally.

[0173] In certain embodiments, the compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof, or the compound of the present invention or a pharmaceutically acceptable salt thereof for use in tyrosine kinase (TK)-mediated diseases or disease states when administered to a mammal can be administered via the rectal route.

[0174] The compounds described in the present disclosure can be obtained in any suitable form, such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories, etc. Illustrative examples of the tablets include, but are not limited to, plain tablets, sugar-coated tablets, and film-coated tablets.

[0175] Examples of pharmaceutically acceptable excipients that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and any carriers that have no side effects on the composition of the pharmaceutical composition. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety.

[0176] The pharmaceutical composition of the present disclosure can be applied by any method that realizes its intended purpose.For example, application can be carried out by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intraspinal, transtracheal, per ocular, subcutaneous, intraperitoneal, transdermal or buccal routes.The route of administration can be parenteral, oral and rectal routes.The dosage applied will depend on the age, health status and weight of the recipient, and if concurrent treatment is provided, also depends on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0177] Suitable dosage forms include, but are not limited to, capsules, tablets, pills, dragees, semisolid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be prepared according to methods known in the art.

[0178] Particularly suitable for oral administration are ordinary tablets (plain tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, also can be oil-based solutions or aqueous solutions, in addition there are also suspensions, emulsions or implants, suitable for topical use are ointments, creams or powders. The product in the present disclosure can also be lyophilized, and the lyophilized material generated is used for example to prepare injections. The given preparation can be sterilized and / or comprise adjuvants (assistant), such as wetting agents, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for changing osmotic pressure, buffer substances, dyes, flavorings and / or numerous other active ingredients, such as one or more vitamins.

[0179] In certain embodiments, the pharmaceutical compositions of the present disclosure are prepared as tablets, solutions, granules, patches, ointments, capsules, aerosols, or suppositories for parenteral, transdermal, mucosal, nasal, buccal, sublingual, or oral use.

[0180] Preservatives, stabilizers, dyes, sweeteners, aromatics, spices, etc. can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used.

[0181] In different embodiments, alcohols, esters, sulfated aliphatic alcohols, etc. can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, hydroxymethylcellulose calcium, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspending agents or lubricants; cellulose acetate phthalate, which is a derivative of sugars such as cellulose or sugar, or methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, can be used as a suspending agent; and plasticizers such as phthalates can be used as suspending agents.

[0182] Suitable routes of administration may include, for example, oral administration, rectal administration, transmembrane administration, parenteral delivery, topical administration or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection. The compound can also be extended and / or timed, pulsed at a predetermined rate in a sustained-release or controlled-release dosage form including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, etc.

[0183] The pharmaceutical compositions of the present disclosure can be manufactured in a known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting operations.

[0184] Therefore, according to the present disclosure, the pharmaceutical composition used can be prepared in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate processing of the active compound into a pharmaceutically useful preparation. Suitable formulations depend on the selected route of administration. Any known techniques, carriers, and excipients can be used as is suitable and understood in the art.

[0185] Injection can be prepared into the following conventional forms: as a solution or suspension, a solid dosage form suitable for making a solution or suspension before injection, or as an emulsion. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, etc. In addition, if necessary, the injection pharmaceutical composition can contain a small amount of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include but are not limited to Hank's solution, Ringer's solution, or physiological saline buffer. If necessary, absorption enhancing preparations (such as liposomes) can be used.

[0186] For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compounds of the present disclosure to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, pastes, suspensions, solutions, powders, and the like for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral administration can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture, if necessary, after adding suitable adjuvants, to obtain tablets or lozenge cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or alginates such as sodium alginate may be added if necessary. The dragee core is carried out to suitable coating.For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally comprise gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel (carbopol gel), polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to identify or characterize the different combinations of active compound dosage, dyestuff or pigment can be added in tablet or dragee coating.For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally comprise gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.

[0187] Pharmaceutical formulations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0188] In certain embodiments, the pharmaceutical compositions of the present disclosure may contain 0.1%-95% of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0189] In certain embodiments, the pharmaceutical compositions of the present disclosure may comprise 1%-70% of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0190] In any case, the composition or formulation to be administered will contain an amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, that is effective to treat the disease / condition in the subject being treated.

[0191] Dosage

[0192] At least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be administered to a patient by any method suitable for systemic and / or local delivery of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Non-limiting examples of methods of administration include (a) oral administration, including administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) non-oral administration, such as rectal, vaginal, intraurethral, ​​intraocular, intranasal or intraaural, including administration in the form of aqueous suspensions, oily preparations, etc. or in the form of drops, sprays, suppositories, ointments, ointments, etc.; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including delivery by infusion pump; (d) local administration, such as injection directly in the kidney area or heart area, for example, by reservoir implantation; and (e) topical administration; as recognized by those skilled in the art, an appropriate mode of administration is contact of the compounds described in the present disclosure with living tissue.

[0193] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients and other matters related to delivering the compound, its stereoisomer or its pharmaceutically acceptable salt to a subject in need.

[0194] Pharmaceutical compositions suitable for administration include compositions containing an effective amount of an active ingredient to achieve their desired effect. The dosage required for a therapeutically effective amount of the pharmaceutical compositions described in this disclosure depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal being considered. The dosage can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medications, and other factors recognized by those skilled in the art of medicine. More specifically, a therapeutically effective amount refers to an amount of a compound that effectively prevents, alleviates, or ameliorates symptoms of a disease, or prolongs the lifespan of the individual being treated. A therapeutically effective amount is well within the skill of those skilled in the art, particularly in light of the detailed disclosure provided herein.

[0195] As will be apparent to those skilled in the art, the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight, and type of mammal being treated, the specific compound being used, and the specific purpose of the compound being used. Conventional pharmacological methods can be used by those skilled in the art to determine effective dosage levels, i.e., dosage levels necessary for the desired effect. Typically, clinical use of the product in humans is initiated at lower dosage levels, with the dosage levels increasing until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish effective dosages and routes of administration for the compositions identified by the present method.

[0196] In non-human animal studies, the use of potential products is initiated at higher dose levels, with the dose being reduced until the desired effect is no longer achieved or the adverse side effects disappear. Depending on the desired effect and the therapeutic indication, the dosage range can be relatively wide. Typically, the dosage can be from about 10 μg / kg body weight to 1000 mg / kg body weight, and in certain embodiments, from about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dosage can be based on and calculated according to the patient's body surface area.

[0197] Each physician will be able to select the exact formulation, route of administration, and dosage of the pharmaceutical compositions described herein based on the patient's condition. Typically, the composition administered to a patient may be administered in a dosage range of about 0.5 mg / kg to 1000 mg / kg of the patient's body weight. Depending on the patient's needs, the dosage may be administered once alone or twice or more frequently over a day or several days. In cases where human dosages for a compound have been established for at least some conditions, the present disclosure will use those same dosages, or dosages ranging from about 0.1% to 500% of the established human dosage, and in certain embodiments, from 25% to 250% of the established human dosage. In cases where there is no established human dosage, such as in the case of a newly discovered pharmaceutical compound, an appropriate human dosage can be inferred from the median effective dose or infective dose, or other appropriate values ​​from in vitro or in vivo studies, as quantified in animal toxicity studies and efficacy studies.

[0198] It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust the administration. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The size of the dosage in the treatment of the disease being paid attention to will change with the severity of the disease state to be treated and the change of the route of administration. For example, the severity of the disease state can be evaluated in part by a standard prognostic evaluation method. In addition, the dosage and possible dosage frequency will also change according to the age, body weight, and reaction of the individual patient. A scheme comparable to the above-mentioned discussion scheme can be used in veterinary medicine.

[0199] Although the exact dosage can be determined based on a drug-by-drug analysis, in most cases, it is possible to make certain generalizations about the medicament. The daily dosing regimen for adult patients is, for example, an oral dose of 0.1 mg to 2000 mg of each active ingredient, in certain embodiments 1 mg to 2000 mg of each active ingredient, for example 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, in certain embodiments 0.1 mg to 1000 mg, for example 1 mg to 800 mg. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In certain embodiments, the composition is administered 1 to 4 times daily. Alternatively, the composition described in the present disclosure can be administered by continuous intravenous infusion, in certain embodiments administered at a dosage of up to 2000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in some cases, it may be necessary to administer the compounds described herein in amounts exceeding or far exceeding the above dosage ranges in order to effectively and rapidly treat rapidly developing diseases or infections. In certain embodiments, the compounds are administered over a continuous treatment period, such as one or several weeks, or several months or years.

[0200] Dosage and dosing interval can be adjusted individually to provide a plasma level of the active moiety sufficient to maintain the adjustment effect or minimum effective concentration (MEC). The MEC of each compound is different, but it is possible to estimate the MEC from in vitro data. The required dosage to reach the MEC depends on individual characteristics and route of administration. However, plasma concentration can be determined using HPLC (high performance liquid chromatography) assays or bioassays.

[0201] Dosage intervals can also be determined using the MEC. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, in certain embodiments 30-90% of the time, and in certain embodiments 50-90% of the time.

[0202] In cases of local administration or selective uptake, the effective local concentration of the drug is independent of plasma concentration.

