CN120187435A

CN120187435A - Treatment or prevention of tumors

Info

Publication number: CN120187435A
Application number: CN202380074358.6A
Authority: CN
Inventors: 黄湧; 蒋晨然; 陈学明; 陈杰安; 刘运; 安源; 吴冠林
Original assignee: Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center; Hong Kong University of Science and Technology
Current assignee: Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center; Hong Kong University of Science and Technology
Priority date: 2022-10-27
Filing date: 2023-10-27
Publication date: 2025-06-20
Also published as: WO2024088379A1

Abstract

Disclosed are methods of treating or preventing tumors comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁、R₂, X, and Y are as defined in the disclosure.

Description

Method for treating or preventing tumor

Citation of related application

The present disclosure claims the full rights of the inventive patent application filed at 10.27 of 2022 to the national intellectual property agency of the people's republic of China, application number 202211329128.3, entitled "method of treatment or prevention of tumors", the entire contents of which are incorporated herein by reference.

FIELD

The present disclosure relates generally to the field of pharmaceutical chemistry, and more particularly, to methods of treatment and prevention of tumors.

Background

Currently, the incidence of cancer is increasing, and about 420 tens of thousands die of cancer annually worldwide. Cancer in China is the first most common case in 2012, and almost half of the world is seen. The drugs for treating cancer mainly comprise a cytotoxic drug (cytotoxic drugs) and a molecular targeting drug (molecular target drugs). Cytotoxic drugs, i.e. traditional chemotherapeutics, achieve the goal of inhibiting tumor growth mainly by killing rapidly dividing tumor cells. However, cytotoxic drugs can simultaneously damage cells that divide rapidly under normal conditions, such as bone marrow, gastrointestinal tract and hair follicle cells, leading to the common side effects of chemotherapy, such as myelosuppression, mucositis, hair loss, etc. Targeted drug therapy achieves treatment by interfering with specific protein targets that affect tumor cell proliferation. An excellent protein or enzyme target has tumor cell specific mutations or other genetic alterations, whereas in normal tissue cells it is not, thus achieving specific cell selectivity. However, the targeting drugs often have defects such as drug resistance and toxic and side effects related to target molecules, so that many drug candidates have failed in clinical experiments although showing good effects on animal models. By adopting a drug administration mode of combining the targeted inhibitor and the cytotoxic drug, the drug effect can be improved through two different action mechanisms, and further, a better drug effect/toxicity window can be obtained through reducing the dosage.

Anaplastic Lymphoma Kinase (ALK) is a transmembrane protein tyrosine kinase, belonging to the insulin receptor kinase subfamily. It was first found in Anaplastic Large Cell Lymphoma (ALCL) with a fusion form of Nucleophosmin (NPM) -ALK, a T-cell non-hodgkin lymphoma, typically associated with chromosomal translocation. Thereafter, many cancers were found to be associated with different forms of ALK fusion. These include non-small cell lung cancer (NSCLC, EML 4-ALK), inflammatory myofibroblastic tumor (IMT, TPM 3-ALK), and diffuse large B cell lymphoma (DLBCL, CLTC-ALK). In addition, amplification of the ALK gene and mutation of the wild-type ALK protein have been reported in various tumors.

Targeted inhibition of Anaplastic Lymphoma Kinase (ALK) significantly improves the therapeutic outcome of treatment of ALK-positive cancers, but unfortunately, acquired drug resistant mutations of ALK have occurred. It is therefore important to provide a class of pyrimidine-pyrrole kinase inhibitors that act on ALK with high activity and selectivity. Currently marketed ALK inhibitors are class I kinase inhibitors that compete with ATP for binding pockets.

SUMMARY

In one aspect, the present disclosure relates to a method of treating or preventing a tumor comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I):

Wherein:

R ₁ is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;

R ₂ is selected from optionally substituted hydrocarbyl, optionally substituted aryl or optionally substituted cyclic hydrocarbyl, and

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

In another aspect, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a tumor:

Wherein:

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

Brief description of the drawings

FIG. 1 shows the pattern of interaction of the compound YH-I-001 of the present disclosure with ALK;

FIG. 2 shows a blood concentration versus time curve for compound YH-I-001 of the disclosure in ICR mice after intravenous administration at a dose of 1 mg-kg ^-1;

FIG. 3 shows a blood concentration versus time curve for compound YH-I-001 of the disclosure in ICR mice after intravenous administration at a dose of 5 mg-kg ^-1;

FIG. 4 shows a graph of tumor volume change in KELLY tumor-bearing mice, and

Figure 5 shows a graph of weight change in key tumor bearing mice.

Detailed description of the preferred embodiments

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, etc.

Throughout the specification and claims which follow, unless the context requires otherwise, the words "comprise" and "comprising" are to be construed in an open-ended, inclusive sense, i.e. "including but not limited to.

Reference throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" means that a particular reference element, structure, or feature described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "one embodiment" or "an embodiment" or "another embodiment" appearing in various places throughout the 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.

It should be understood that, as used in the specification of this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof includes a compound of formula (I) or a pharmaceutically acceptable salt thereof, or two or more compounds of formula (I) or pharmaceutically acceptable salts thereof.

Definition of the definition

Accordingly, the following terms, as used in the specification and the appended claims, have the following meanings, unless otherwise indicated to the contrary:

The shorthand notation preceded by the designation of certain chemical groups in this disclosure indicates the total number of carbon atoms present in the indicated chemical group. For example, C ₁-C₄ alkyl describes alkyl groups having a total of 1 to 4 carbon atoms as defined below, while C ₃-C₁₀ cycloalkyl describes cycloalkyl groups having a total of 3 to 10 carbon atoms as defined below. The total number of carbons in the shorthand notation does not include carbons that may be present in a substituent of the group.

In the present disclosure, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

In the present disclosure, the term "hydroxy" refers to an-OH group.

In the present disclosure, the term "amino" refers to the-NH ₂ group.

In the present disclosure, the term "cyano" refers to a-CN group.

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

A hydrocarbyl group may have from 1 to 8 carbon atoms (in this disclosure, a numerical range such as "1 to 8" refers to each integer in the given range, and "1 to 8" means that the hydrocarbyl group may be substituted with up to and including 8 carbon atoms from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., although the present definition also covers the occurrence of the term "hydrocarbyl" where a numerical range is not specified).

The hydrocarbyl group may be optionally substituted, i.e., substituted or unsubstituted. When substituted, the substituent groups are independently and independently one or more groups selected from 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-carboxy, O-carboxy, isocyanato (isocyanato), thiocyanato (isothiocyanato), nitro, silyl, trihalomethanesulfonyl, -NR 'R "(R' and R" are hydrocarbyl groups as defined herein), or amino groups 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, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted with one of the substituents described above.

In certain embodiments, "C ₁-C₄ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing one to four carbon atoms. The C ₁-C₄ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₁-C₄ hydrocarbon group" may be a C ₁-C₄ alkyl group. The C ₁-C₄ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, "C ₁-C₆ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing one to six carbon atoms. The C ₁-C₆ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₁-C₆ hydrocarbon group" may be a C ₁-C₆ alkyl group. The C ₁-C₆ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, "C ₁-C₁₂ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing from one to twelve carbon atoms. The C ₁-C₁₂ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₁-C₁₂ hydrocarbon group" may be a C ₁-C₁₂ alkyl group. The C ₁-C₁₂ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, "C ₂-C₆ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing from two to six carbon atoms. The C ₂-C₆ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₂-C₆ hydrocarbon group" may be a C ₂-C₆ alkyl group. The C ₂-C₆ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₂-C₆ hydrocarbon group" may be a C ₂-C₆ alkenyl group. The C ₂-C₆ alkenyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₂-C₆ hydrocarbon group" may be a C ₂-C₆ alkynyl group. The C ₂-C₆ alkynyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, "C ₃-C₆ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing from three to six carbon atoms. The C ₃-C₆ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₃-C₆ hydrocarbon group" may be a C ₃-C₆ alkyl group. The C ₃-C₆ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₃-C₆ hydrocarbon group" may be a C ₃-C₆ alkenyl group. The C ₃-C₆ alkenyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₃-C₆ hydrocarbon group" may be a C ₃-C₆ alkynyl group. The C ₃-C₆ alkynyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, "C ₃-C₁₂ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing from three to twelve carbon atoms. The C ₃-C₁₂ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₃-C₁₂ hydrocarbon group" may be a C ₃-C₁₂ alkyl group. The C ₃-C₁₂ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₃-C₁₂ hydrocarbon group" may be a C ₃-C₁₂ alkenyl group. The C ₃-C₁₂ alkenyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₃-C₁₂ hydrocarbon group" may be a C ₃-C₁₂ alkynyl group. The C ₃-C₁₂ alkynyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, "C ₆-C₁₂ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing six to twelve carbon atoms. The C ₆-C₁₂ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₆-C₁₂ hydrocarbon group" may be a C ₆-C₁₂ alkyl group. The C ₆-C₁₂ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₆-C₁₂ hydrocarbon group" may be a C ₆-C₁₂ alkenyl group. The C ₆-C₁₂ alkenyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₆-C₁₂ hydrocarbon group" may be a C ₆-C₁₂ alkynyl group. The C ₆-C₁₂ alkynyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, "C ₇-C₁₂ hydrocarbyl" refers to a hydrocarbyl group of the definition above containing seven to twelve carbon atoms. The C ₇-C₁₂ hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.

