WO2024088377A1 - 嘧啶并吡咯类似物 - Google Patents

嘧啶并吡咯类似物 Download PDF

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Publication number
WO2024088377A1
WO2024088377A1 PCT/CN2023/127058 CN2023127058W WO2024088377A1 WO 2024088377 A1 WO2024088377 A1 WO 2024088377A1 CN 2023127058 W CN2023127058 W CN 2023127058W WO 2024088377 A1 WO2024088377 A1 WO 2024088377A1
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Prior art keywords
phenyl
pyrimidin
benzo
oxy
substituted
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PCT/CN2023/127058
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English (en)
French (fr)
Inventor
黄湧
蒋晨然
陈梦婷
陈学明
陈杰安
刘运
安源
吴冠林
赵娟
武丰瑾
Original Assignee
香港科技大学
深圳湾实验室坪山生物医药研发转化中心
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Publication of WO2024088377A1 publication Critical patent/WO2024088377A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates generally to the field of medicinal chemistry and, more particularly, to pyrimidopyrrole analogs.
  • Drugs for treating cancer mainly include cytotoxic drugs and molecular targeted drugs.
  • Cytotoxic drugs that is, traditional chemotherapy drugs, mainly inhibit tumor growth by killing rapidly dividing tumor cells.
  • cytotoxic drugs can also harm cells that divide rapidly under normal circumstances, such as bone marrow, gastrointestinal tract and hair follicle cells, leading to common side effects in chemotherapy: bone marrow suppression, 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 changes that are not present in normal tissue cells, thereby achieving specific cell selectivity.
  • targeted drugs often have defects such as drug resistance and target molecule-related toxic side effects, resulting in many drug candidates failing in clinical trials despite showing good effects in animal models.
  • the combined use of targeted inhibitors and cytotoxic drugs can improve drug efficacy through two different mechanisms of action, thereby achieving a better efficacy/toxicity window by reducing the dosage.
  • Anaplastic lymphoma kinase is a transmembrane protein tyrosine kinase that belongs to the insulin receptor kinase subfamily. It was first discovered in anaplastic large cell lymphoma (ALCL) with a nucleophosmin (NPM)-ALK fusion form, a T-cell non-Hodgkin lymphoma that is often associated with a chromosomal translocation. Since then, many cancers have been found to be associated with different forms of ALK fusion.
  • NSCLC non Small cell lung cancer
  • EML4-ALK inflammatory myofibroblastic tumor
  • IMT inflammatory myofibroblastic tumor
  • DLBCL diffuse large B-cell lymphoma
  • CLTC-ALK diffuse large B-cell lymphoma
  • ALK anaplastic lymphoma kinase
  • the present disclosure relates to compounds represented by general formula (I), and pharmaceutically acceptable salts thereof:
  • R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;
  • R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group;
  • X and Y are each independently selected from O, S or N.
  • the present disclosure relates to compounds, and pharmaceutically acceptable salts thereof, wherein the compound is selected from:
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure relates to a method for preparing a compound represented by general formula (Ia),
  • X1 and Y1 are each independently selected from amino, thiol or hydroxyl;
  • X and Y are each independently selected from O, S or N;
  • R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group.
  • the present disclosure relates to a method for preparing a compound represented by general formula (Ib),
  • R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;
  • B is selected from boric acid or boric acid esters.
  • the present disclosure relates to a method for preparing a compound represented by general formula (Id),
  • the present disclosure relates to a method for inhibiting tyrosine kinase (TK), which comprises contacting tyrosine kinase with an inhibitory effective amount of a compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • TK tyrosine kinase
  • the present disclosure relates to treating or preventing tyrosine kinase (TK)-mediated
  • TK tyrosine kinase
  • a method for treating a disease or disease state caused by a disease or disease state comprising administering to an individual in need of the method a therapeutically or preventively effective amount of a compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure relates to compounds represented by the general formula (I) of the present disclosure and their pharmaceutically acceptable salts or compounds of the present disclosure and their pharmaceutically acceptable salts for inhibiting tyrosine kinase (TK).
  • TK tyrosine kinase
  • the present disclosure relates to compounds of the general formula (I) of the present disclosure and their pharmaceutically acceptable salts or compounds of the present disclosure and their pharmaceutically acceptable salts for treating or preventing diseases or disease states mediated by tyrosine kinase (TK).