[0203] The amount of composition administered will, of course, be dependent on the individual being treated, on the individual's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0204] The efficacy and toxicity of the compounds described herein can be assessed using known methods. For example, the toxicology of a specific compound, or a subset of compounds sharing certain chemical moieties, can be established by in vitro toxicity assays in cell lines, such as mammalian cell lines, and in certain embodiments, human cell lines. The results of such studies are generally predictive of toxicity in animals such as mammals, or more specifically, in humans. Alternatively, the toxicity of a specific compound can be assessed in animal models such as mice, rats, rabbits, or monkeys using known methods. The efficacy of a specific compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every disease state, including but not limited to cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to determine the efficacy of chemical agents used to treat these disease states. When selecting a model to determine efficacy, the skilled artisan can select an appropriate model, dosage, route of administration, and treatment regimen, guided by existing knowledge in the art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0205] If desired, the composition can be placed in a package or dispensing device that can contain one or more unit dosage forms containing the active ingredient. The package can, for example, include metal or plastic foil, such as a blister pack. The package or dispensing device can carry instructions for administration. The package or dispensing device can also carry notes associated with the container, which are prescribed by a government agency that manages drug production, use, or sales, reflecting that the drug form has been approved by the agency for human or veterinary administration. Such notes, for example, can be a label approved for prescription drugs by the State Food and Drug Administration or the U.S. Food and Drug Administration, or an approved product instruction sheet. Compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can also be prepared in a suitable container and placed in a compatible pharmaceutical carrier and labeled for use in the treatment of a specified disease state.

[0206] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ia),

[0207] It involves carrying out the reaction shown below:

[0208] in:

[0209] X1 and Y1 are each independently selected from amino, thiol or hydroxyl;

[0210] X and Y are each independently selected from O, S or N; and

[0211] R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group.

[0212] In certain embodiments, the reaction to prepare the compound represented by formula (Ia) is carried out in the presence of a base and a strong oxidizing agent.

[0213] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0214] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0215] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.

[0216] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0217] In certain embodiments, illustrative examples of strong oxidizing agents that can be used in the present disclosure include, but are not limited to, periodates, dichromates, pyridinium chlorochromates, or any mixture thereof.

[0218] In certain embodiments, illustrative examples of periodate salts that can be used in the present disclosure include, but are not limited to, sodium periodate, potassium periodate, or any mixture thereof.

[0219] In certain embodiments, illustrative examples of dichromates that can be used in the present disclosure include, but are not limited to, potassium dichromate, sodium dichromate, or any mixture thereof.

[0220] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ib),

[0221] It involves carrying out the reaction shown below:

[0222] in:

[0223] R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;

[0224] B is selected from boric acid or boric acid esters.

[0225] In certain embodiments, the reaction to prepare the compound represented by formula (Ib) is carried out in the presence of a palladium catalyst and a base.

[0226] In certain embodiments, illustrative examples of palladium catalysts that can be used in the present disclosure include, but are not limited to, palladium, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(OAc)2, Pd(dppf)Cl2, or any mixture thereof.

[0227] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0228] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0229] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.

[0230] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0231] In certain embodiments, illustrative examples of borate esters that can be used in the present disclosure include, but are not limited to, bis(pinacolato)diboron (Bpin), Bcat, or any mixture thereof.

[0232] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Id),

[0233] It comprises reacting a compound represented by general formula (Ic) with a compound represented by general formula (Ib):

[0234] In certain embodiments, the method for preparing the compound represented by formula (Ic) is carried out in the presence of a base.

[0235] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0236] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0237] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.

[0238] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0239] In certain embodiments, the compound of formula (Ia) is reacted in the presence of boron bromide to obtain the compound of formula (Ib).

[0240] In another aspect, the present disclosure relates to a method for inhibiting tyrosine kinase (TK), comprising contacting tyrosine kinase with an effective inhibitory amount of a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0241] In certain embodiments, the tyrosine kinases that can be used in the present disclosure are Illustrative examples of kinases (TKs) include, but are not limited to, anaplastic lymphoma kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS1), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast growth factor receptor (FGFR), interleukin receptor-associated kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma viral oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular endothelial growth factor (VEGFR), rearranged by transfection kinase (RET), Bruton's tyrosine kinase (BTK), B-lymphoid tyrosine kinase (BLK), cytoplasmic tyrosine-protein kinase (BMX), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), isocitrate dehydrogenase (IDH), discoidin domain receptor 1 (DDR1), interleukin-2-induced T-cell kinase (ITK), and human protein tyrosine kinase 4 (TXK).

[0242] On the other hand, the present disclosure relates to a method for treating or preventing a disease or disease state mediated by tyrosine kinase (TK), comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0243] In certain embodiments, illustrative examples of individuals that can be used in the disclosed methods of treating or preventing tyrosine kinase (TK)-mediated diseases or conditions include, but are not limited to, mammals.

[0244] In certain embodiments, the subject is a human.

[0245] In certain embodiments, the tyrosine kinases that can be used in the present disclosure are Illustrative examples of kinases (TKs) include, but are not limited to, anaplastic lymphoma kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS1), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast growth factor receptor (FGFR), interleukin receptor-associated kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma viral oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular endothelial growth factor (VEGFR), rearranged by transfection kinase (RET), Bruton's tyrosine kinase (BTK), B-lymphoid tyrosine kinase (BLK), cytoplasmic tyrosine-protein kinase (BMX), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), isocitrate dehydrogenase (IDH), discoidin domain receptor 1 (DDR1), interleukin-2-induced T-cell kinase (ITK), and human protein tyrosine kinase 4 (TXK).

[0246] In certain embodiments, illustrative examples of diseases or conditions that can be used in the methods of treating or preventing tyrosine kinase (TK)-mediated diseases or conditions of the present disclosure include, but are not limited to, lymphoma, blastoma, sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancies, lung cancer, squamous cell carcinoma of the lung, peritoneal cancer, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumors, head and neck cancer, and hematological malignancies.

[0247] In certain embodiments, a method for treating or preventing a disease or condition mediated by tyrosine kinase (TK) comprises administering 1 mg to 10 g of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0248] In certain embodiments, a method for treating or preventing a disease or condition mediated by tyrosine kinase (TK) comprises administering to a subject in need thereof 10 mg to 3000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0249] In certain embodiments, a method for treating or preventing a tyrosine kinase (TK)-mediated disease or condition comprises administering 100 mg to 1000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0250] In certain embodiments, a method for treating or preventing a tyrosine kinase (TK) mediated disease or condition comprises administering 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg or 1000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0251] In certain embodiments, the disclosed methods of treating or preventing a tyrosine kinase (TK)-mediated disease or condition further comprise administering to the individual an additional active agent.

[0252] In certain embodiments, examples of active agents that can be used in the methods of treating or preventing tyrosine kinase (TK)-mediated diseases or conditions of the present disclosure include, but are not limited to, nitrogen mustards, aziridines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors, anticancer vaccines, acivicin, aclarubicin, acodazole hydrochloride, aclonine, adolesin, acodazole, chloramphenicol ... Deleukin, amblycin, ametrine acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, triclinamycin, azacitidine, azatepa, azotocin, batimastat, benzotepa, bicalutamide, bisantrene hydrochloride, binafadol mesylate, bisezole, bleomycin sulfate, busulfan, actinomycin C, captestosterone, caracetamide, carbetamol, carboplatin, carmustine, carrubicin hydrochloride , chlorambucil, cilomycin, cladribine, clinatrol mesylate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, epirubicin hydrochloride, esorubicin hydrochloride, estramustine, etanercept, etoposide, floxuridine, fluorouracil, flucitabine, gemcitabine, idarubicin hydrochloride, ifosfamide , interleukin II, interferon α-2a, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, chlorpheniramine, selenomethoxazole, mitoxantrone, paclitaxel, procarbazine, thiotepa, vinblastine, vincristine, angiogenesis inhibitors, camptothecin, dexamethasone, aspirin, acetaminophen, indomethacin, ibuprofen, ketoprofen, meloxicam, corticosteroids and corticosteroids.

[0253] In another aspect, the present disclosure relates to the compound represented by general formula (I) of the present disclosure and its pharmaceutically acceptable salt for inhibiting tyrosine kinase (TK).

[0254] In another aspect, the present disclosure relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof for use in treating or preventing diseases or conditions mediated by tyrosine kinase (TK).

[0255] On the other hand, the present disclosure relates to the compound represented by general formula (I) of the present disclosure and its pharmaceutically acceptable salt or the use of the compound of the present disclosure and its pharmaceutically acceptable salt in the preparation of a medicament for inhibiting tyrosine kinase (TK).

[0256] In another aspect, the present disclosure relates to the compounds of general formula (I) of the present disclosure and pharmaceutically acceptable salts thereof, or the use of the compounds of the present disclosure and pharmaceutically acceptable salts thereof in the preparation of drugs for treating or preventing diseases or disease states mediated by tyrosine kinase (TK).

[0257] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0258] Example

[0259] The reagents and equipment used in the examples of this disclosure are conventional and commercially available. For example:

[0260] Preparation Example

[0261] Preparation Example 1

[0262] Preparation of N-(4-chlorophenyl)-5-((6-(2-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-001)

[0263] Step a: To a mixture of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 17.9 mmol) in THF (60 mL) was added NaH (1.08 g, 27 mmol, 60%), and the mixture was stirred at 0°C for 30 minutes. SEMCl (3.58 g, 3.8 mL, 8.64 mmol) was added to the reaction mixture, which was warmed to room temperature and stirred for 2 hours. The mixture was quenched with saturated NH4C solution. The mixture was extracted with EtOAc (60 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was further purified by silica gel column chromatography to obtain the desired product F1 as a white solid (5.72 g, 78%).