In certain embodiments, the "C ₇-C₁₂ hydrocarbon group" may be a C ₇-C₁₂ alkyl group. The C ₇-C₁₂ alkyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₇-C₁₂ hydrocarbon group" may be a C ₇-C₁₂ alkenyl group. The C ₇-C₁₂ alkenyl group may be optionally substituted as defined for the hydrocarbon group.

In certain embodiments, the "C ₇-C₁₂ hydrocarbon group" may be a C ₇-C₁₂ alkynyl group. The C ₇-C₁₂ alkynyl group may be optionally substituted as defined for the hydrocarbyl group.

In the present disclosure, the term "hydrocarbyloxy" refers to a hydrocarbyl group of the general formula-O-wherein the hydrocarbyl group is as defined in the disclosure. Illustrative examples of hydrocarbyloxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and tert-pentyloxy.

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 fully delocalized Pi-electron system. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. The aryl group may have, for example, five to twelve carbon atoms. The aryl groups of the present disclosure may be substituted or unsubstituted. When substituted, the hydrogen atom is substituted with one or more groups independently selected from hydrocarbyl, cyclic hydrocarbyl, 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 groups as defined in the disclosure), or protected amino groups. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted with one of the substituents described above.

In the present disclosure, the term "heteroaryl" refers to a 5-to 18-membered aromatic cyclic 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 a fused or bridged ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Illustrative examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ] [1,4] dioxaheptyl, 1, 4-benzodioxanyl, benzonaphthylfuryl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzopyronyl, benzofuranyl, benzofuranonyl, benzothienyl, benzotriazolyl, benzo [4,6] imidazo [1,2-a ] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxo-azepinyl, oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenanthrazinyl, phenanthrothiazinyl, phenanthroxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quininyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. Heteroaryl groups of the present disclosure may be substituted or unsubstituted. When substituted, the hydrogen atom is substituted with one or more groups independently selected from hydrocarbyl, cyclic hydrocarbyl, 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 groups as defined in the disclosure), or protected amino groups. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted with one of the substituents described above.

In the present disclosure, the term "cycloalkyl" refers to a stable, non-aromatic, monocyclic or bicyclic hydrocarbon group consisting of only 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 attached to the remainder of the molecule by a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, and the like. Unless explicitly stated otherwise in the present disclosure, the term "cycloalkyl" is intended to include cycloalkyl groups as defined above optionally substituted with one or more groups selected from 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-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR 'R "(R' and R" are hydrocarbyl groups as defined in the present disclosure) or amino groups including mono-and di-substituted amino groups, and protected derivatives thereof.

In certain embodiments, "C ₃-C₆ cycloalkyl" refers to a cycloalkyl group as defined above having three to six carbon atoms. The C ₃-C₆ cycloalkyl group may be optionally substituted as defined for the cycloalkyl group above.

In certain embodiments, "C ₃-C₁₀ cycloalkyl" refers to a cycloalkyl group as defined above having from three to ten carbon atoms. The C ₃-C₁₀ cycloalkyl group may be optionally substituted as defined for the cycloalkyl group above.

In certain embodiments, "C ₃-C₁₂ cycloalkyl" refers to a cycloalkyl group as defined above having three to twelve carbon atoms. The C ₃-C₁₂ cycloalkyl group may be optionally substituted as defined for the cycloalkyl group above.

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, dioxacyclopentyl, 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, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl.

In the present disclosure, the term "compound of the present disclosure or a pharmaceutically acceptable salt thereof" refers to a 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.

In the present disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cattle, sheep, horses, and humans. In certain embodiments, the mammal comprises a human.

In the present disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cows, pigs, and sheep). In certain embodiments, the patient is a mammal comprising a male and a female. In certain embodiments, the patient is a human.

In the present 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.

In this disclosure, the term "arbitrary" or "arbitrarily" means that the subsequently described event or condition may or may not occur, and that the description includes instances where the event or condition occurs as well as instances where it does not.

In the present disclosure, the term "pharmaceutically acceptable adjuvant" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, and the like that have been approved by the U.S. food and drug administration for use in humans or animals.

In the present disclosure, the term "vector" is defined as a compound that facilitates the introduction of the compound into a cell or tissue. Dimethyl sulfoxide (DMSO), for example, is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

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

In the present disclosure, the term "acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and are formed using inorganic or organic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzene carboxylic acid, 4-acetamidobenzene carboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexaneaminosulfonic 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, glutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, tartaric acid, sulfuric acid, sulfanilic acid, succinic acid, toluenesulfonic acid, tricarboxylic acid, undecylenic acid, and the like.

In the present disclosure, the term "acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid, which are biologically or otherwise appropriate. These salts are prepared by adding an inorganic or organic base to the free acid. 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 salts of basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

In the present disclosure, the term "pharmaceutical composition" refers to a formulation of a compound described in the present disclosure with a medium that delivers a biologically active compound to a mammal, such as a human, as is commonly accepted in the art. Such vehicles include all pharmaceutically acceptable carriers, diluents or excipients.

In this disclosure, the term "therapeutically effective amount" refers to an amount of a compound or combination of compounds that improves, reduces, or eliminates a particular disease or condition and symptoms of a particular disease or condition, or avoids 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 this disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age, weight, etc., of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the present disclosure.

As used herein, "treating" or "treatment" encompasses treatment-related diseases or disease states in a mammal, such as a human, having a related disease or disorder, and includes:

(i) Preventing a disease or a disease state from occurring in a mammal, particularly when the mammal is susceptible to the disease state, but has not been diagnosed with the disease state;

(ii) Inhibiting the disease or condition, i.e. preventing it from occurring, or

(Iii) The disease or disease state is alleviated even if the disease or disease state regresses or does not progress.

In the present disclosure, the term "preventing" refers to preventing the onset, recurrence or spread of a disease or disease state, or one or more symptoms thereof.

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

As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably or may be different in that a particular disease or disease state may not have known causative agents (and therefore cannot be interpreted by etiology) and therefore is not recognized as a disease, but rather is considered an undesired disease state or condition in which a clinician has identified more or less of a particular set of symptoms.

In the present disclosure, the term "topoisomerase" refers to an enzyme that corrects the number of DNA loops by cleaving the phosphodiester bonds in one or both strands of DNA, and then rewinding and sealing.

Detailed Description

Wherein:

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

In certain embodiments, R ₁ is selected from the group consisting of halo, unsubstituted aryl, optionally substituted alkyl-substituted aryl, alkoxy-substituted aryl, halo-substituted aryl, cyano-substituted aryl, optionally substituted amino-substituted aryl, sulfonamide-substituted aryl, unsubstituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted amino-substituted heteroaryl, or heterocycloalkyl-substituted heteroaryl.

In certain embodiments, R ₁ is selected from halogen, unsubstituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted heterocycloalkyl-substituted alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, optionally substituted amino-substituted phenyl, sulfonamide-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.

In certain embodiments, R ₁ is selected from the group consisting of halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-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, sulfonamide-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, and heterocycloalkyl-substituted heteroaryl.

In some embodiments of the present invention, in some embodiments, R ₁ is selected from the group consisting of iodo, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4- (4-methylpiperazin-1-yl) methylphenyl, 4- (4-methylpiperazin-1-yl) oxymethylphenyl, methoxyphenyl, isopropoxyphenyl, 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-methyltetrazolyl) -amino-substituted phenyl, bromophenyl, and 2-methyl-4-sulfonylamino-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.

In certain embodiments, R ₁ is selected from:

In certain embodiments, R ₂ is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted arylheterocycloalkylene.

In certain embodiments, R ₂ is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted benzoheterocycloalkyl.

In certain embodiments, R ₂ is selected from unsubstituted alkyl, halo-substituted aryl, optionally-substituted alkyl-substituted aryl, optionally-substituted alkoxy-substituted aryl, unsubstituted cycloalkyl, unsubstituted benzoheterocycloalkyl, or halo-substituted benzoheterocycloalkyl.