  • TK tyrosine kinase
  • the present disclosure relates to the compounds represented by the general formula (I) of the present disclosure and their pharmaceutically acceptable salts, or the compounds of the present disclosure and their pharmaceutically acceptable salts in the preparation of drugs for inhibiting tyrosine kinase (TK).
  • TK tyrosine kinase
  • the present disclosure relates to the compounds represented by the general formula (I) of the present disclosure and their pharmaceutically acceptable salts, or the compounds of the present disclosure and their pharmaceutically acceptable salts in the preparation of drugs for treating or preventing diseases or disease states mediated by tyrosine kinase (TK).
  • TK tyrosine kinase
  • FIG1 shows the interaction pattern between the compound YH-I-001 of the present disclosure and ALK
  • FIG2 shows the blood concentration-time curve of the compound YH-I-001 of the present disclosure in ICR mice after intravenous administration at a dose of 1 mg ⁇ kg -1 ;
  • FIG3 shows the blood concentration-time curve of the compound YH-I-001 of the present disclosure in ICR mice after intravenous administration at a dose of 5 mg ⁇ kg -1 ;
  • FIG4 shows a graph showing the changes in tumor volume of KELLY tumor-bearing mice.
  • FIG. 5 shows the body weight changes of KELLY tumor-bearing mice.
  • the pharmaceutical composition mentioned containing "a compound or a pharmaceutically acceptable salt thereof represented by the general formula (I)” includes one compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, or two or more compounds represented by the general formula (I) or pharmaceutically acceptable salts thereof.
  • C1 - C4 alkyl describes an alkyl group as defined below having a total of 1 to 4 carbon atoms
  • C3 - C10 cycloalkyl describes a cycloalkyl group as defined below having a total of 3 to 10 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may be present in substituents of the group being described.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to an -OH group.
  • amino refers to a -NH2 group.
  • cyano refers to a -CN group.
  • hydrocarbyl refers to an aliphatic hydrocarbon group.
  • the hydrocarbyl portion may be a "saturated hydrocarbyl” group, meaning that it does not contain any alkene or alkyne moieties.
  • the hydrocarbyl portion may also be an "unsaturated hydrocarbyl” moiety, meaning that it contains at least one alkene or alkyne moiety.
  • An “alkene” moiety refers to a group consisting of two to eight carbon atoms and at least one carbon-carbon double bond and is bound to the rest of the molecule by single bonds.
  • alkyne refers to a straight or branched hydrocarbon chain group connected to a moiety, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc.
  • alkyne refers to a group consisting of two to eight carbon atoms and at least one carbon-carbon triple bond, and connected to the rest of the molecule by a single bond.
  • the hydrocarbon moiety whether saturated or unsaturated, can be branched or straight chain.
  • the hydrocarbyl group can have 1 to 8 carbon atoms (each time it appears in this disclosure, a numerical range such as “1 to 8” refers to each integer in the given range; e.g., "1 to 8” means that the hydrocarbyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 8 carbon atoms, although this definition also covers the occurrence of the term "hydrocarbyl" without specifying a numerical range).
  • the hydrocarbyl group may be optionally substituted, i.e., substituted or unsubstituted.
  • the substituent groups are individually and independently selected from one or more of the following groups: cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbyl, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and
  • Typical hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
  • substituents may be substituted by one of the substituents described above.
  • C 1 -C 4 hydrocarbyl refers to a hydrocarbyl group as defined above containing from one to four carbon atoms.
  • the C 1 -C 4 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • C 1 -C 4 hydrocarbyl may be a C 1 -C 4 alkyl group.
  • the C 1 -C 4 alkyl group may be optionally substituted as defined for a hydrocarbyl group.
  • C 1 -C 6 hydrocarbyl refers to a hydrocarbyl group as defined above containing from one to six carbon atoms.
  • the C 1 -C 6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 1 -C 6 hydrocarbon group” may be a C 1 -C 6 alkyl group .
  • the groups may be optionally substituted as defined for hydrocarbyl groups.
  • C 1 -C 12 hydrocarbyl refers to a hydrocarbyl group as defined above containing from one to twelve carbon atoms.
  • the C 1 -C 12 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 1 -C 12 hydrocarbyl” may be a C 1 -C 12 alkyl group.