[0264] Step b: To a mixture of 2-amino-4-methoxyphenol (1.39 g, 10 mmol) in THF (100 mL) was added p-chlorophenylisothiocyanate (2.54 g, 15 mmol) and K CO (2.764 g, 20 mmol). The reaction was stirred at room temperature overnight. NaIO solution (427.78 mg in 100 mL H O, 20 mol%) was poured into the reaction. TLC showed that 2-amino-4-methoxyphenol was completely consumed. Extracted with EA. Concentrated and purified by silica gel column to obtain the desired intermediate (2.1976 g, 80%).

[0265] Step c: To a suspension of the product from step b (2.1976 g, 8 mmol) in DCM (80 mL) was added BBr3·DCM (2 M, 20 mL, 5 equivalents). The reaction was stirred at room temperature. The reaction was quenched with MeOH until TLC showed no starting material remaining. Concentration and purification on a silica gel column gave the desired product F2 (1.88 g, 90%).

[0266] Step d: To a suspension of 4-bromo-3-methylaniline (9.30 g, 50 mmol) in DCE (165 mL) was added 1-methylpiperidin-4-one (7.92 g, 8.12 mL, 70 mmol). STAB (14.84 g, 70 mmol, 1.4 eq) and HOAc (3 g, 5 mL, 50 mmol) were added to the reaction. The mixture was stirred at room temperature overnight. The mixture was adjusted to pH = 8, extracted with DCM, washed with NaCl (aq.), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Further purification by column chromatography gave the desired product as a white solid (10.7 g, 75%).

[0267] Step e: To a solution of the product from step d (2.83 g, 10 mmol) in DMF (50 mL) was added Pd(dppf)Cl (408.3 mg, 0.5 mmol), KCO (6.91 mg, 50 mmol) and pinacol borane (5.06 g, 20 mmol). The atmosphere was purged with nitrogen three times and then stirred at 100° C. for 4 hours. The product was extracted with EA, washed with brine, dried over sodium sulfate, concentrated and purified on a silica gel column to give the desired product F3 (2.805 g, 85%) as a yellow oil.

[0268] Step f: A 100 mL round-bottom flask was charged with compound F1 (1.9632 g, 4.8 mmol), Pd(PPh3)2Cl2 (280.7 mg, 0.4 mmol), K2CO3 (1.66 g, 12 mmol), and compound F3 (1.346 g, 4.0 mmol) in dioxane / H2O (36 mL / 4 mL, 0.1 M). The atmosphere was purged with nitrogen three times, and then stirred at 100°C overnight. The mixture was concentrated and purified on a silica gel column to afford the desired intermediate (1.34 g, 69%) as a yellow solid.

[0269] Step g: To a solution of the product obtained in the previous step (0.32 g, 0.658 mmol) in NMP (3 mL, 0.2 M) was added compound F2 (0.343 g, 1.32 mmol) and Cs2CO3 (0.643 g, 1.974 mmol). The reaction was stirred at 120°C for 4 hours. The mixture was extracted with EA, washed with saturated NaCl solution and dried over Na2SO4. Purification on a silica gel column gave the desired product (288.8 mg, 62%) as a brown solid.

[0270] Step h: DCM / TFA (4 mL / 4 mL, 0.1 M) was added to the product in step g (288.8 mg, 0.406 mmol). The reaction was stirred at room temperature. After 1 hour, TLC showed that no starting material remained. Concentration removed most of the DCM and TFA. Et2O was added to obtain the TFA salt of the product. Extraction with EA and adjustment of pH to 12 made the compound a free amine. The crude product was further purified by silica gel column to obtain the title compound YH-I-001 (153.7 mg, 65%) as a white solid.

[0271] 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),10.89(s,1H),8.38(d,J=5.3Hz,1H),7.79(d ,J=8.9Hz,2H),7.56(d,J=8.6Hz,1H),7.47-7.29(m,4H),7.04(dt,J=8.4,1.7Hz,2 H),6.65(t,J=7.4Hz,1H),6.52-6.35(m,3H),5.48-5.17(m,3H),4.22(t,J=6.6Hz, 1H),2.63-2.36(m,3H),1.72-1.55(m,1H),1.47-1.29(m,1H),0.91(t,J=7.4Hz,1H)

[0272] HRMS (ES+) calculated value: C 32 H 30 ClN7O2[M+H] + :580.2222, measured value: 580.2232

[0273] Preparation Example 2

[0274] Preparation of N-(4-chlorophenyl)-5-((6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-002)

[0275] Step i: To a solution of compound F1 (0.82 g, 2 mmol) in NMP (4 mL, 0.2 M) was added compound F2 (0.51 g, 2 mmol) and CsCO (1.629 g, 5 mmol). The reaction was stirred at 120°C for 4 hours. Extraction was performed with EA, washed with saturated NaCl solution, and dried over NaSO. Purification on a silica gel column afforded the desired product (509.8 mg, 40%) as a white solid.

[0276] Then follow steps f and h in Preparation Example 1 to obtain the title compound YH-I-002.

[0277] 1 H NMR(400MHz, DMSO-d6)δ8.31(s,1H),8.04-7.94(m,2H),7.80(d,J=8.9Hz,2H),7.58(d,J=8.6Hz,1H),7 .56-7.43(m,4H),7.40(d,J=2.3Hz,1H),7.38(d,J=7.4Hz,1H),7.08(s,1H),7.04(dd,J=8.6,2.3Hz,1H)

[0278] HRMS (ES+) calculated value: C 25 H 16 ClN5O2[M+H] + :454.1065, measured value: 454.1073.

[0279] Preparation Example 3

[0280] Preparation of N-(4-chlorophenyl)-5-((6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-010)

[0281] Step j: To a mixture of 3,5-dimethylpyrrolopinacol (1.11 g, 5.0 mmol) in THF (15 mL) was added NaH (0.30 g, 7.5 mmol, 60%), and the mixture was stirred at 0°C for 30 minutes. SEMCl (2.49 g, 2.66 mL, 6.0 mmol) was added to the reaction mixture, which was warmed to room temperature and stirred for 2 hours and quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was further purified by silica gel column chromatography to give the desired intermediate as a white solid (1.26 g, 71%).

[0282] Then, according to steps f, g and h in Preparation Example 1, the title compound YH-I-010 was obtained.

[0283] 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),12.05(s,1H),10.89(s,1H),8.26(s,1H),7.79(d,J=8.9Hz,2H),7.56(d,J=8.6 Hz,1H),7.44(d,J=8.9Hz,2H),7.39(d,J=2.4Hz,1H),7.03(dd,J=8.6,2.4Hz,1H),6.30(d,J=1.9Hz,1H),2.28(s,6H)

[0284] HRMS(ES+)C 24 H 18 ClN7O2[M+H] + :Calculated value: 472.1283, measured value: 472.1287

[0285] Preparation Example 4

[0286] Preparation of N-(4-chlorophenyl)-5-((6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-011)

[0287] Step k: To a mixture of 3,5-dimethyl-4-bromopyrrole (1.75 g, 10.0 mmol) in DMF (33 mL) was added NaH (0.60 g, 15 mmol, 60%) and the mixture was stirred at 0 ° C for 30 minutes. 4-Sulfonate-Boc piperidine (3.35 g, 12 mmol, 5.32 mL) was added to the reaction mixture, which was warmed to room temperature and stirred for 2 hours and quenched by saturated NH4Cl solution. It was extracted with EtOAc (20 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was further purified by silica gel column chromatography to give the desired intermediate as a white solid (2.11 g, 59%).

[0288] Step 1: To a solution of the product from step k (179.14 mg, 0.5 mmol) in DMA (2 mL) was added Pd(OAc)2 (11.2 mg, 0.05 mmol), KOAc (408.3 mg, 2 mmol), and pinacol borane (0.506 g, 2 mmol). The atmosphere was purged with nitrogen three times, then stirred at 100°C for 4 hours. The mixture was extracted with EA, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford the desired intermediate (0.108 g, 53%) as a tan oil.

[0289] Then, according to steps f, g and h in Preparation Example 1, the title compound YH-I-011 was obtained.

[0290] 1 H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.27(s,1H),7.80(d,J=8.5Hz,2H),7 .56(d,J=8.6Hz,1H),7.44(d,J=8.6Hz,2H),7.38(s,1H),7.02(d,J=8.6Hz,1 H),6.30(s,1H),4.58-4.38(m,1H),3.85(s,1H),3.03(t,J=12.5Hz,2H),2. 35(s,3H),2.24(s,3H),2.17(dd,J=19.2,8.5Hz,2H),1.97(d,J=13.1Hz,2H)

[0291] HRMS(ES+)C 29 H 27 ClN8O2[M+H] + :Calculated value: 555.2018, measured value: 555.2020

[0292] Preparation Example 5

[0293] Preparation of N-(4-chlorophenyl)-5-((6-(p-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-003)

[0294] Using a method similar to Example 1, replacing F3 with 4-toluenepinacol borane, and going through steps f, g, and h, the title compound YH-I-003 was prepared.

[0295] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.40(s,1H),7.79(d,J=9.0Hz,2H),7.70(d,J=8.0Hz,2H),7.55(d,J=8.6Hz,1H),7.43(d, J=8.9Hz,2H),7.39(d,J=2.4Hz,11H),7.33(d,J=8.0Hz,2H),7.02(dd,J=8.6,2.4Hz,1H),6.65(s,1H),5.61(s,2H),2.37(s,3H)

[0296] HRMS (ES+) calculated value: C 26 H 18 ClN5O2[M+H] + :468.1222, measured value: 468.1228

[0297] Preparation Example 6

[0298] Preparation of N-(4-chlorophenyl)-5-((6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-004)

[0299] Using a method similar to Example 1, replacing F3 with 4-methoxybenzopinacol borane, and going through steps f, g, and h, the title compound YH-I-004 was prepared.