In certain embodiments, R ₂ is selected from unsubstituted alkyl, halo-substituted phenyl, optionally-substituted alkyl-substituted phenyl, optionally-substituted alkoxy-substituted phenyl, optionally-substituted pyridinyl, optionally-substituted pyrrolyl, optionally-substituted pyrazolyl, optionally-substituted thiazolyl, optionally-substituted oxazolyl, optionally-substituted thienyl, unsubstituted cycloalkyl, unsubstituted benzo [1,3] dioxolyl, or halo-substituted benzo [1,3] dioxolyl.

In certain embodiments, R ₂ is selected from hexyl, 3, 4-dichlorophenyl, 4-chlorophenyl, 4-isopropyl phenyl, 3, 5-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, cyclopentyl, or cyclohexenyl.

In certain embodiments, R ₂ is selected from:

In certain embodiments, X is N and Y is O.

In certain embodiments, X is N and Y is S.

In certain embodiments, X is O and Y is N.

In certain embodiments, X is O and Y is S.

In another aspect, the present disclosure relates to compounds, and pharmaceutically acceptable salts thereof, wherein the compounds are selected from the group consisting 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;

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-tolyl) -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-pyrrolo [2,3-d ] 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 ] oxazol-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.

In certain embodiments, the compounds of the present disclosure have potent ALK inhibiting activity.

In certain embodiments, the compounds of the present disclosure are resistant to ALK mutants.

In certain embodiments, the compounds of the present disclosure have excellent stability.

In certain embodiments, the compounds of the present disclosure have excellent potency.

In certain embodiments, the methods of treating or preventing tumors of the present disclosure further comprise administering to the subject an additional active agent.

In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, and other active agents are administered to an individual simultaneously, sequentially, overlapping, concomitantly, intermittently, sequentially, synchronously, or any combination thereof.

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.

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

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, idamycin, etoposide, and mitoxantrone.

In certain embodiments, the tumor that can be used in the methods of treating or preventing tumors of the present disclosure is mediated by a Tyrosine Kinase (TK).

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of 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 adjuvant.

Pharmaceutical composition

In certain embodiments, the pharmaceutical composition comprises a compound of 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 adjuvant.

In certain embodiments, the compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, or the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a Tyrosine Kinase (TK) -mediated disease or condition may be administered to a mammal by the gastrointestinal or parenteral route.

In certain embodiments, the compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, or the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a Tyrosine Kinase (TK) -mediated disease or condition may be administered orally to a mammal.

In certain embodiments, the compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, or the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a Tyrosine Kinase (TK) -mediated disease or condition may be administered to a mammal by the intrarectal route.

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

Examples of pharmaceutically acceptable excipients that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, and the like that have been approved by the U.S. food and drug administration for use in humans or animals. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences (rest, pharmacia), 18th Ed., mack Publishing co., easton, PA (1990)), the entire contents of which are incorporated herein by reference.

The pharmaceutical compositions of the present disclosure may be administered by any method that achieves its intended purpose. For example, administration may be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, tracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. The route of administration may be parenteral, oral or intrarectal. The dose administered will depend on the age, health and weight of the recipient, if any concurrent therapy, and also on the type of concurrent therapy, the frequency of the therapy, and the nature of the effect desired.

Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees (dragee), semi-solid formulations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, strips (tape), eye drops, solutions, syrups, aerosols, suspensions, emulsions, which may be prepared according to methods known in the art.

Particularly suitable for oral administration are ordinary tablets (plain tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suppositories, solutions or aqueous solutions based on oil, suspensions, emulsions or implants, and ointments, creams or powders for topical use. The products of the present disclosure may also be lyophilized, the resulting lyophilizate being used, for example, to prepare injections. The formulations given may be sterilized and/or contain adjuvants (auxiliary), such as wetting agents, preserving agents, stabilizers and/or wetting agents, emulsifying agents, salts for varying the osmotic pressure, buffer substances, dyes, flavouring agents and/or a number of further active ingredients, for example one or more vitamins.

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.

Preservatives, stabilizers, dyes, sweeteners, fragrances, perfumes and the like may be provided in the pharmaceutical compositions. For example, sodium benzoate, ascorbic acid, and esters of parahydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspensions may be used.

In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surfactants, sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, methyl magnesium aluminate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, hydroxymethyl cellulose calcium, and the like may be used as excipients, magnesium stearate, talc, hardened oil, and the like may be used as a smoothing agent, coconut oil, olive oil, sesame oil, peanut oil, soybean, and the like may be used as a suspension or lubricant, cellulose acetate, as derivatives of sugars such as cellulose or sugar, or methyl acetate-methacrylate copolymers, as derivatives of polyethylene, may be used as a suspension, and plasticizers such as phthalate, and the like may be used as a suspension.

Suitable routes of administration may include, for example, oral, rectal, transdermal, parenteral, topical or enteral administration, parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injection. The compounds can also be administered at a predetermined rate and/or at a predetermined timing, in sustained or controlled release dosage forms including depot injections (depot injections), osmotic pumps, pills, transdermal (including electrotransport) patches, and the like.

The pharmaceutical compositions of the present disclosure may be produced in known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting procedures.

Thus, in accordance with the present disclosure, the pharmaceutical compositions employed may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable formulations depend on the route of administration selected. Any known techniques, carriers and excipients may be used as appropriate and understood in the art.

The injection can be prepared in conventional form as a solution or suspension, a solid dosage form suitable for preparation of a solution or suspension prior to injection, or as an emulsion. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, if desired, the injectable pharmaceutical composition may contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffers and the like. Physiologically suitable buffers include, but are not limited to, hank's solution, ringer's solution, or physiological saline buffer. If desired, absorption enhancing agents (e.g., liposomes) may be used.

For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. For oral ingestion by a patient to be treated, such carriers enable the compounds of the present disclosure to be formulated as tablets, pills, troches, capsules, liquids, gels, syrups, slurries, suspensions, solutions, powders and the like. Pharmaceutical formulations for oral administration can be obtained by mixing the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, if desired after adding suitable auxiliaries, to obtain tablets or dragee cores. Suitable excipients include, 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, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, for example crosslinked polyvinylpyrrolidone, agar or alginic acid or an alginate such as sodium alginate. The lozenge cores are suitably coated. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel (carbopol gel), polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound doses, dyes or pigments may be added to the tablet or lozenge coating. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

Pharmaceutical formulations that can be used for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, such as glycerol or sorbitol, and a plasticizer. The push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, for example a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers may be added. All formulations for oral administration should be in a dosage suitable for such administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may comprise 0.1% to 95% of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

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

In any event, 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, in an amount effective to treat the subject disease/condition being treated.

Administration method

The 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, may be administered to a patient by any method of delivering the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in any suitable system and/or locally. Non-limiting examples of methods of administration include (a) administration by oral route, including administration in capsules, tablets, granules, sprays, syrups or other such forms, (b) administration by non-oral route, such as rectal, vaginal, intra-urethral, intra-ocular, intranasal or intra-aural, including administration in aqueous suspension, oily formulation or the like or in drops, sprays, suppositories, ointments or the like, (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection or the like, including infusion pump delivery, (d) local (locally) such as injection directly in the renal or cardiac area, such as by depot type implantation, and (e) local (topically), as appropriate administration by those of skill in the art is by contacting the compounds described in this disclosure with living tissue.

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 methods of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, appropriate pharmaceutical excipients, and other matters related to delivering the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

Pharmaceutical compositions suitable for administration include those which contain an effective amount of the active ingredient to achieve its intended effect. The dosage required for a therapeutically effective amount of the pharmaceutical compositions described in this disclosure will depend 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 may be adjusted to achieve the desired effect, but will depend on the weight, diet, concurrent medication, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a compound effective to prevent, reduce or ameliorate symptoms of a disease, or to extend the life of an individual receiving treatment. The actual ability of those skilled in the art to determine a therapeutically effective amount is well within the scope of the detailed disclosure provided herein.

As will be apparent to those skilled in the art, the dosage and particular mode of administration used for in vivo administration will vary depending upon the age, weight and type of mammal being treated, the particular compound being used, and the particular use for which such compound is being used. The aim of determining an effective dosage level, i.e. the dosage level necessary to determine the desired effect, can be achieved by the person skilled in the art using conventional pharmacological methods. Typically, the human clinical application of the product is started at lower dosage levels, with the dosage level increasing until the desired effect is achieved. Or using established pharmacological methods, an acceptable in vitro study can be used to establish effective dosages and routes of administration for the compositions identified by the present methods.

In non-human animal studies, the use of potential products begins at higher dosage levels, with the dosage decreasing until the desired effect is no longer achieved or the adverse side effects disappear. The dosage range may be wide depending on the intended effect and the therapeutic indication. Typically, the dosage may be from about 10 μg/kg body weight to 1000mg/kg body weight, and in certain embodiments from about 100 μg/kg body weight to 300mg/kg body weight. Or as will be appreciated by those skilled in the art, the dose may be based on and calculated from the body surface area of the patient.