  • the C 1 -C 12 alkyl group may be optionally substituted as defined for a hydrocarbyl group.
  • C 2 -C 6 hydrocarbyl refers to a hydrocarbyl group as defined above containing two to six carbon atoms.
  • the C 2 -C 6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 2 -C 6 hydrocarbyl” may be a C 2 -C 6 alkyl group.
  • the C 2 -C 6 alkyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 2 -C 6 alkyl” may be a C 2 -C 6 alkenyl group.
  • the C 2 -C 6 alkenyl group may be optionally substituted as defined for an alkyl group.
  • a "C 2 -C 6 alkyl” may be a C 2 -C 6 alkynyl group.
  • a C 2 -C 6 alkynyl group may be optionally substituted as defined for an alkyl group.
  • C 3 -C 6 hydrocarbyl refers to a hydrocarbyl group as defined above containing three to six carbon atoms.
  • the C 3 -C 6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 3 -C 6 hydrocarbyl” may be a C 3 -C 6 alkyl group.
  • the C 3 -C 6 alkyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 3 -C 6 alkyl” may be a C 3 -C 6 alkenyl group.
  • the C 3 -C 6 alkenyl group may be optionally substituted as defined for an alkyl group.
  • a "C 3 -C 6 alkyl” may be a C 3 -C 6 alkynyl group.
  • a C 3 -C 6 alkynyl group may be optionally substituted as defined for an alkyl group.
  • C 3 -C 12 hydrocarbyl refers to a hydrocarbyl group as defined above containing three to twelve carbon atoms.
  • the C 3 -C 12 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 3 -C 12 hydrocarbyl” may be a C 3 -C 12 alkyl group.
  • the C 3 -C 12 alkyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 3 -C 12 alkyl” may be a C 3 -C 12 alkenyl group.
  • the C 3 -C 12 alkenyl group may be optionally substituted as defined for an alkyl group.
  • a "C 3 -C 12 alkyl” may be a C 3 -C 12 alkynyl group.
  • the C 3 -C 12 alkynyl group may be optionally substituted as defined for an alkyl group.
  • C 6 -C 12 hydrocarbyl refers to a hydrocarbyl group as defined above containing six to twelve carbon atoms.
  • the C 6 -C 12 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 6 -C 12 hydrocarbyl” may be a C 6 -C 12 alkyl group.
  • the C 6 -C 12 alkyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 6 -C 12 alkyl” may be a C 6 -C 12 alkenyl group.
  • the C 6 -C 12 alkenyl group may be optionally substituted as defined for an alkyl group.
  • a "C 6 -C 12 alkyl” may be a C 6 -C 12 alkynyl group.
  • the C 6 -C 12 alkynyl group may be optionally substituted as defined for an alkyl group.
  • C7 - C12 hydrocarbyl refers to a hydrocarbyl group as defined above containing seven to twelve carbon atoms.
  • the C7 - C12 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 7 -C 12 hydrocarbyl” may be a C 7 -C 12 alkyl group.
  • the C 7 -C 12 alkyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 7 -C 12 hydrocarbyl” may be a C 7 -C 12 alkenyl group.
  • the C 7 -C 12 alkenyl group may be optionally substituted as defined for a hydrocarbyl group.
  • a "C 7 -C 12 alkyl” may be a C 7 -C 12 alkynyl group.
  • the C 7 -C 12 alkynyl group may be optionally substituted as defined for an alkyl group.
  • alkyloxy refers to the general formula -O-alkyl, wherein alkyl is as defined in the present disclosure.
  • alkyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and tert-pentoxy.
  • aryl refers to a carbocyclic ring (all carbon) or two or more fused rings (rings that share two adjacent carbon atoms) with a completely delocalized pi electron system.
  • Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Aryl groups, for example, may have five to twelve carbon atoms. The aryl groups of the present disclosure may be substituted or unsubstituted.
  • the hydrogen atoms are replaced by one or more groups independently selected from the following substituents: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, 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 hydrocarbon groups as defined in the following substituent
  • heteroaryl refers to a 5- to 18-membered aromatic ring group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen and sulfur.