[0300] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.39(s,1H),7.78(dd,J=11.3,8.5Hz,4H),7.57(d,J=8.6Hz,1H),7.44(d,J= 8.7Hz,2H),7.39(d,J=2.5Hz,1H),7.10(d,J=8.5Hz,2H),7.07-7.00(m,1H),6.63(s,1H),5.61(s,2H),3.83(s,3H)

[0301] HRMS (ES+) calculated value: C 26 H 18 ClN5O3[M+H] + :484.1171, measured value: 484.1172

[0302] Preparation Example 7

[0303] Preparation of 5-((6-(4-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-chlorophenyl)benzo[d]oxazol-2-amine (Compound YH-I-005)

[0304] Using a method similar to Example 1, replacing F3 with 4-bromophenylpinacol borane, and going through steps f, g, and h, the title compound YH-I-005 was prepared.

[0305] 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.08(d,J=8.4Hz,1H),7.93(d,J=8.6Hz,1H),7.79(d,J=8.9Hz,2H),7.68(d,J=8.5Hz,1H),7 .57(dd,J=8.7,3.3Hz,1H),7.44(d,J=8.6Hz,2H),7.39(dd,J=5.6,2.4Hz,1H),7.15(d,J=7.2Hz,1H),7.03(dd,J=8.5,2.4Hz,1H)

[0306] HRMS (ES+) calculated value: C 25 H 15 BrClN5O2[M+H] + :532.0170,Measurement value:532.0170

[0307] Preparation Example 8

[0308] Preparation of N-(4-chlorophenyl)-5-((6-(thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-006)

[0309] Using a method similar to Example 1, replacing F3 with 2-thiophenepinacol borane, and going through steps f, g, and h, the title compound YH-I-006 was prepared.

[0310] 1H NMR(400MHz,DMSO-d6)δ8.21(d,J=2.7Hz,1H),7.79-7.64(m,2H),7.61-7.4 7(m,3H),7.33(d,J=9.2Hz,4H),7.24-7.07(m,2H),6.84(s,1H),6.57(s,1H)

[0311] HRMS (ES+) calculated value: C 23 H 14 ClN5O2S[M+H] + :460.0629, measured value: 460.0636.

[0312] Preparation Example 9

[0313] Preparation of N-(4-chlorophenyl)-5-((6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-007)

[0314] Using a method similar to Example 1, replacing F3 with 3-pyridinepinacolborane, and going through steps f, g, and h, the title compound YH-I-007 was prepared.

[0315] 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),10.91(s,1H),9.27(s,1H),8.65(s,0H),8.36(s,1H),7.80(d,J=8.8H z,2H),7.58(dd,J=8.5,2.3Hz,1H),7.45(d,J=8.9Hz,2H),7.41(d,J=2.5Hz,1H),7.05(dd,J=8.6,2.4Hz,1H)

[0316] HRMS (ES+) calculated value: C 24 H 15 ClN6O2[M+H] + :455.1018, measured value: 455.1024

[0317] Preparation Example 10

[0318] Preparation of N-(4-chlorophenyl)-5-((6-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-008)

[0319] Using a method similar to Example 1, replacing F3 with 4-pyridinepinacolborane, and going through steps f, g, and h, the title compound YH-I-008 was prepared.

[0320] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=6.0Hz,2H),8.27(s,1H),7.92(d,J=6.1Hz,2H),7.75(d,J=8.9 Hz,2H),7.46(d,J=8.5Hz,1H),7.43-7.32(m,2H),7.33-7.22(m,2H),6.93(dd,J=8.6,2.4Hz,1H)

[0321] HRMS (ES+) calculated value: C 24 H 15 ClN6O2[M+H] + :455.1018, measured value: 455.1024.

[0322] Preparation Example 11

[0323] Preparation of N-(4-chlorophenyl)-5-((6-(pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-009)

[0324] Using a method similar to Example 1, replacing F3 with 5-pyrimidine pinacol borane, and going through steps f, g, and h, the title compound YH-I-009 was prepared.

[0325] 1 H NMR (400MHz, DMSO-d6) δ9.37 (s, 2H), 9.11 (s, 1H), 8.26 (s, 1H), 7.78 (d, J = 8.6Hz, 3H), 7. 51(d,J=8.5Hz,1H),7.42(d,J=8.6Hz,3H),7.36-7.21(m,2H),6.98(dd,J=8.6,2.5Hz,1H)

[0326] HRMS (ES+) calculated value: C 23 H 14 ClN7O2[M+H] + :456.0970, measured value: 456.0978

[0327] Preparation Example 12

[0328] Preparation of 4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzonitrile (Compound YH-I-012)

[0329] Using a method similar to Example 1, replacing F3 with 4-cyanophenylpinacol borane, and going through steps f, g, and h, the title compound YH-I-012 was prepared.

[0330] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),10.86(s,1H),8.31(s,1H),8.12(d,J=8.3Hz,2H),7.91(d,J=8.4Hz,2H),7.75(d,J =9.0Hz,2H),7.53(d,J=8.5Hz,1H),7.40(d,J=9.0Hz,2H),7.36(d,J=2.4Hz,1H),7.31(s,1H),7.00(dd,J=8.6,2.4Hz,1H)

[0331] HRMS (ES+) calculated value: C 26 H 15 ClN6O2[M+H] + :479.1018, measured value: 580.2232

[0332] Preparation Example 13

[0333] Preparation of N-(4-chlorophenyl)-5-((6-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-013)

[0334] Using a method similar to Example 1, replacing F3 with 4-trifluoromethylphenylpinacol borane, and going through steps f, g, and h, the title compound YH-I-013 was prepared.

[0335] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),10.87(s,1H),8.30(s,1H),8.15(d,J=8.2Hz,2H),7.80(d,J=8.3Hz,2H),7.75(d,J=9.0 Hz,2H),7.53(d,J=8.6Hz,1H),7.40(d,J=8.9Hz,2H),7.36(d,J=2.4Hz,1H),7.24(d,J=1.6Hz,1H),7.00(dd,J=8.6,2.4Hz,1H)

[0336] HRMS (ES+) calculated value: C 26 H 15 ClF3N5O2[M+H] + :522.0939, measured value: 580.2232

[0337] Preparation Example 14

[0338] Preparation of N-(4-chlorophenyl)-5-((6-(2-isopropylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-014)

[0339] Using a method similar to Example 1, replacing F3 with 2-isopropylphenylpinacol borane, and going through steps f, g, and h, the title compound YH-I-014 was prepared.

[0340] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),10.86(s,1H),8.29(s,1H),7.75(d,J=8.9Hz,2H),7.53(d,J=8.5Hz,1H), 7.48-7.33(m,6H),7.26(dd,J=7.7,1.4Hz,1H),7.02(dd,J=8.6,2.4Hz,1H),2.04(s,1H),1.10(d,J=6.9Hz,6H)

[0341] HRMS (ES+) calculated value: C 28 H 22 ClN5O2[M+H] + :496.1535, measured value: 580.2232

[0342] Preparation Example 15

[0343] Preparation of N-(4-chlorophenyl)-5-((6-(4-(dimethylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-015)

[0344] Using a method similar to Example 1, replacing F3 with 4-N,N-dimethylaminophenylpinacol borane, and going through steps f, g, and h, the title compound YH-I-015 was prepared.

[0345] 1H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.03-7.95(m,2H),7.70(d,J=7.5Hz,1H),7.67-7.59(m,2H),7.36( d,J=1.5Hz,1H),7.29(dd,J=6.1,1.5Hz,3H),7.09(dd,J=7.5,1.5Hz,1H),6.80-6.72(m,2H),3.02(s,6H)

[0346] HRMS (ES+) calculated value: C 27 H 21 ClN6O2[M+H] + :497.1487, measured value: 580.2232

[0347] Preparation Example 16

[0348] Preparation of N-(4-chlorophenyl)-5-((6-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-016)

[0349] Using a method similar to Example 1, replacing F3 with 2-isopropoxyphenylpinacol borane, and going through steps f, g, and h, the title compound YH-I-016 was prepared.

[0350] 1 H NMR (400MHz, DMSO-d6) δ8.55 (s, 1H), 7.99 (dd, J=7.5, 1.8Hz, 1H),7.70(d,J=7.5Hz,1H),7.67-7.59(m,2H),7.51(s,1H),7.46-7.34(m,3H),7.29(dd,J=7 .7,2.1Hz,3H),7.09(dd,J=7.5,1.5Hz,1H),4.41(hept,J=6.7Hz,1H),1.31(d,J=6.8Hz,6H)

[0351] HRMS (ES+) calculated value: C 28 H 22 ClN5O3[M+H] + :512.1484, measured value: 580.2232

[0352] Preparation Example 17

[0353] Preparation of N-(4-chlorophenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-017)

[0354] Using a method similar to Example 1, replacing F3 with 2-methyl-4-(4-aminopiperidinyl)benzopinacol borane, and going through steps f, g, and h, the title compound YH-I-017 was prepared.