Each physician is able to select the exact formulation, route of administration, and dosage of the pharmaceutical compositions described in the present disclosure, depending on the patient's condition. Generally, the dosage of the composition administered to the patient may range from about 0.5mg/kg to 1000mg/kg of patient body weight. The dose may be administered alone or in two or more doses over a single day or days, depending on the patient's needs. Where the human dosage of the compound is 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, in certain embodiments ranging from 25% to 250% of the established human dosage. Without a defined human dose, as in the case of the newly discovered pharmaceutical compounds, the appropriate human dose can be inferred from the median number of half-effective or infectious doses, or other suitable values from in vitro or in vivo studies, as quantified by toxicity and efficacy studies in animals.

It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust administration. Conversely, if the clinical response is inadequate (toxicity is excluded), the attending physician will also know to adjust the treatment to a higher level. The size of the dose administered in the treatment of the condition of interest will vary with the severity of the disease state being treated and the route of administration. The severity of the disease state may be assessed, for example, in part by standard prognostic assessment methods. Furthermore, the dose and possibly the frequency of doses will also vary according to the age, weight, and response of the individual patient. Protocols comparable to those discussed above may be used in veterinary medicine.

While the exact dosage may be determined on a drug-by-drug basis, in most cases some generalization can be made with respect to the agent. The daily dosage regimen for an adult patient is, for example, an oral dosage of 0.1mg to 2000mg of each active ingredient, in certain embodiments 1mg to 2000mg of each active ingredient, for example 5mg to 1500mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is from 0.01mg to 1000mg, in certain embodiments from 0.1mg to 1000mg, for example from 1mg to 800mg. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. In certain embodiments, the composition is administered 1 to 4 times daily. Alternatively, the compositions described in the present disclosure may be administered by continuous intravenous infusion, in certain embodiments at doses of up to 2000mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain instances, it may be necessary to administer the compounds described in the present disclosure in amounts exceeding or far exceeding the dosage ranges described above in order to effectively and rapidly treat a rapidly developing disease or infection. In certain embodiments, the compound is administered during a continuous treatment period, e.g., one or more weeks, or months or years.

The dosage and dosage interval may be individually adjusted to provide a plasma level of the active moiety sufficient to maintain a modulating effect or Minimum Effective Concentration (MEC). The MEC for each compound was different, but the MEC could be assessed from in vitro data. The required dose to achieve MEC depends on the individual characteristics and route of administration. However, HPLC (high performance liquid chromatography) assays or bioassays can be used to determine plasma concentrations.

The use of MEC values also enables the dosing interval to be determined. The composition should be administered using a treatment regimen that maintains plasma levels above MEC for 10-90% of the time, in some embodiments 30-90% of the time, and in some embodiments 50-90% of the time.

In the case of local administration or selective absorption, the effective local concentration of the drug is independent of plasma concentration.

The amount of composition administered will, of course, depend on the individual to be treated, on the weight of the individual, the severity of the affliction, the mode of administration and the discretion of the prescribing physician.

The efficacy and toxicity of the compounds described in the present disclosure can be assessed using known methods. For example, the toxicology of a particular compound or subset of compounds sharing certain chemical moieties can be established by assaying the toxicity of a cell line, such as a mammalian cell line and in certain embodiments a human cell line, in vitro. The results of such studies are generally predictive of toxicity in animals such as mammals, or more specifically, in humans. Alternatively, toxicity of a particular compound in an animal model such as mouse, rat, rabbit or monkey can be determined using known methods. The potency of a particular compound can be determined using several well-known methods, such as in vitro methods, animal models, or human clinical trials. There are well-known in vitro models for almost every type of disease state, including but not limited to cancer, cardiovascular disease and various immune dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of chemicals to treat these disease states. When selecting a model to determine efficacy, the skilled artisan is able to select the appropriate model, dosage and route of administration, as well as treatment regimen, under the direction of the art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

If desired, the composition may be placed in a packaging or dispensing device which may contain one or more unit dosage forms containing the active ingredient. The package may for example comprise a metal or plastic foil, such as a blister pack. The packaging or dispensing device may carry instructions for administration. The packaging or dispensing device may also carry precautions associated with the container, the precautions being prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which precautions reflect approval of the pharmaceutical form by the agency for human or veterinary administration. Such notice may be, for example, a label for prescription drugs approved by the national food and drug administration or the U.S. food and drug administration, or an approved product specification. Compositions comprising the compounds of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof, formulated in compatible pharmaceutical carriers, may also be prepared in suitable containers and labeled for treatment of the indicated disease states.

In yet another aspect, the present disclosure is directed to a process for preparing a compound of formula (Ia),

Which comprises carrying out the following reaction:

Wherein:

X ₁ and Y ₁ are each independently selected from amino, mercapto or hydroxy;

X and Y are each independently selected from O, S or N, and

R ₂ is selected from optionally substituted hydrocarbyl, optionally substituted aryl or optionally substituted cyclic hydrocarbyl.

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

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 mixtures thereof.

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.

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

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

In certain embodiments, illustrative examples of strong oxidants that can be used in the present disclosure include, but are not limited to, periodate salts, dichromate salts, pyridinium chlorochromate, or any mixture thereof.

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.

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.

In another aspect, the present disclosure is directed to a method of preparing a compound of formula (Ib),

Which comprises carrying out the following reaction:

Wherein:

b is selected from boric acid or boric acid ester.

In certain embodiments, the reaction to prepare the compound of formula (Ib) is performed in the presence of a palladium catalyst and a base.

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 mixtures thereof.

In certain embodiments, illustrative examples of borates that can be used in the present disclosure include, but are not limited to, bis (pinacolato) diboron (Bpin), bcat, or any mixtures thereof.

In yet another aspect, the present disclosure is directed to a process for preparing a compound of formula (Id),

Comprising reacting a compound represented by the general formula (Ic) with a compound represented by the general formula (Ib):

in certain embodiments, the process for preparing the compound of formula (Ic) is carried out in the presence of a base.

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

In yet another aspect, the present disclosure relates to a method of inhibiting Tyrosine Kinase (TK) comprising contacting a tyrosine kinase with an inhibiting effective amount of a compound of 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.

In certain embodiments, illustrative examples of Tyrosine Kinases (TKs) that can be used in the present disclosure include, but are not limited to, anaplastic Lymphoma Kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS 1), epidermal Growth Factor Receptor (EGFR), platelet growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast Growth Factor Receptor (FGFR), interleukin receptor-related kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma virus oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular Endothelial Growth Factor (VEGFR), transfected rearrangement kinase (RET), bruton's Tyrosine Kinase (BTK), B-lymphotyrosine kinase (BLK), cytoplasmic tyrosine protein kinase (BMX), human epidermal growth factor receptor 2 (HER 2), human epidermal growth factor receptor 4 (HER 4), isocitrate Dehydrogenase (IDH), discoid domain receptor 1 (DDR 1), interleukin 2-induced T cell kinase (k), and human protein tyrosine kinase 4 (TXK).

In another aspect, the present disclosure relates to a method of treating or preventing a Tyrosine Kinase (TK) -mediated disease or condition comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of 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.

In certain embodiments, illustrative examples of individuals that can be used in the methods of the present disclosure for treating or preventing Tyrosine Kinase (TK) mediated diseases or conditions include, but are not limited to, mammals.

In certain embodiments, the subject is a human.

In certain embodiments, illustrative examples of diseases or disease states that can be used in the methods of treating or preventing Tyrosine Kinase (TK) -mediated diseases or disease states of the present disclosure include, but are not limited to, lymphomas, blastomas, sarcomas, neuroendocrine tumors, carcinoid tumors, gastrinomas, islet cell carcinomas, mesotheliomas, schwannomas, acoustic neuromas, meningiomas, adenocarcinomas, melanomas, leukemias, lymphoid malignancies, lung cancer, lung squamous cell carcinomas, peritoneal carcinomas, stomach cancers, intestinal cancers, pancreatic cancers, glioblastomas, cervical cancers, ovarian cancers, liver cancers, bladder cancers, breast cancers, colon cancers, rectal cancers, colorectal cancers, uterine cancers, salivary gland cancers, kidney cancers, prostate cancers, vulval cancers, thyroid cancers, anal cancers, penile cancers, merkel cell cancers, esophageal cancers, biliary tract tumors, head and neck cancers, and hematological malignancies.

In certain embodiments, a method of treating or preventing a Tyrosine Kinase (TK) -mediated disease or condition, comprising administering to a subject in need thereof 1mg to 10g of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating or preventing a Tyrosine Kinase (TK) -mediated disease or condition, comprising administering to a subject in need thereof 10mg to 3000mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating or preventing a Tyrosine Kinase (TK) -mediated disease or condition, comprising administering to a subject in need thereof 100mg to 1000mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating or preventing a Tyrosine Kinase (TK) -mediated disease or condition, comprising administering to an individual in need thereof 100mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, or 1000mg of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the methods of the present disclosure for treating or preventing a Tyrosine Kinase (TK) mediated disease or condition further comprise administering to the subject an additional active agent.