  • 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 be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heteroaryl groups include, but are not limited to, azepine, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzo
  • the heteroaryl groups of the present disclosure may be substituted or
  • the hydrogen atoms are substituted by one or more groups independently selected from the group consisting of hydrocarbon, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbonoxy, aryloxy, mercapto, hydrocarbonthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, Silyl, trihalomethanesulfonyl, -NR'R" (wherein R' and R" are hydrocarbon groups as defined in the group consisting
  • cycloalkyl refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having three to fifteen carbon atoms, in certain embodiments having three to twelve carbon atoms, and which is saturated or unsaturated and connected to the rest of the molecule by a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, and the like.
  • cycloalkyl is intended to include cycloalkyl as defined above optionally substituted by one or more substituents selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinylamino, N-sulfinylamino, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group as defined above having three to six carbon atoms.
  • the C 3 -C 6 cycloalkyl group may be optionally substituted as defined for the cycloalkyl group above.
  • C 3 -C 10 cycloalkyl refers to a cycloalkyl group as defined above having three to ten carbon atoms.
  • the C 3 -C 10 cycloalkyl group may be optionally substituted as defined for the cycloalkyl group above.
  • C 3 -C 12 cycloalkyl refers to a cycloalkyl group as defined above having three to twelve carbon atoms.
  • the C 3 -C 12 cycloalkyl group may be optionally substituted as defined for the cycloalkyl group above.
  • heterocycloalkyl refers to a stable three- to twelve-membered non-aromatic ring radical consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclyl radicals include, but are not limited to, dioxolane, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, Piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl
  • the term "compound of the present disclosure or a pharmaceutically acceptable salt thereof” refers to the compound represented by the general formula (I) of the present disclosure and a pharmaceutically acceptable salt thereof, as well as any specific compound falling within the general formula (I) and a pharmaceutically acceptable salt thereof.
  • mammal refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.
  • the term "patient” refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep).
  • the patient is a mammal, including males and females.
  • the patient is a human.
  • the term "pharmaceutically acceptable” refers to the carrier, vehicle, diluent, excipient and/or salt which must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the terms “optional” or “arbitrarily” mean that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur.
  • the term "pharmaceutically acceptable excipients” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.
  • carrier is defined as a compound that facilitates the introduction of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • pharmaceutically acceptable salt includes “acceptable acid addition salts” and “acceptable base addition salts”.
  • the term "acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are biologically or otherwise suitable and are formed using inorganic or organic acids, such as but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as but not limited to acetic acid, 2,2-dichloroethane, Acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethane
  • organic acids
  • the term "acceptable base addition salts” refers to those salts which retain the biological effectiveness and properties of the free acids, which are biologically or otherwise suitable. These salts are prepared by adding inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
  • the organic base is isooprop
  • the term "pharmaceutical composition” refers to a preparation of the compounds described in the present disclosure and a medium generally accepted in the art for delivering the bioactive compound to mammals such as humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients.
  • the term "therapeutically effective amount” refers to an amount of a compound or combination of compounds that improves, attenuates or eliminates a specific disease or condition and symptoms of a specific disease or condition, or avoids or delays the onset of a specific disease or condition or symptoms of a specific disease or condition.
  • the amount of the compounds described in the present disclosure that constitutes a “therapeutically effective amount” will vary depending on the disease state and its severity, as well as the age, weight, etc. of the mammal to be treated, but the amount of the compounds described in the present disclosure can be routinely determined by a person skilled in the art based on his or her own knowledge and the present disclosure.
  • treating encompasses treating a relevant disease or condition in a mammal, such as a human, that suffers from the relevant disease or condition, and includes:
  • preventing refers to preventing the onset, recurrence, or spread of a disease or disease state, or one or more symptoms thereof.
  • the term "prophylactically effective amount” refers to an amount of a compound or combination of compounds sufficient to prevent a disease or disease state, or to prevent its recurrence or spread. Depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, the amount of the compound described in the present disclosure that constitutes a “prophylactically effective amount” will vary, but those skilled in the art can determine the amount of the compound described in the present disclosure according to routine based on their own knowledge and the present disclosure.
  • disease and “disease state” may be used interchangeably, or may be distinct in that a particular disease or disease state may have no known causative agent (and therefore cannot be explained etiologically) and therefore is not recognized as a disease, but rather is considered an undesirable disease state or condition in which clinicians have identified a more or less specific set of symptoms.