[0355] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,2H),8.38(s,1H),7.80(d,J=9.0Hz,3H),7.57(d,J=8.5Hz,2H), 7.45(d,J=8.9Hz,3H),7.40(d,J=2.5Hz,1H),7.17(d,J=8.3Hz,1H),7.03(dd,J=8.6,2.3Hz,1H),6 .60(s,2H),6.56(d,J=8.4Hz,2H),6.34(s,1H),3.59(s,3H),3.49-3.25(m,6H),3.04(d,J=11.3H z,4H),2.12(s,4H),2.09(s,3H),1.57(d,J=11.9Hz,4H),1.09(t,J=7.0Hz,1H),0.78-0.58(m,1H)

[0356] HRMS (ES+) calculated value: C 31 H 28 ClN7O2[M+H] + :566.2066, measured value: 566.2068

[0357] Preparation Example 18

[0358] Preparation of N-(3,5-bis(trifluoromethyl)phenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-023)

[0359] Using a method similar to Example 1, replacing 1-chloro-4-isothiocyanatobenzene with 1-trifluoromethyl-3-trifluoromethyl-4-isothiocyanatobenzene, and going through steps b, c, g and h, the title compound YH-I-023 was prepared.

[0360] 1H NMR (400MHz, Methanol-d4) δ8.53(s,2H),8.40(s,1H),7.74(s,1H),7.64(d,J=8.6Hz,1H),7.58(d,J=2.4Hz,1H),7.44(d,J=8.3Hz,1H),7. 23(dd,J=8.6,2.4Hz,1H),6.82-6.73(m,2H),6.32(s,1H),3.86(d,J=4.0Hz,0H),3.62(dt,J=13.2,4.0Hz,3H),3.54-3.44(m,2H),2.40(dd, J=14.4,3.8Hz,2H),1.90(td,J=14.3,8.0Hz,3H)

[0361] HRMS (ES+) calculated value: C 33 H 27 F6N7O2[M+H] + :668.2203, measured value: 668.2216

[0362] Preparation Example 19

[0363] Preparation of N-(3,4-dichlorophenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-024)

[0364] Using a method similar to Example 1, replacing 1-chloro-4-isothiocyanatobenzene with 1-chloro-2-chloro-4-isothiocyanatobenzene, and going through steps b, c, g and h, the title compound YH-I-024 was prepared.

[0365] 1H NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.26(s,1H),8.17(d,J=2.5Hz,1H),7.72(dd,J=8.9,2.5Hz,1H) ,7.63(d,J=8.9Hz,1H),7.58(d,J=8.6Hz,1H),7.45(d,J=2.4Hz,1H),7.31(d,J=8.2Hz,1H),7.05(dd, J=8.6,2.4Hz,1H),6.59(s,2H),6.32(s,1H),6.01(d,J=8.0Hz,1H),3.60(q,J=9.6,6.8Hz,1H),3.29( d,J=13.1Hz,1H),3.07-2.91(m,2H),2.05(dd,J=14.1,3.8Hz,2H),1.64(ddt,J=14.0,10.0,5.1Hz,2H)

[0366] HRMS (ES+) calculated value: C 31 H 27 Cl2N7O2[M+H] + :600.1676, measured value: 600.1683

[0367] Preparation Example 20

[0368] Preparation of 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-025)

[0369] Using a method similar to Example 1, replacing 1-chloro-4-isothiocyanatobenzene with 1-trifluoromethyl-4-isothiocyanatobenzene, and going through steps b, c, g and h, the title compound YH-I-025 was prepared.

[0370] 1H NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.26(s,1H),7.87(d,J=9.1Hz,2H),7.57(d,J=8.6 Hz,1H),7.42(d,J=8.6Hz,3H),7.39(d,J=2.4Hz,1H),7.28(d,J=8.2Hz,1H),7.04(dd,J=8 .6,2.4Hz,1H),6.32(s,1H),5.72(d,J=8.1Hz,1H),2.99(dt,J=12.9,3.6Hz,3H),2.60(t d,J=12.1,2.6Hz,3H),2.34(s,4H),2.09(s,2H),2.01(q,J=7.2Hz,1H),1.95-1.83(m,3H)

[0371] HRMS (ES+) calculated value: C 32 H 28 F3N7O2[M+H] + :600.2335,Measurement value: 600.2339

[0372] Preparation Example 21

[0373] Preparation of 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-026)

[0374] Using a method similar to Example 1, replacing 1-chloro-4-isothiocyanatobenzene with 1-trifluoromethoxy-4-isothiocyanatobenzene, and going through steps b, c, g and h, the title compound YH-I-026 was prepared.

[0375] 1H NMR (400MHz, DMSO-d6) δ12.20(d,J=2.1Hz,1H),11.12(s,1H),8.26(s,1H),7.90(d,J=9.1Hz,2H), 7.56(d,J=8.6Hz,1H),7.44-7.34(m,3H),7.30(d,J=8.3Hz,1H),7.03(dd,J=8.6,2.4Hz,1H),6.64- 6.51(m,2H),6.31(d,J=2.0Hz,1H),6.03(d,J=7.9Hz,1H),4.76(s,2H),3.60(d,J=9.2Hz,1H),3.29 (dd,J=12.8,3.9Hz,1H),2.34(s,3H),2.08(s,1H),2.08-1.94(m,2H),1.64(q,J=11.2,10.8Hz,2H)

[0376] HRMS (ES+) calculated value: C 32 H 28 F3N7O3[M+H] + :616.2284, measured value: 616.2285

[0377] Preparation Example 22

[0378] Preparation of N-(4-isopropylphenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-027)

[0379] Using a method similar to Example 1, replacing 1-chloro-4-isothiocyanatobenzene with 1-isopropyl-4-isothiocyanatobenzene, and going through steps b, c, g and h, the title compound YH-I-027 was prepared.

[0380] 1H NMR (400MHz, DMSO-d6) δ8.48 (s, 1H), 7.62 (d, J = 7.5Hz, 1H), 7.42-7.33 (m, 3H), 7. 12-6.98(m,3H),6.86(s,1H),4.46(p,J=7.0Hz,1H),3.10(dt,J=12.5,7.1Hz,2H), 2.93-2.77(m,1H),2.71(dtd,J=12.5,7.0,2.5Hz,2H),2.64(s,3H),2.52(s,3H),2 .44(s,1H),1.91-1.71(m,2H),1.63(dq,J=13.9,7.1Hz,2H),1.20(d,J=6.8Hz,6H)

[0381] HRMS (ES+) calculated value: C 34 H 35 N7O2[M+H] + :574.2930, measured value: 574.2925

[0382] Preparation Example 23

[0383] Preparation of N-cyclopentyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-028)

[0384] Using a method similar to Example 1, replacing 1-chloro-4-benzeneisothiocyanate with cyclopentane isothiocyanate, and going through steps b, c, g and h, the title compound YH-I-028 was prepared.

[0385] 1H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.23(d,J=2.8Hz,1H),8.05(t,J=4.6Hz,1H),7.36(dd,J=8.5,2.8Hz, 1H),7.27(dd,J=8.5,4.0Hz,1H),7.12(d,J=3.2Hz,1H),6.83(d,J=8.0Hz,1H),6.52(s,2H),6.25(d,J=3.2H z,1H),5.69(d,J=7.8Hz,1H),4.08(d,J=21.5Hz,2H),3.17(d,J=4.1Hz,2H),3.04-2.83(m,3H),2.54(s,0H) ,2.31(s,3H),2.08(d,J=11.7Hz,2H),2.00-1.84(m,6H),1.70(s,3H),1.57(s,6H),1.38(s,2H),1.23(s,2H)

[0386] HRMS (ES+) calculated value: C 30 H 33 N7O2[M+H] + :524.2774, measured value: 524.2771

[0387] Preparation Example 24

[0388] Preparation of N-cyclohexyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-029)

[0389] Using a method similar to Example 1, replacing 1-chloro-4-benzeneisothiocyanate with cyclohexane isothiocyanate, and going through steps b, c, g and h, the title compound YH-I-029 was prepared.

[0390] 1H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.22(d,J=1.8Hz,1H),7.99(d,J=7.7Hz,1H),7.35(dd,J=8.5,1.8Hz,1H) ,7.25(d,J=8.0Hz,1H),7.11(d,J=2.2Hz,1H),6.82(dt,J=8.5,2.1Hz,1H),6.50(d,J=10.0Hz,2H),6.23(d,J=1. 7Hz,1H),5.69(d,J=8.1Hz,1H),2.94(d,J=11.8Hz,2H),2.55(d,J=12.2Hz,2H),2.31(d,J=1.7Hz,3H),2.04-1.9 5(m,3H),1.86(d,J=12.6Hz,2H),1.74(d,J=10.3Hz,3H),1.57(s,1H),1.29(d,J=10.9Hz,7H),1.25-1.13(m,3H)

[0391] HRMS (ES+) calculated value: C 31 H 35 N7O2[M+H] + :538.2930,Measurement value:538.2933

[0392] Preparation Example 25

[0393] Preparation of N-hexyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-030)

[0394] Using a method similar to Example 1, replacing 1-chloro-4-benzeneisothiocyanate with hexane isothiocyanate, and going through steps b, c, g and h, the title compound YH-I-030 was prepared.

[0395] 1H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.23(s,1H),8.04(d,J=5.6Hz,1H),7.36(d,J=8.5Hz,1H),7 .25(d,J=8.1Hz,1H),7.11(d,J=2.4Hz,1H),6.82(dd,J=8.5,2.4Hz,1H),6.51(s,2H),6.22(s,1H) ,5.69(d,J=8.1Hz,1H),4.10(d,J=5.4Hz,3H),3.16(d,J=3.9Hz,9H),2.94(dt,J=12.4,3.6Hz,2H) ,2.66-2.52(m,1H),2.30(s,3H),1.86(d,J=12.3Hz,2H),1.57(q,J=7.1Hz,2H),0.95-0.79(m,3H).