In certain embodiments, can be used in the treatment or prevention of tyrosine kinase (tyrosine kinase), examples of TK) mediated diseases or conditions include, but are not limited to, nitrogen mustard, aziridine, methyl melamine, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors, anticancer vaccines, acitretin, arubicin, acodazole hydrochloride, alcaine, adorinin, aldesleukin, an Bomei, amitraquinone acetate, aminoglutethimide, amsacrine, anastrozole, angustin, asparaginase, clindamycin, azacytidine, azatepa, arzomycin, bamarstat, benzotepa, bicaluromide, bisnaftifine mesylate, bifenoxine, busulfan actinomycin C, carbosterone, carmustine, carmellose, carboplatin, carmustine hydrochloride, chlorambucil, sirolimus, cladribine, clenbuterol mesylate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin hydrochloride, droxifene, epirubicin hydrochloride, elfeubicin hydrochloride, estramustine, itraconazole, etoposide, fluorouridine, fluorouracil, fluoxetine, gemcitabine, idarubicin hydrochloride, ifosfamide, interleukin II, interferon alpha-2 a, interferon alpha-2 b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, chlorthalidine, sericin, mi Tuoen ketone, paclitaxel, procarbazine hydrochloride, cetirizine, vinblastine, vincristine, angiogenesis inhibitors, camptothecins, dexamethasone, aspirin, acetaminophen, indomethacin, ibuprofen, ketoprofen, meloxicam, corticosteroids, and adrenocorticosteroids.

In yet another aspect, the present disclosure relates to compounds of formula (I) of the present disclosure and pharmaceutically acceptable salts thereof for inhibiting Tyrosine Kinase (TK).

In yet another aspect, the present disclosure relates to compounds of formula (I) of the present disclosure and pharmaceutically acceptable salts thereof for use in the treatment or prevention of Tyrosine Kinase (TK) mediated diseases or conditions.

In another aspect, the present disclosure relates to the use of a compound of formula (I) of the present disclosure and pharmaceutically acceptable salts thereof or a compound of the present disclosure and pharmaceutically acceptable salts thereof in the manufacture of a medicament for inhibiting Tyrosine Kinase (TK).

In yet another aspect, the present disclosure relates to the use of a compound of formula (I) of the present disclosure and pharmaceutically acceptable salts thereof or a compound of the present disclosure and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of a Tyrosine Kinase (TK) mediated disease or condition.

Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand the aspects of the present application and the advantages thereof. However, it should be understood that the following examples are non-limiting and are merely illustrative of certain embodiments of the present disclosure.

Examples

Reagents and equipment used in the examples of the present disclosure were all conventional and commercially available. For example:

Preparation example

Preparation example 1

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)

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,27mmol, 60%), and the mixture was stirred at 0℃for 30min. To the reaction mixture was added SEMCl (3.58 g,3.8ml,8.64 mmol) which was warmed to room temperature and stirred for 2 hours, quenched by saturated NH ₄ C solution. Extraction with EtOAc (60 ml×2), drying over Na ₂SO₄, filtration and concentration under reduced pressure gave the crude product, which was further purified by silica gel column chromatography to give the desired product F1 as a white solid (5.72 g, 78%).

Step b to a mixture of 2-amino-4-methoxyphenol (1.39 g,10 mmol) in THF (100 mL) was added phenyl p-chloroisothiocyanate (2.54 g,15 mmol) and K ₂CO₃ (2.764 g,20 mmol). The reaction was stirred at room temperature overnight. A solution of NaIO ₄ (427.78 mg in 100mL H ₂ O, 20 mol%) was poured into the reaction. TLC showed that 2-amino-4-methoxyphenol was consumed. Extracted with EA. Concentrated and purified by column on silica gel to give the desired intermediate (2.1976 g, 80%).

Step c to a suspension of the product from step b (2.1976 g,8 mmol) in DCM (80 mL) was added BBr ₃.DCM (2M, 20mL, 5-fold equivalents). The reaction was stirred at room temperature. The reaction was quenched with MeOH until TLC showed no starting material remained. Concentrated and purified by silica gel column to give the desired product F2 (1.88 g, 90%).

Step d 1-methylpiperidin-4-one (7.92 g,8.12mL,70 mmol) was added to a suspension of 4-bromo-3-methylaniline (9.30 g,50 mmol) in DCE (165 mL). STAB (14.84 g,70mmol,1.4 eq) and HOAc? 3g,5mL,50 mmol) was added to the reaction system. The mixture was stirred at room temperature overnight. The mixture was adjusted to ph=8, extracted with DCM, washed with NaCl (aq.), dried over Na ₂SO₄, 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%).

Step e to a solution of the product of step d (2.83 g,10 mmol) in DMF (50 mL) was added Pd (dppf) Cl ₂(408.3mg,0.5mmol)、K₂CO₃ (6.91 mg,50 mmol) and pinacol borane (5.06 g,20 mmol). Nitrogen was exchanged 3 times and then stirred at 100 ℃ for 4 hours. Extraction with EA, washing with brine, drying over sodium sulfate, concentration and purification over a silica gel column afforded the desired product F3 (2.805 g, 85%) as a yellow oil.

Step F to a 100mL round bottom flask was added compound F1(1.9632g,4.8mmol)、Pd(PPh₃)₂Cl₂(280.7mg,0.4mmol)、K₂CO₃(1.66g,12mmol) and compound F3 (1.348 g,4.0 mmol) in dioxane/H ₂ O (36 mL/4mL, 0.1M). Nitrogen was exchanged 3 times and then stirred overnight at 100 ℃. Concentrated and purified by silica gel column to give the desired intermediate (1.34 g, 69%) as a yellow solid.

Step g to a solution of the product from the previous step (0.32 g, 0.618 mmol) in NMP (3 mL, 0.2M) was added compound F2 (0.323 g,1.32 mmol) and Cs ₂CO₃ (0.643 g,1.974 mmol). The reaction was stirred at 120 ℃ for 4 hours. Extracted with EA, washed with saturated NaCl solution and dried over Na ₂SO₄. Purification on a silica gel column gave the desired product (288.8 mg, 62%) as a brown solid.

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

¹H 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,2H),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)

HRMS (ES+) calculated C ₃₂H₃₀ClN₇O₂[M+H]⁺: 580.2222, measured value 580.2232

Preparation example 2

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)

Step i to a solution of compound F1 (0.82 g,2 mmol) in NMP (4 mL, 0.2M) was added compound F2 (0.51 g,2 mmol) and Cs ₂CO₃ (1.629 g,5 mmol). The reaction was stirred at 120 ℃ for 4 hours. Extracted with EA, washed with saturated NaCl solution and dried over Na ₂SO₄. Purification by silica gel column gave the desired product (509.8 mg, 40%) as a white solid.

The title compound YH-I-002 was then obtained according to steps f and h in preparation example 1.

¹H 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)

HRMS (ES+) calculated C ₂₅H₁₆ClN₅O₂[M+H]⁺: 454.1065, measured 454.1073.

Preparation example 3

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)

Step j to a mixture of 3, 5-dimethylpyrrolpinacol (1.11 g,5.0 mmol) in THF (15 mL) was added NaH (0.30 g, 7.5mmol, 60%) and the mixture stirred at 0deg.C for 30 min. To the reaction mixture was added SEMCl (2.49 g,2.66ml,6.0 mmol), which was warmed to room temperature and stirred for 2 hours, quenched by saturated NH ₄ Cl solution. Extraction with EtOAc (15 ml×2), drying over Na ₂SO₄, filtration and concentration under reduced pressure gave 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%).

The title compound YH-I-010 was then obtained according to steps f, g and h in preparation example 1.

¹H 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＝8.6Hz,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)

HRMS (ES+) C ₂₄H₁₈ClN₇O₂[M+H]⁺ calculated 472.1283, measured 472.1287

Preparation example 4

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)

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,15mmol, 60%) and the mixture stirred at 0deg.C for 30 min. To the reaction mixture was added 4-sulfonate-Boc piperidine (3.35 g,12mmol,5.32 mL), which was warmed to room temperature and stirred for 2 hours, quenched by saturated NH4Cl solution. Extraction with EtOAc (20 ml×3), drying over Na ₂SO₄, filtration and concentration under reduced pressure gave 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%).

Step l to a solution of the product of 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). Nitrogen was exchanged 3 times and then stirred at 100 ℃ for 4 hours. Extraction with EA, washing with brine, drying over anhydrous sodium sulfate, concentration and purification over a silica gel column afforded the desired intermediate (0.108 g, 53%) as a tan oil.