  • the present disclosure relates to compounds represented by general formula (I), and pharmaceutically acceptable salts thereof:
  • R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;
  • R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group;
  • X and Y are each independently selected from O, S or N.
  • R is selected from halogen, unsubstituted aryl, optionally substituted alkyl substituted aryl, alkoxy substituted aryl, halogen substituted aryl, cyano substituted aryl, optionally substituted amino substituted aryl, sulfonamido substituted aryl, unsubstituted heteroaryl, optionally substituted alkyl substituted heteroaryl, alkoxy substituted heteroaryl, cyano substituted heteroaryl, optionally substituted amino substituted heteroaryl or heterocycloalkyl substituted heteroaryl.
  • R is selected from halogen, unsubstituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted heterocycloalkyl-substituted optionally substituted alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, optionally substituted amino-substituted phenyl, sulfonamido-substituted phenyl, unsubstituted pyridyl, unsubstituted thienyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, optionally substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-
  • R is selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-substituted alkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, alkyl-substituted heterocycloalkyl-substituted alkyl-substituted aryl, alkyl-substituted heterocycloalkyl-substituted oxoalkyl-substituted aryl, alkyl-substituted amino-substituted aryl, optionally substituted heterocycloalkyl-substituted amino-substituted aryl, sulfonamido-substituted phenyl, unsubstituted heteroaryl, optionally substituted alkyl-substituted
  • R 1 is selected from iodo, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4-(4-methylpiperazin-1-yl)methylphenyl, 4-(4-methylpiperazin-1-yl)oxymethylphenyl, methoxyphenyl, isopropoxyphenyl, bromophenyl, cyano-substituted phenyl, dimethylamino phenyl, 2-methyl-4-piperidinyl substituted amino substituted phenyl, 2-methyl-4-(N-methylpiperidinyl)-amino substituted phenyl, 2-methyl-4-tetrahydropyrrolyl substituted amino substituted phenyl, 2-methyl-4-(N-methyltetrahydropyrrolyl)-amino substituted phenyl, 2-methyl-4-sulfonamido substituted phenyl, pyridyl, thienyl, pyr
  • R is selected from:
  • R 2 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted aryl and heterocycloalkyl.
  • R 2 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted benzoheterocycloalkyl.
  • R 2 is selected from unsubstituted alkyl, halogen-substituted aryl, optionally substituted alkyl-substituted aryl, optionally substituted alkoxy-substituted aryl, unsubstituted cycloalkyl, unsubstituted benzoheterocycloalkyl, or halogen-substituted benzoheterocycloalkyl.
  • R2 is selected from unsubstituted alkyl, halogen-substituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkoxy-substituted phenyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted thienyl, unsubstituted cycloalkyl, unsubstituted benzo[1,3]dioxolanyl, or halogen-substituted benzo[1,3]dioxolanyl.
  • R2 is selected from hexyl, 3,4-dichlorophenyl, 4-chlorophenyl, 4-isopropylphenyl, 3,5-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, cyclopentyl or cyclohexyl.
  • R2 is selected from:
  • X is N and Y is O.
  • X is N and Y is S.
  • X is O and Y is N.
  • X is O and Y is S.
  • the present disclosure relates to compounds, and pharmaceutically acceptable salts thereof, wherein the compound is selected from:
  • the compounds of the present disclosure have potent inhibitory activity against ALK.
  • the compounds of the present disclosure are resistant to drug resistance of ALK mutants.
  • the compounds of the present disclosure have excellent stability.
  • the compounds of the present disclosure have excellent pharmaceutical efficacy.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound represented by the general formula (I) of the present invention or its pharmaceutically acceptable salt, or the compound of the present invention or its pharmaceutically acceptable salt for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states when administered to mammals can be administered by the gastrointestinal route or the parenteral route.
  • the compound represented by the general formula (I) of the present invention or its pharmaceutically acceptable salt, or the compound of the present invention or its pharmaceutically acceptable salt for tyrosine kinase (TK)-mediated diseases or disease states when administered to mammals can be an oral route.
  • the compound of the present invention represented by the general formula (I) or its pharmaceutically acceptable salt, or the compound of the present invention or its pharmaceutically acceptable salt for tyrosine kinase (TK)-mediated diseases or disease states when administered to mammals can be administered via the rectal route.