[0396] HRMS (ES+) calculated value: C 31 H 37 N7O2[M+H] + :540.3087, measured value: 540.3085

[0397] Preparation Example 26

[0398] Preparation of N-(4-chlorophenyl)-5-((6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-031)

[0399] Using a method similar to Example 1, using F1 and F2 as raw materials, and going through steps g and h, the title compound YH-I-031 was prepared.

[0400] 1 H NMR (400MHz, DMSO-d6) δ9.50 (s, 1H), 8.34 (s, 1H), 7.67-7.59 (m, 2H), 7.52 (d, J = 7.6Hz, 1H),7.33-7.25(m,2H),7.15(d,J=1.5Hz,1H),6.78(dd,J=7.5,1.5Hz,1H),6.20(s,1H)

[0401] HRMS (ES+) calculated value: C 19 H 11 ClIN5O2[M+H] + :503.9724, measured value: 503.9725

[0402] Preparation Example 27

[0403] Preparation of 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-phenylbenzo[d]oxazol-2-amine (Compound YH-I-040)

[0404] Using a method similar to Example 1, replacing F3 with (2-methyl-4-(piperidin-4-amino)phenyl)pinacolborane and replacing 1-chloro-4-isothiocyanate with benzene isothiocyanate, the title compound YH-I-040 was prepared through steps b, c, f, g and h.

[0405] 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.66-7.57(m,3H),7.41-7.29(m,4H),7.07-6.96(m,3 H),6.63(dd,J=2.1,1.1Hz,1H),6.44(dd,J=7.5,2.0Hz,1H),6.26(s,1H),3.43(p,J=7.0Hz, 1H),3.08(dtd,J=12.5,7.1,2.2Hz,2H),2.71(dtd,J=12.4,7.1,2.7Hz,2H),2.53(d,J=1.0 Hz,3H),2.44(s,1H),1.63(dtd,J=14.1,7.1,1.3Hz,2H),1.31(ddq,J=14.1,8.3,7.1Hz,2H)

[0406] HRMS (ES+) calculated value: C 31 H 29 N7O2[M+H] + :532.2461,Measurement value:532.2462

[0407] Preparation Example 28

[0408] Preparation of 5-((6-(2-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-047)

[0409] Using a method similar to Example 1, replacing 1-chloro-4-isothiocyanatobenzene with 1-trifluoromethyl-4-isothiocyanatobenzene, and going through steps b, c, g, and h, the title compound YH-I-047 was prepared.

[0410] 1H NMR (400MHz, DMSO-d6) δ8.50 (s, 1H), 7.62 (d, J = 7.5Hz, 1H), 7.57-7.50 (m, 2H), 7.41-7.27 (m, 4H), 7 .02(dd,J=7.5,1.5Hz,1H),6.99(s,1H),6.65(dd,J=2.2,1.1Hz,1H),6.43(dd,J=7.5,2.1Hz,1H),6. 26(s,1H),3.41(p,J=7.0Hz,1H),2.88(dtd,J=12.6,7.2,1.9Hz,2H),2.53(d,J=1.0Hz,3H),2.34(s ,3H),1.96(dtd,J=12.4,7.0,2.9Hz,2H),1.68(dq,J=14.0,7.1Hz,2H),1.43(dt,J=13.2,7.0Hz,2H)

[0411] HRMS (ES+) calculated value: C 33 H 30 F3N7O2[M+H] + :614.2491, measured value: 614.2493

[0412] Preparation Example 29

[0413] Preparation of 5-((6-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-048)

[0414] Using a method similar to Example 1, replacing F3 with (3,5-dimethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-pinacol borane, and replacing 1-chloro-4-isothiocyanate benzene with 1-trifluoromethyl-4-isothiocyanate benzene, and going through steps b, c, f, g and h, the title compound YH-I-048 was prepared.

[0415] 1H NMR (400MHz, DMSO-d6) δ8.48 (s, 1H), 7.62 (d, J = 7.6Hz, 1H), 7.57-7.50 (m, 2H), 7. 39-7.27(m,3H),7.02(dd,J=7.6,1.6Hz,1H),6.86(s,1H),4.42(p,J=7.0Hz,1H),2 .92(dt,J=12.5,7.1Hz,2H),2.66(s,3H),2.52(s,3H),2.25(s,3H),2.16(dtd,J=1 2.3,7.0,1.0Hz,2H),2.07-1.91(m,2H),1.69(dddd,J=14.1,11.8,7.1,4.6Hz,2H)

[0416] HRMS (ES+) calculated value: C 31 H 29 F3N8O2[M+H] + :603.2444,Measurement value:603.2444

[0417] Preparation Example 30

[0418] Preparation of 5-((6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-049)

[0419] Using a method similar to Example 1, replacing F3 with (3,5-dimethyl-1-(1-piperidin-4-yl)-1H-pyrazole-4-pinacol borane, and replacing 1-chloro-4-isothiocyanate benzene with 1-trifluoromethyl-4-isothiocyanate benzene, and going through steps b, c, f, g and h, the title compound YH-I-049 was prepared.

[0420] 1 H NMR (400MHz, DMSO-d6) δ8.47 (s, 1H), 7.62 (d, J = 7.5Hz, 1H), 7.57-7.50 (m, 2H) ,7.39-7.27(m,3H),7.02(dd,J=7.5,1.5Hz,1H),6.86(s,1H),4.46(p,J=7.0H z,1H),3.10(dtd,J=12.6,7.2,1.3Hz,2H),2.71(dtd,J=12.6,7.1,2.2Hz,2H) ,2.64(s,3H),2.52(s,3H),2.44(s,1H),1.91-1.71(m,2H),1.70-1.56(m,2H)

[0421] HRMS (ES+) calculated value: C 30 H 27 F3N8O2[M+H] + :589.2287, measured value: 589.2286

[0422] Preparation Example 31

[0423] Preparation of 5-((6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-050)

[0424] Using a method similar to Example 1, replacing F3 with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and replacing 1-chloro-4-isothiocyanate with 1-trifluoromethyl-4-isothiocyanate benzene, and going through steps b, c, f, g and h, the title compound YH-I-050 was prepared.

[0425] 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=0.6Hz,1H),7.89(s,1H),7.52(d,J=8.8Hz,1H),7.49-7.42(m,2H),7.35-7.27(m,3H),6.99- 6.92(m,2H),6.83(dd,J=8.8,1.9Hz,1H)

[0426] MS (ESI) calculated value: C 24 H 16 F3N7O2[M+H] + :492.44,Measurement value:492.46

[0427] Preparation Example 32

[0428] Preparation of 5-((6-(2-methyl-4-(pyrrolidin-3-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-051)

[0429] Using a method similar to that of Example 1, replacing F3 with (2-methyl-4-(pyrrolidin-3-ylamino)phenyl)boronic acid and replacing 1-chloro-4-isothiocyanate with 1-trifluoromethyl-4-isothiocyanate benzene, and going through steps b, c, f, g and h, the title compound YH-I-051 was prepared.

[0430] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.55 (dd, J = 20.0, 8.6Hz, 2H), 7.49-7.42 (m, 2H), 7.35-7.2 7(m,2H),6.99-6.92(m,2H),6.87-6.79(m,2H),6.41(dd,J=8.5,1.9Hz,1H),5.89(d,J=6.7Hz,1H ),3.48-3.33(m,2H),3.26-3.16(m,1H),3.08(ddd,J=12.2,3.8,1.5Hz,1H),2.72(dtd,J=8.4,3. 6,1.8Hz,1H),2.09-1.99(m,1H),2.00(tt,J=3.8,2.4Hz,1H),1.60(dtd,J=12.5,3.6,1.5Hz,1H)

[0431] MS (ESI) calculated value: C 31 H 26 F3N7O2[M+H] + :586.60, measured value: 586.31

[0432] Preparation Example 33

[0433] Preparation of 5-((6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-052)

[0434] Using a method similar to Example 1, replacing F3 with (1H-pyrazol-4-yl)boronic acid and replacing 1-chloro-4-isothiocyanate with 1-trifluoromethyl-4-isothiocyanate benzene, and going through steps b, c, f, g and h, the title compound YH-I-052 was prepared.

[0435] 1 H NMR (400MHz, DMSO-d6) δ7.91-7.85(m,3H),7.52(d,J=8.8Hz,1H),7.49-7.42(m,2H),7.35-7.27(m,2H),6.99-6.92(m,2H),6.83(dd,J=8.8,1.9Hz,1H)

[0436] MS (ESI) calculated value: C 23 H 14 F3N7O2[M+H] + :478.42, measured value: 478.51

[0437] Preparation Example 34

[0438] Preparation of N-(4-chlorophenyl)-5-((6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-053)

[0439] Using a method similar to Example 1, replacing F3 with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and going through steps f, g and h, the title compound YH-I-053 was prepared.

[0440] 1 H NMR(400MHz,DMSO-d6)δ8.18(d,J=1.8Hz,1H),7.89(s,1H),7.67-7.59(m,2H),7.52 (d,J=8.8Hz,1H),7.33-7.25(m,3H),6.99-6.92(m,2H),6.83(dd,J=8.8,1.9Hz,1H)

[0441] MS (ESI) calculated value: C 23 H 16 ClN7O2[M+H] + :458.89,Measurement value:458.78

[0442] Preparation Example 35

[0443] Preparation of 5-((6-(4-(4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-amine (Compound YH-I-079)

[0444] Using a method similar to that of Example 1, replacing F3 with (4-(4-methylpiperazin-1-yl)methyl)phenyl)boronic acid and replacing 1-chloro-4-isothiocyanate with 1-trifluoromethyl-4-isothiocyanate benzene, and going through steps b, c, f, g and h, the title compound YH-I-079 was prepared.