The title compound YH-I-011 was then obtained according to steps f, g and h in preparation example 1.

¹H 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,1H),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)

HRMS (ES+) C ₂₉H₂₇ClN₈O₂[M+H]⁺ calculated 555.2018, measured 555.2020

Preparation example 5

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

The title compound YH-I-003 was prepared in analogy to example 1 using steps F, g and h by substituting 4-toluenepinacolborane for F3.

¹H 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)

HRMS (ES+) calculated C ₂₆H₁₈ClN₅O₂[M+H]⁺: 468.1222, measured value 468.1228

Preparation example 6

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)

Using a method similar to example 1, substituting 4-methoxybenzene pinacol borane for F3, the title compound YH-I-004 was prepared by steps F, g and h.

¹H 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)

HRMS (ES+) calculated C ₂₆H₁₈ClN₅O₃[M+H]⁺: 484.1171, measured value 484.1172

Preparation example 7

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)

The title compound YH-I-005 was prepared in analogy to example 1 using steps F, g and h by substituting 4-bromophenylpinacol borane for F3.

¹H 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)

HRMS (ES+) calculated C ₂₅H₁₅BrClN₅O₂[M+H]⁺: 532.0170, measured value 532.0170

Preparation example 8

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)

The title compound YH-I-006 was prepared using a procedure analogous to example 1 substituting 2-thiopheneppinacolborane for F3, passing steps F, g and h.

¹H NMR(400MHz,DMSO-d6)δ8.21(d,J＝2.7Hz,1H),7.79-7.64(m,2H),7.61-7.47(m,3H),7.33(d,J＝9.2Hz,4H),7.24-7.07(m,2H),6.84(s,1H),6.57(s,1H)

HRMS (ES+) calculated C ₂₃H₁₄ClN₅O₂S[M+H]⁺: 460.0629, measured 460.0636.

Preparation example 9

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)

Using a method similar to example 1, substituting 3-pyridinium pinacoline borane for F3, the title compound YH-I-007 was prepared via steps F, g and h.

¹H 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＝8.8Hz,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)

HRMS (ES+) calculated C ₂₄H₁₅ClN₆O₂[M+H]⁺: 455.1018, measured value 455.1024

Preparation example 10

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)

The title compound YH-I-008 was obtained by a procedure analogous to example 1, using 4-pyridine pinacolborane instead of F3, through steps F, g and h.

¹H 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＝8.9Hz,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)

HRMS (ES+) calculated C ₂₄H₁₅ClN₆O₂[M+H]⁺: 455.1018, measured 455.1024.

Preparation example 11

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)

Using a method similar to example 1, substituting 5-pyrimidine pinacol borane for F3, steps F, g, and h were performed to give the title compound YH-I-009.

¹H 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)

HRMS (ES+) calculated C ₂₃H₁₄ClN₇O₂[M+H]⁺: 456.0970, measured value 456.0978

Preparation example 12

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)

The title compound YH-I-012 was prepared using a procedure analogous to example 1 substituting 4-cyanobenzenepinacol borane for F3, passing steps F, g and h.

¹H 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)

HRMS (ES+) calculated C ₂₆H₁₅ClN₆O₂[M+H]⁺: 479.1018, measured value 580.2232

Preparation example 13

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)

Using a method similar to example 1, substituting 4-trifluoromethylbenzene pinacol borane for F3, steps F, g, and h were performed to afford the title compound YH-I-013.

¹H 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＝9.0Hz,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)

HRMS (ES+) calculated C ₂₆H₁₅ClF₃N₅O₂[M+H]⁺: 522.0939, measured value 580.2232

Preparation example 14

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)

The title compound YH-I-014 was obtained by a procedure similar to that of example 1, substituting 2-isopropylphenyl pinacol borane for F3, passing steps F, g and h.

¹H 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)

HRMS (ES+) calculated C ₂₈H₂₂ClN₅O₂[M+H]⁺: 496.1535, measured value 580.2232

Preparation example 15

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)

The title compound YH-I-015 was prepared in analogy to example 1 using 4-N, N-dimethylaminobenzenepinacol borane instead of F3 and through steps F, g and h.

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)

HRMS (ES+) calculated C ₂₇H₂₁ClN₆O₂[M+H]⁺: 497.1487, measured value 580.2232

Preparation example 16

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)

Using a method similar to example 1, substituting 2-isopropoxyphenylpinacol borane for F3, steps F, g and h were performed to give the title compound YH-I-016.

¹H 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)

HRMS (ES+) calculated C ₂₈H₂₂ClN₅O₃[M+H]⁺: 512.1484, measured value 580.2232

Preparation example 17

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)

Using a method similar to example 1, substituting 2-methyl-4- (4-aminopiperidine) benzopinacol borane for F3, the title compound YH-I-017 was prepared by steps F, g and h.

¹H 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＝11.3Hz,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)

HRMS (ES+) calculated C ₃₁H₂₈ClN₇O₂[M+H]⁺: 566.2066, measured value 566.2068

Preparation example 18

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)

The title compound YH-I-023 was prepared in analogy to example 1 using 1-trifluoromethyl-3-trifluoromethyl-4-isothiocyanate instead of 1-chloro-4-isothiocyanate through steps b, c, g and h.

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)

HRMS (ES+) calculated C ₃₃H₂₇F₆N₇O₂[M+H]⁺: 668.2203, measured value 668.2216

Preparation example 19

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)

The title compound YH-I-024 was prepared in analogy to example 1 using 1-chloro-2-chloro-4-isothiocyanate instead of 1-chloro-4-isothiocyanate through steps b, c, g and h.

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)

HRMS (ES+) calculated C ₃₁H₂₇Cl₂N₇O₂[M+H]⁺: 600.1676, measured value 600.1683

Preparation example 20

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)

The title compound YH-I-025 was obtained by following steps b, c, g and h using a procedure analogous to example 1 substituting 1-trifluoromethyl-4-isothiocyanate for 1-chloro-4-isothiocyanate.

¹H NMR(400MHz,DMSO-d₆)δ12.16(s,1H),8.26(s,1H),7.87(d,J＝9.1Hz,2H),7.57(d,J＝8.6Hz,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(td,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)

HRMS (ES+) calculated C ₃₂H₂₈F₃N₇O₂[M+H]⁺: 600.2335, measured value 600.2339

Preparation example 21

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)

The title compound YH-I-026 was prepared in analogy to example 1 using 1-trifluoromethoxy-4-isothiocyanate instead of 1-chloro-4-isothiocyanate via steps b, c, g and h.

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)

HRMS (ES+) calculated C ₃₂H₂₈F₃N₇O₃[M+H]⁺: 616.2284, measured value 616.2285

Preparation example 22

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)

The title compound YH-I-027 was prepared in analogy to example 1 using 1-isopropyl-4-isothiocyanate instead of 1-chloro-4-isothiocyanate via steps b, c, g and h.

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)

HRMS (ES+) calculated C ₃₄H₃₅N₇O₂[M+H]⁺: 574.2930, measured value 574.2925

Preparation example 23

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)

Using a method similar to example 1, substituting cyclopentane isothiocyanate for 1-chloro-4-phenylisothiocyanate, the title compound YH-I-028 was prepared via steps b, c, g and h.

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＝3.2Hz,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)

HRMS (ES+) calculated C ₃₀H₃₃N₇O₂[M+H]⁺: 524.2774, measured value 524.2771

Preparation example 24

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)

Using a method similar to example 1, substituting cyclohexane isothiocyanate for 1-chloro-4-isothiocyanate, the title compound YH-I-029 was prepared via steps b, c, g and h.

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),2.04-1.95(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)

HRMS (ES+) calculated C ₃₁H₃₅N₇O₂[M+H]⁺: 538.2930, measured value 538.2933

Preparation example 25

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)

Using a method similar to example 1, substituting hexane isothiocyanate for 1-chloro-4-benzene isothiocyanate, the title compound YH-I-030 was prepared by steps b, c, g and h.

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).

HRMS (ES+) calculated C ₃₁H₃₇N₇O₂[M+H]⁺: 540.3087, measured value 540.3085

Preparation example 26

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)

The title compound YH-I-031 was prepared in analogy to example 1, using F1 and F2 as starting materials and through steps g and h.

¹H 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)

HRMS (ES+) calculated C ₁₉H₁₁ClIN₅O₂[M+H]⁺: 503.9724, measured value 503.9725

Preparation example 27

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)

The title compound YH-I-040 was prepared by following steps b, c, F, g and h in analogy to example 1 using the procedure described for the replacement of F3 with (2-methyl-4- (piperidin-4-amino) phenyl) pinacol borane and the replacement of 1-chloro-4-isothiocyanate with benzene isothiocyanate.