[0445] 1H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.81-7.73 (m, 2H), 7.52 (d, J = 8.8Hz, 1H), 7.49-7.42 (m, 2H), 7.35-7.26 (m, 4H),6.99-6.92(m,2H),6.83(dd,J=8.7,2.3Hz,1H),3.79(t,J=1.0Hz,2H),3.13-3.03(m,4H),2.95-2.81(m,4H).

[0446] MS (ESI) calculated value: C 32 H 28 F3N7O2[M+H] + :600.63,Measurement value:600.80

[0447] Preparation Example 36

[0448] Preparation of (4-methylpiperazin-1-yl)(4-(4-((4-(trifluoromethyl)phenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methanone (Compound YH-I-080)

[0449] Using a method similar to Example 1, replacing F3 with (4-(4-methylpiperazine-1-carbonyl)phenyl)boronic acid and replacing 1-chloro-4-isothiocyanate with 1-trifluoromethyl-4-isothiocyanate benzene, and going through steps b, c, f, g and h, the title compound YH-I-080 was prepared.

[0450] 1 H NMR (400MHz, DMSO-d6) δ8.05(s,2H),7.55-7.42(m,1H),7.35-7.27(m,1H),6.99-6.92(m,1H),6.83(dd,J= 8.7,2.3Hz,0H),3.90(ddd,J=12.3,6.2,3.0Hz,1H),3.35-3.19(m,2H),2.75(ddd,J=11.7,6.1,3.0Hz,1H)

[0451] MS (ESI) calculated value: C 32 H 26 F3N7O3[M+H] + :614.61,Measurement value:614.70

[0452] Preparation Example 37

[0453] Preparation of N-(4-chlorophenyl)-5-((6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-081)

[0454] Using a method similar to Example 1, replacing F3 with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine, and going through steps f, g and h, the title compound YH-I-081 was prepared.

[0455] 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.89(s,1H),7.67-7.59(m,2H),7.52(d,J=8.8Hz,1H),7.40 (d,J=0.8Hz,1H),7.33-7.25(m,2H),6.99-6.92(m,2H),6.83(dd,J=8.8,1.9Hz,1H),4.40(qd,J= 3.8,0.7Hz,1H),3.04(ddt,J=12.3,5.6,2.9Hz,2H),2.74(ddt,J=12.5,5.8,2.9Hz,2H),2.44(p, J=3.1Hz,1H),1.93(dddd,J=12.1,5.4,3.7,2.8Hz,2H),1.79(dddd,J=12.3,5.6,3.7,2.8Hz,2H)

[0456] MS (ESI) calculated value: C 27 H 23 ClN8O2[M+H] + :527.99, measured value: 528.06

[0457] Preparation Example 38

[0458] Preparation of 5-((6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine (Compound YH-I-090)

[0459] Using a method similar to Example 3, replacing 1-chloro-4-isothiocyanatobenzene with 1-trifluoromethyl-4-isothiocyanatobenzene, and going through steps j, f, g, and h, the title compound YH-I-090 was prepared.

[0460] 1H NMR(400MHz, DMSO-d6)δ7.89(s,1H),7.52(d,J=8.8Hz,1H),7.49-7.42(m,2H),7.35-7.27(m,2H),6.99-6.92(m,2H),6.83(dd,J=8.7,2.3Hz,1H)

[0461] MS (ESI) calculated value: C 25 H 18 F3N7O2[M+H] + :506.47, measured value: 506.51

[0462] Preparation Example 39

[0463] Preparation of N-(4-chlorophenyl)-5-((6-(1,3-dimethyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine (Compound YH-I-091)

[0464] Using a method similar to Example 1, replacing F3 with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and going through steps f, g and h, the title compound YH-I-091 was prepared.

[0465] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.67-7.59 (m, 2H), 7.52 (d, J = 8.8Hz, 1H), 7.33- 7.25(m,2H),6.99-6.92(m,2H),6.83(dd,J=8.7,2.3Hz,1H),6.17(s,1H),3.95(s,3H)

[0466] MS (ESI) calculated value: C 24 H 18 ClN7O2[M+H] + :472.91,Measurement value:472.99

[0467] Preparation Example 40

[0468] Preparation of 2-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethan-1-ol (Compound YH-I-092)

[0469] Using a method similar to Example 1, replacing F3 with 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethane-1-ol, and going through steps f, g and h, the title compound YH-I-092 was prepared.

[0470] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.67-7.59 (m, 2H), 7.52 (d, J = 8.8Hz, 1H), 7.33-7.25 (m, 2H), 6.99-6.92 (m,2H),6.83(dd,J=8.8,1.9Hz,1H),4.82(t,J=6.0Hz,1H),4.02(t,J=3.3Hz,2H),3.72(dt,J=6.0,3.3Hz,2H)

[0471] MS (ESI) calculated value: C 26 H 22 ClN7O3[M+H] + :516.97, measured value: 517.21

[0472] Preparation Example 41

[0473] Preparation of 1-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Compound YH-I-093)

[0474] Using a method similar to Example 1, replacing F3 with 1-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, and going through steps f, g and h, the title compound YH-I-093 was prepared.

[0475] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.67-7.59 (m, 2H), 7.52 (d, J = 8.8Hz, 1H), 7.33-7.25 (m, 2H), 6.99-6.92(m,2H),6.83(dd,J=8.8,1.9Hz,1H),4.40(s,1H),2.71(s,3H),2.24(s,3H),1.23(s,6H)

[0476] MS (ESI) calculated value: C 28 H26 ClN7O3[M+H] + :545.02, measured value: 545.11

[0477] Preparation Example 42

[0478] Preparation of 1-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol (Compound YH-I-094)

[0479] Using a method similar to Example 1, replacing F3 with 1-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol, and going through steps f, g and h, the title compound YH-I-094 was prepared.

[0480] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.67-7.59 (m, 2H), 7.52 (d, J = 8.8Hz, 1H), 7.33-7.25 (m, 2H), 6.99-6.92 (m, 2H), 6.83 (dd,J=8.8,1.9Hz,1H),5.17(d,J=5.3Hz,1H),4.90-4.78(m,2H),3.70(qdt,J=6.8,5.4,4.4Hz,1H),1.17(d,J=6.7Hz,3H)

[0481] MS (ESI) calculated value: C 27 H 24 ClN7O3[M+H] + :530.99,Measurement value:530.90

[0482] Biological Examples

[0483] Biological Example 1

[0484] ALK inhibitory activity

[0485] Dilute 1 volume of protein culture medium 4-fold and add 50μM dithiothreitol as culture medium for standby use. Add different concentrations of the test compound to the 384-well plate (10μM as the starting concentration, 3-fold dilution, 10 concentrations, duplicate wells). Seal the 384-well plate to be tested and centrifuge the plate at 1000g for 1 minute. After mixing 2 times the ALK protein (test protein) with the 1 times protein culture medium, take 2.5μL of the protein mixture and add it to each well plate, centrifuge the plate at 1000g for 30s, and react at room temperature for 10min. At the same time, mix 2 times the substrate and ATP with the 1 times protein culture medium and shake well. Add 2.5μL of the substrate and ATP mixture to the well plate, centrifuge the plate at 1000g for 30s, seal the well plate, and react at room temperature for 1h. After the reaction is completed, add 5μL of ADP-Glo ​​reagent to each well and react at room temperature for 40min. Afterwards, add 10μL of protein detection reagent and react at room temperature for 40min. Finally, Envision 2104 was used to obtain the fluorescence values ​​and calculate the corresponding protein inhibition rate.

[0486] Table 1. IC values ​​of the compounds disclosed herein for wild-type ALK inhibitory activity 50 (Unit: nM)

[0487] Table 2. IC inhibitory activity of the compounds disclosed herein against mutant ALK 50 (Unit: nM)

[0488] Biological Example 2

[0489] Tumor cell growth inhibitory activity

[0490] Cytotoxicity test (taking Kelly cell toxicity as an example): Kelly cells were cultured in the culture medium recommended by the supplier (containing 10% fetal bovine serum). 1×10 cells were added to a 96-well culture plate. 3 Each well was incubated overnight at 37°C and 5% CO2. Culture medium containing varying concentrations of the test compound (10 μM as a starting concentration, 3-fold dilution, 10 concentrations, replicate) was then added to each well and incubated for a further 72 hours. Trypan blue staining confirmed viable cells exceeding 95%. Four hours before termination of incubation, 20 μL of MTT solution (5 mg / mL) was added to each well and incubated for a further 4 hours. The culture medium was discarded, and 150 μL of dimethyl sulfoxide was added, followed by shaking for 15 minutes. The absorbance (A value) was measured using a microplate reader at a wavelength of 570 nm, and the proliferation inhibition rate was calculated. The compound incubation time for Kelly, SH-SY5Y, TGW, and NCIH2228 cells was 72 hours, and for SUDHL-1, SK-N-SH, and KP-N-RT-BM-1 cells was 120 hours.

[0491] Table 3. Tumor cell growth inhibition rate of 1 μM compounds of the present disclosure

[0492] Table 4. Half-maximal inhibitory concentration (IC) of the compounds disclosed herein against tumor cell growth 50 (nM)

[0493] Biological Example 3

[0494] Pharmacokinetic property testing

[0495] The compounds disclosed in the present invention were tested for pharmacokinetic properties, and the test operation was as follows: the compound to be tested was dissolved and prepared into a stock solution of the required concentration for standby use. Then, healthy male mice were divided into groups of 3 mice per group. The mice were fasted for one night, allowed to drink water freely, and then fed and dosed 4 hours later. The dosage was as shown in the following table. Whole blood samples were collected through the orbital vein at designated time points (0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h), and 30μL of the sample was flowed into a sodium heparin anticoagulant tube and centrifuged at 4000rcf / 4℃ for 5 minutes, after which the upper plasma sample was taken. Finally, LC-MS / MS was used to collect data on the sample, and after data processing, the pharmacokinetic parameters of the compound to be tested were obtained.

[0496] Tables 5 and 6 show the blood concentration-time data of compound YH-I-001 of the present disclosure.

[0497] Table 5. Note: NA = Not Applicable

[0498] Table 6. Note: NA=Not Applicable NR=Not Reportable

[0499] FIG2 and FIG3 show the blood concentration-time curves of the compound YH-I-001 disclosed in the present invention.

[0500] Biological Example 4

[0501] In vivo anti-tumor test

[0502] The prepared compound YH-I-001, the purchased inhibitors Crizotinib, Ceritinib and Topotecan were subjected to in vivo anti-tumor activity analysis, and the solvent was provided as a control group. KELLY (brain, neuroblastoma, purchased from ECACC, Cat No.: 92110411, Lot No. 14A023) cells were cultured in a monolayer in vitro under the conditions of RPMI-1640 medium supplemented with 2mM Glutamine, 10% heat-inactivated fetal bovine serum, and cultured at 37°C without CO2. The cells were digested and passaged twice a week using trypsin-EDTA. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated. 5×10 5 0.2 mL cell suspension of KELLY cells (cells suspended in 1640:Martigel = 1:1) was subcutaneously inoculated on the right back of each mouse. On the 22nd day after inoculation, the average tumor volume reached 150.50 mm 3 The group dosing started at 14:00.

[0503] The experimental indicator is to examine whether tumor growth can be inhibited, delayed, or cured. Tumor diameter is measured twice a week with a vernier caliper. The formula for calculating tumor volume is: V = 0.5 × a × b 2 , a and b represent the long and short diameters of the tumor, respectively. The anti-tumor efficacy of the compound was evaluated using T / C (%). T / C% = TRTV / CRTV × 100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The formula for calculating relative tumor volume (RTV) is RTV = V t / V1. Where V1 is the tumor volume measured at the time of administration (i.e. Day 1), and Vt is the tumor volume measured on day t. The efficacy of tumor volume is evaluated by TGI, TGI (%) = (1-(TV treatment-Dn -TV treatment-D1 ) / (TV Control-Dn -TV Control-D1 ))×100%, TV Control : tumor volume of control group, TV Treatment : Tumor volume of the treated group. The therapeutic effect of tumor weight was evaluated by TGI%, and the tumor weight inhibition rate (TGI)% = (TW C -TW T ) / TW C ×100%, TW C : Tumor weight in control group, TW T : Tumor weight in treatment group.

[0504] Table 7. Preparation method of drugs

[0505] Table 8. Comparison of tumor inhibition rate (TGI) of KELLY tumor-bearing mice

[0506] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0507] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. A method for treating or preventing tumors, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof: in: R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl; R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group; and X and Y are each independently selected from O, S or N.

2. The method of claim 1 , wherein R is selected from the group consisting of halogen, unsubstituted aryl, optionally substituted alkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, optionally substituted amino-substituted aryl, sulfonamido-substituted aryl, unsubstituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted amino-substituted heteroaryl, and heterocycloalkyl-substituted heteroaryl.

3. The method of claim 1 or 2, wherein R is selected from halogen, unsubstituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkyl-substituted phenyl substituted by optionally substituted heterocycloalkyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, optionally substituted amino-substituted phenyl, sulfonamido-substituted phenyl, unsubstituted pyridyl, unsubstituted thienyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, optionally substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocycloalkyl-substituted amino-substituted pyrazolyl, or heterocycloalkyl-substituted pyrazolyl.

4. The method of any one of claims 1 to 3, wherein R is selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-substituted alkyl-substituted aryl, alkyl-substituted heterocycloalkyl-substituted alkyl-substituted aryl, alkyl-substituted heterocycloalkyl-substituted oxoalkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, alkyl-substituted amino-substituted aryl, optionally substituted heterocycloalkyl-substituted amino-substituted aryl, sulfonamido-substituted phenyl, unsubstituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocycloalkyl-substituted amino-substituted heteroaryl, or heterocycloalkyl-substituted heteroaryl.

5. The method of any one of claims 1 to 4, wherein R is selected from the group consisting of iodine, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4-(4-methylpiperazin-1-yl)methylphenyl, 4-(4-methylpiperazin-1-yl)oxymethylphenyl, methoxyphenyl, isopropyloxyphenyl, bromophenyl, cyano-substituted phenyl, dimethylaminophenyl, 2-methyl-4-piperidinyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methylpiperidinyl)-amino-substituted phenyl, 2-methyl-4-tetrahydropyrrolyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methyltetrahydropyrrolyl)-amino-substituted phenyl, , phenyl substituted with 2-methyl-4-sulfonamido, pyridyl, thienyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

6. The method according to any one of claims 1 to 5, wherein R1 is selected from:

7. The method according to any one of claims 1 to 6, wherein R2 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted aryl-heterocycloalkyl.

8. The method according to any one of claims 1 to 7, wherein R2 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted benzoheterocycloalkyl.

9. The method of any one of claims 1 to 8, wherein R2 is selected from unsubstituted alkyl, halogen-substituted aryl, optionally substituted alkyl-substituted aryl, optionally substituted alkoxy-substituted aryl, unsubstituted cycloalkyl, unsubstituted benzoheterocycloalkyl, or halogen-substituted benzoheterocycloalkyl.

10. The method of any one of claims 1 to 9, wherein R2 is selected from unsubstituted alkyl, halogen-substituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkoxy-substituted phenyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted thienyl, unsubstituted cycloalkyl, unsubstituted benzo[1,3]dioxolanyl, or halogen-substituted benzo[1,3]dioxolanyl.

11. The method of any one of claims 1 to 10, wherein R2 is selected from hexyl, 3,4-dichlorophenyl, 4-chlorophenyl, 4-isopropylphenyl, 3,5-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, cyclopentyl or cyclohexyl.

12. The method of any one of claims 1 to 11, wherein R2 is selected from:

13. The method according to any one of claims 1 to 12, wherein X is N and Y is selected from O or S; or X is O and Y is N.

14. The method according to any one of claims 1 to 13, wherein the compound represented by general formula (I) is selected from: N-(4-chlorophenyl)-5-((6-(2-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(p-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; 5-((6-(4-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-chlorophenyl)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrazol-4-yl)- pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; 4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzonitrile; N-(4-chlorophenyl)-5-((6-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(2-isopropylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(4-(dimethylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(3,5-bis(trifluoromethyl)phenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(3,4-dichlorophenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-2-amine; N-(4-isopropylphenyl)-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-cyclopentyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-cyclohexyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-hexyl-5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; N-(4-Chlorophenyl)-5-((6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazole -2-amine; 5-((6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-phenylbenzo[d]oxazol-2-amine; 5-((6-(2-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; 5-((6-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; 5-((6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; 5-((6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; 5-((6-(2-methyl-4-(pyrrolidin-3-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; 5-((6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; 5-((6-(4-(4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-amine; (4-methylpiperazin-1-yl)(4-(4-((4-(trifluoromethyl)phenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methanone; N-(4-chlorophenyl)-5-((6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; 5-((6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-2-amine; N-(4-chlorophenyl)-5-((6-(1,3-dimethyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzo[d]oxazol-2-amine; 2-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethan-1-ol; 1-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d] pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol; and 1-(4-(4-((2-((4-chlorophenyl)amino)benzo[d]oxazol-5-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol.

15. The method of any one of claims 1 to 14, further comprising administering to the subject an additional active agent.

16. The method of claim 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the other active agent are administered to the subject simultaneously, sequentially, overlappingly, concomitantly, intermittently, continuously, synchronously or any combination thereof.

17. The method of claim 15 or 16, wherein the additional active agent is a topoisomerase inhibitor, preferably a topoisomerase I inhibitor.

18. The method of claim 17, wherein the topoisomerase inhibitor is selected from the group consisting of topotecan, irinotecan, belotecan, aclarubicin, doxorubicin, epirubicin, idarubicin, etoposide, and mitoxantrone.

19. The method of any one of claims 1 to 18, wherein the tumor is mediated by tyrosine kinase (TK).

20. The method of any one of claims 1 to 19, wherein the subject is a mammal, preferably a human.

21. The method of claim 19 or 20, wherein the tyrosine kinase (TK) is selected from the group consisting of anaplastic lymphoma kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS1), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast growth factor receptor (FGFR), interleukin receptor-associated kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma viral oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular endothelial growth factor (VEGFR), The cells were transfected with rearranged kinase (RET), Bruton's tyrosine kinase (BTK), B-lymphoid tyrosine kinase (BLK), cytoplasmic tyrosine protein kinase (BMX), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), isocitrate dehydrogenase (IDH), discoidin domain receptor 1 (DDR1), interleukin-2-induced T-cell kinase (ITK), and human protein tyrosine kinase 4 (TXK).

22. The method of any one of claims 1 to 21, wherein the tumor is selected from the group consisting of lymphoma, blastoma, sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancies, lung cancer, squamous cell lung cancer, peritoneal cancer, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumors, head and neck cancer, and hematological malignancies.

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