¹H 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,3H),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＝1.0Hz,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)

HRMS (ES+) calculated C ₃₁H₂₉N₇O₂[M+H]⁺: 532.2461, measured value 532.2462

Preparation example 28

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)

Using a method similar to example 1, substituting 1-trifluoromethyl-4-isothiocyanate for 1-chloro-4-isothiocyanate passes steps b, c, g and h to afford the title compound YH-I-047.

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)

HRMS (ES+) calculated C ₃₃H₃₀F₃N₇O₂[M+H]⁺: 614.2491, measured value 614.2493

Preparation example 29

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)

The title compound YH-I-048 was prepared in analogy to example 1 using the procedure described for the replacement of F3 with (3, 5-dimethyl-1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-pinacol borane and the replacement of 1-chloro-4-isothiocyanate with 1-trifluoromethyl-4-isothiocyanate by steps b, c, F, g and H.

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＝12.3,7.0,1.0Hz,2H),2.07-1.91(m,2H),1.69(dddd,J＝14.1,11.8,7.1,4.6Hz,2H)

HRMS (ES+) calculated C ₃₁H₂₉F₃N₈O₂[M+H]⁺: 603.2444, measured value 603.2444

Preparation example 30

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)

The title compound YH-I-049 was prepared in analogy to example 1 using procedures b, c, F, g and H substituting (3, 5-dimethyl-1- (1-piperidin-4-yl) -1H-pyrazol-4-pinacol borane for F3 and 1-trifluoromethyl-4-isothiocyanate for 1-chloro-4-isothiocyanate.

¹H 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＝7.0Hz,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)

HRMS (ES+) calculated C ₃₀H₂₇F₃N₈O₂[M+H]⁺: 589.2287, measured value 589.2286

Preparation example 31

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)

The title compound YH-I-050 was prepared by steps b, c, F, g and H using a procedure analogous to example 1 substituting 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole for F3 and 1-trifluoromethyl-4-isothiocyanate for 1-chloro-4-isothiocyanate.

¹H 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)

MS (ESI) calculated C ₂₄H₁₆F₃N₇O₂[M+H]⁺: 492.44, measured value 492.46

Preparation example 32

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)

Using a method similar to example 1, substituting (2-methyl-4- (pyrrolidin-3-ylamino) phenyl) boronic acid for F3 and substituting 1-trifluoromethyl-4-isothiocyanate for 1-chloro-4-isothiocyanate steps b, c, F, g and h, the title compound YH-I-051 was prepared.

¹H NMR(400MHz,DMSO-d₆)δ7.89(s,1H),7.55(dd,J＝20.0,8.6Hz,2H),7.49-7.42(m,2H),7.35-7.27(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)

MS (ESI) calculated C ₃₁H₂₆F₃N₇O₂[M+H]⁺: 586.60, measured value 586.31

Preparation example 33

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)

The title compound YH-I-052 was prepared in analogy to example 1 using procedures b, c, F, g and H substituting (1H-pyrazol-4-yl) boronic acid for F3 and 1-trifluoromethyl-4-phenylisothiocyanate for 1-chloro-4-phenylisothiocyanate.

¹H 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)

MS (ESI) calculated C ₂₃H₁₄F₃N₇O₂[M+H]⁺: 478.42, measured value 478.51

Preparation example 34

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)

The title compound YH-I-053 was prepared in analogy to example 1 using the procedure described for the replacement of F3 with 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole by steps F, g and H.

¹H 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)

MS (ESI) calculated C ₂₃H₁₆ClN₇O₂[M+H]⁺: 458.89, measured value 458.78

Preparation example 35

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)

Using a method similar to example 1, substituting (4- (4-methylpiperazin-1-yl) methyl) phenyl) boronic acid for F3 and substituting 1-trifluoromethyl-4-isothiocyanatobenzene for 1-chloro-4-isothiocyanatobenzene via steps b, c, F, g and h, the title compound YH-I-079 was prepared.

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).

MS (ESI) calculated C ₃₂H₂₈F₃N₇O₂[M+H]⁺: 600.63, measured value 600.80

Preparation example 36

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)

Using a method similar to example 1, substituting (4- (4-methylpiperazine-1-carbonyl) phenyl) boronic acid for F3 and substituting 1-trifluoromethyl-4-isothiocyanate for 1-chloro-4-isothiocyanate steps b, c, F, g and h, the title compound YH-I-080 was prepared.

¹H 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)

MS (ESI) calculated C ₃₂H₂₆F₃N₇O₃[M+H]⁺: 614.61, measured value 614.70

Preparation example 37

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)

The title compound YH-I-081 was obtained in analogy to example 1 using the procedure described for the replacement of F3 with 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) piperidine through steps F, g and H.

¹H 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)

MS (ESI) calculated C ₂₇H₂₃ClN₈O₂[M+H]⁺: 527.99, measured value 528.06

Preparation example 38

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)

Using a method similar to example 3, substituting 1-trifluoromethyl-4-isothiocyanate for 1-chloro-4-isothiocyanate passes steps j, f, g and h to afford the title compound YH-I-090.

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)

MS (ESI) calculated C ₂₅H₁₈F₃N₇O₂[M+H]⁺: 506.47, measured value 506.51

Preparation example 39

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)

The title compound YH-I-091 was prepared in analogy to example 1 using the procedure described for the replacement of F3 with 1, 3-dimethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole by steps F, g and H.

¹H 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)

MS (ESI) calculated C ₂₄H₁₈ClN₇O₂[M+H]⁺: 472.91, measured value 472.99

Preparation example 40

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)

The title compound YH-I-092 was prepared in analogy to example 1 using the procedure described above substituting 2- (3, 5-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) ethan-1-ol for F3.

¹H 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)

MS (ESI) calculated C ₂₆H₂₂ClN₇O₃[M+H]⁺: 516.97, measured value 517.21

Preparation example 41

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)

The title compound YH-I-093 was prepared in analogy to example 1 using the procedure described above substituting 1- (3, 5-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol for F3 through steps F, g and H.

¹H 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)

MS (ESI) calculated C ₂₈H₂₆ClN₇O₃[M+H]⁺: 545.02, measured value 545.11

Preparation example 42

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)

The title compound YH-I-094 was prepared in analogy to example 1 using the procedure described above for the replacement of F3 with 1- (3, 5-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) propan-2-ol by steps F, g and H.

¹H 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)

MS (ESI) calculated C ₂₇H₂₄ClN₇O₃[M+H]⁺: 530.99, measured value 530.90

Biological examples

Biological example 1

ALK aprotinin Activity

1 Volume of the protein culture was 4-fold diluted and 50. Mu.M dithiothreitol was added as a culture solution for use. Test compounds were added at different concentrations (10 μm as initial concentration, 3-fold dilution, 10 concentrations, multiplex) to 384 well plates. The 384 well plates to be tested were sealed, and the plates were centrifuged at 1000g for 1 min. After 2 times ALK protein (test protein) and 1 time protein culture solution were mixed uniformly, 2.5. Mu.L of the protein mixture was added to each well plate, 1000g of the well plate was centrifuged for 30s at room temperature for 10min. Simultaneously, 2 times of substrate and ATP are mixed with 1 time of protein culture solution and shaken well. 2.5. Mu.L of substrate and ATP mixture was added to the well plate, 1000g of the well plate was centrifuged for 30s, the well plate was sealed, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, 5. Mu.L of ADP-Glo reagent was added to each well, and the reaction was carried out at room temperature for 40 minutes. Then, 10. Mu.L of a protein detection reagent was added thereto, and the reaction was carried out at room temperature for 40 minutes. Finally, the fluorescence values were obtained using Envision2104 and the corresponding protein inhibition was calculated.

TABLE 1 Compounds of the present disclosure IC ₅₀ (unit: nM) for wild-type ALK aprotinin activity

TABLE 2 aprotinin Activity of the compounds of the present disclosure against mutant ALK IC ₅₀ (Unit: nM)

Biological example 2

Tumor cell growth inhibitory Activity

Cytotoxicity experiments (exemplified by cytotoxicity against Kelly) Kelly cells were grown in a medium (10% fetal bovine serum) recommended by the supplier. Cells were added to a 96-well plate at 1X 10 ³/well and incubated overnight at 37℃in 5% CO ₂. Then, adding culture solution containing different concentrations of the compound to be tested (10 mu M as initial concentration, 3 times dilution, 10 concentrations, multiple wells) into each well, culturing for 72 hours, and dyeing by trypan blue to obtain living cells with more than 95%. Before the end of the incubation for 4h, 20. Mu.L of MTT solution (5 mg/mL) was added to each well and incubation was continued for 4h. The culture broth was discarded, 150. Mu.L of dimethyl sulfoxide was added thereto, and the mixture was shaken for 15 minutes. The absorbance (A value) was measured by a microplate reader at 570nm, and the proliferation inhibition rate was calculated. Wherein the incubation time of the compounds of Kelly and SH-SY5Y, TGW, NCIH2228 cells is 72 hours, and the incubation time of the compounds of SUDHL-1, SK-N-SH and KP-N-RT-BM-1 cells is 120 hours.

TABLE 3.1 tumor cell growth inhibition of compounds of the present disclosure

TABLE 4 half inhibition concentration of anti-tumor cell growth IC ₅₀ (nM) of the compounds of the present disclosure

Biological example 3

Pharmacokinetic property testing

The compounds of the present disclosure are subjected to pharmacokinetic testing by dissolving the test compound, and configuring the test compound to a stock solution of the desired concentration for use. Male healthy mice were then grouped, 3 per group. Mice were fasted overnight, were given free water, and were fed after 4 hours. The dosing amounts are shown in the table below. Whole blood samples were collected via orbital veins at designated time points (0.083 h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24 h) and upper plasma samples were taken after centrifugation at 4000rcf/4 ℃ for 5 minutes at 30 μl of samples flowing into heparin sodium anticoagulation tubes. And finally, carrying out data acquisition on the sample by utilizing LC-MS/MS, and obtaining the pharmacokinetic parameters of the compound to be detected after data processing.

Blood concentration-time data for compound YH-I-001 of the present disclosure are given in tables 5 and 6.

Table 5.Note that na= Not Applicable

Table 6.Note that na= Not ApplicableNR = Not Reportable

Fig. 2 and 3 show blood concentration versus time curves for compound YH-I-001 of the present disclosure.

Biological example 4

In vivo antitumor test

The prepared compound YH-I-001, the purchased inhibitor Crizotinib, ceritinib and Topotecan (Topotecan) were subjected to in vivo antitumor activity analysis, and a solvent was provided as a control group test. KELLY (brain, neuroblastoma, purchased from ECACC, cat No.:92110411,Lot No.14A023) cells were grown in vitro as monolayers under conditions of RPMI-1640 medium plus 2mM Glut amine, 10% heat-inactivated fetal bovine serum, 37℃without CO ₂. The passages were digested twice a week with pancreatin-EDTA. When the cells are in exponential growth phase, the cells are harvested, counted and inoculated. 0.2mL of a cell suspension containing 5X 10 ⁵ KELLY cells (cells suspended in 1640:Martigel=1:1) was inoculated subcutaneously on the right back of each mouse. On day 22 post inoculation, group dosing was started when the average tumor volume reached 150.50mm ³.

The experimental index is to examine whether tumor growth can be inhibited, retarded or cured. Tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is that V=0.5×a×b ², and a and b respectively represent the long diameter and the short diameter of the tumor. The antitumor effect of the compound was evaluated by T/C (%). T/C% = TRTV/CRTV X100% (TRTV: treatment group RTV; CRTV: negative control group RTV). The calculation formula for the relative tumor volume RTV is rtv=v _t/V₁. Where V ₁ is the tumor volume measured at the time of divided administration (i.e., day 1), and Vt is the tumor volume measured on Day t. Tumor volume therapy efficacy TGI evaluation, TGI (%) = (1- (TV _treatment-Dn-TV_treatment-D1)/(TV_Control-Dn-TV_Control-D1))×100％,TV_Control: control tumor volume, TV _Treatment: treatment tumor volume) efficacy of tumor weight was evaluated with TGI% (TGI)% = (TW _C-TW_T)/TW_C×100％,TW_C: control tumor weight, TW _T: treatment tumor weight).

TABLE 7 preparation method of the drugs

Comparison of tumor inhibition (TGI) in KELLY tumor-bearing mice

In this disclosure, relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions.

From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without deviating from the spirit and scope of the disclosure. Such variations or modifications are intended to fall within the scope of the claims appended hereto.

Claims

A method of treating or preventing a tumor comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I):

Wherein:

R ₁ is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;

R ₂ is selected from optionally substituted hydrocarbyl, optionally substituted aryl or optionally substituted cyclic hydrocarbyl, and

X and Y are each independently selected from O, S or N.
The method of claim 1, wherein R ₁ 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, sulfonamide-substituted aryl, unsubstituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted amino-substituted heteroaryl, or heterocycloalkyl-substituted heteroaryl.
The method of claim 1 or 2, wherein R ₁ 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, sulfonamide-substituted phenyl, unsubstituted pyridyl, unsubstituted thienyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, optionally substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocycloalkyl-substituted amino-substituted pyrazolyl, or heterocycloalkyl-substituted pyrazolyl.
A method according to any one of claims 1 to 3 wherein R ₁ is selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-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 aryl, sulfonamide-substituted phenyl, unsubstituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted amino-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocycloalkyl-substituted amino-substituted heteroaryl, or heterocycloalkyl-substituted heteroaryl.
The method according to claim 1 to 4, wherein R ₁ is selected from the group consisting of iodo, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4- (4-methylpiperazin-1-yl) methylphenyl, 4- (4-methylpiperazin-1-yl) oxymethylphenyl, methoxyphenyl, isopropoxyphenyl, 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-methyltetrazolyl) -amino-substituted phenyl, bromophenyl, and 2-methyl-4-sulfonylamino-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.
The method of any one of claims 1 to 5, wherein R ₁ is selected from:
The method of any one of claims 1 to 6, wherein R ₂ is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted arylheterocycloalkylene.
The method of any one of claims 1 to 7, wherein R ₂ is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted benzoheterocycloalkyl.
The method of any one of claims 1 to 8, wherein R ₂ is selected from unsubstituted alkyl, halo-substituted aryl, optionally substituted alkyl-substituted aryl, optionally substituted alkoxy-substituted aryl, unsubstituted cycloalkyl, unsubstituted benzoheterocycloalkyl, or halo-substituted benzoheterocycloalkyl.
The method of any one of claims 1 to 9, wherein R ₂ is selected from unsubstituted alkyl, halo-substituted phenyl, optionally-substituted alkyl-substituted phenyl, optionally-substituted alkoxy-substituted phenyl, optionally-substituted pyridinyl, optionally-substituted pyrrolyl, optionally-substituted pyrazolyl, optionally-substituted thiazolyl, optionally-substituted oxazolyl, optionally-substituted thienyl, unsubstituted cycloalkyl, unsubstituted benzo [1,3] dioxolyl, or halo-substituted benzo [1,3] dioxolyl.
The method of any one of claims 1 to 10, wherein R ₂ is selected from hexyl, 3, 4-dichlorophenyl, 4-chlorophenyl, 4-isopropyl phenyl, 3, 5-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, cyclopentyl, or cyclohexenyl.
The method of any one of claims 1 to 11, wherein R ₂ is selected from:
The method of 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.
The method according to any one of claims 1 to 13, wherein the compound of 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-tolyl) -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-pyrrolo [2,3-d ] 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 ] oxazol-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.
The method of any one of claims 1 to 14, further comprising administering to the individual an additional active agent.
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 individual simultaneously, sequentially, overlapping, concomitantly, intermittently, consecutively, simultaneously, or any combination thereof.
The method of claim 15 or 16, wherein the other active agent is a topoisomerase inhibitor, preferably a topoisomerase I inhibitor.
The method of claim 17, wherein the topoisomerase inhibitor is selected from topotecan, irinotecan, belotecan, aclarubicin, doxorubicin, epirubicin, idamycin, etoposide, and mitoxantrone.
The method of any one of claims 1 to 18, wherein the tumor is mediated by Tyrosine Kinase (TK).
The method of any one of claims 1 to 19, wherein the subject is a mammal, preferably a human.
The method of claim 19 or 20, wherein the Tyrosine Kinase (TK) is selected from Anaplastic Lymphoma Kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS 1), epidermal Growth Factor Receptor (EGFR), platelet growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast Growth Factor Receptor (FGFR), interleukin receptor-related kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma virus oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular Endothelial Growth Factor (VEGFR), transfected rearrangement kinase (RET), bruton's Tyrosine Kinase (BTK), B-lymphotyrosine kinase (BLK), cytoplasmic tyrosine protein kinase (BMX), human epidermal growth factor receptor 2 (HER 2), human epidermal growth factor receptor 4 (HER 4), isocitrate Dehydrogenase (IDH), disc domain receptor 1 (DDR 1), interleukin 2-induced T cell kinase (ITK), and human protein tyrosine kinase 4 (TXK).
The method of any one of claims 1 to 21, wherein the tumor is selected from lymphoma, blastoma, sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, auditory neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancy, lung cancer, lung squamous carcinoma, peritoneal carcinoma, 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, renal cancer, prostate cancer, vulval cancer, thyroid cancer, anal cancer, penile cancer, merkel cell carcinoma, esophageal cancer, biliary tract tumor, head and neck cancer, and hematological malignancy.