  • TK tyrosine kinase
  • the compounds described in the present disclosure can be obtained in any suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories, etc.
  • suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories, etc.
  • the 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, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.
  • the pharmaceutical composition of the present disclosure can be applied by any method to achieve its intended purpose.
  • application can be carried out by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal or oral routes.
  • the route of administration can be parenteral, oral and rectal routes.
  • the dosage applied will depend on the age, health status and weight of the recipient, and if there is concurrent treatment, also depends on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.
  • Suitable dosage forms include, but are not limited to, capsules, tablets, pills, dragees, semisolid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can 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, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, can also be oil-based solutions or aqueous solutions, in addition there are suspensions, emulsions or implants, suitable for local use are ointments, creams or powders.
  • the product in the present disclosure can also be lyophilized, and the generated lyophilized material is used for example to prepare injections.
  • the given preparation can be sterilized and/or contain an assistant, such as a wetting agent, a preservative, a stabilizer and/or a wetting agent, an emulsifier, a salt for changing the osmotic pressure, a buffer substance, a dye, a flavoring agent and/or numerous other active ingredients, such as one or more vitamins.
  • an assistant such as a wetting agent, a preservative, a stabilizer and/or a wetting agent, an emulsifier, a salt for changing the osmotic pressure, a buffer substance, a dye, a flavoring agent and/or numerous other active ingredients, such as one or more vitamins.
  • 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 Preservatives, stabilizers, dyes, sweeteners, aromatics, spices, etc. can be provided in the pharmaceutical composition.
  • sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives.
  • antioxidants and suspending agents can be used.
  • alcohols, esters, sulfated aliphatic alcohols, etc. can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, hydroxymethylcellulose calcium, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc.
  • lubricants can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspending agents or lubricants; cellulose acetate phthalate, which is a derivative of sugars such as cellulose or sugar, or methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, can be used as suspending agents; and plasticizers such as phthalates can be used as suspending agents.
  • Suitable routes of administration may include, for example, oral administration, rectal administration, transmembrane administration, parenteral delivery, topical administration or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection.
  • the compound can also be extended and/or timed, pulsed at a predetermined rate in a sustained-release or controlled-release dosage form including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, etc.
  • compositions of the present disclosure can be produced in a known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting operations.
  • the pharmaceutical composition used can be prepared in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which are conducive to processing the active compound into a pharmaceutically available preparation.
  • suitable preparations depend on the selected route of administration. Any known technology, carrier and excipient can be used as suitable and understood in the art.
  • Injectables can be prepared in the following conventional forms: as a solution or suspension, as a solid dosage form suitable for solution or suspension prior to injection, or as an emulsion.
  • Suitable excipients are, for example Such as water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, etc.
  • the injection pharmaceutical composition can contain a small amount of non-toxic adjuvants, such as wetting agents, pH buffers, etc.
  • Physiologically suitable buffers include but are not limited to Hank's solution, Ringer's solution or physiological saline buffer. If necessary, absorption enhancing preparations (such as liposomes) can be used.
  • the compound can be easily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art.
  • a pharmaceutically acceptable carrier known in the art.
  • Such carriers enable the compounds of the present disclosure to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, pastes, suspensions, solutions, powders, etc., for oral ingestion by the patient to be treated.
  • Pharmaceutical preparations for oral administration can be obtained by mixing the active compound with a solid excipient, grinding the resulting mixture at will and processing the granular mixture, if necessary, after adding suitable adjuvants to obtain tablets or lozenge cores.
  • Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP).
  • Disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate may be added if necessary.
  • the lozenge cores are suitably coated.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for the identification or characterization of different combinations of active compound doses.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture.
  • compositions which can be used for oral administration include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredient mixed with fillers such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredient may be dissolved or suspended in a suitable liquid, for example a fatty oil, liquid paraffin or liquid polyethylene glycol.
  • stabilizers may be added. All formulations for oral administration should be of a quality suitable for such administration. dosage.
  • the pharmaceutical compositions of the present disclosure may contain 0.1%-95% of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure may contain 1%-70% of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • 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 disease/condition in the subject being treated.
  • At least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof can be administered to a patient by any method suitable for systemic and/or local delivery of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • administration methods include (a) administration by oral route, which includes administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) administration by non-oral route, such as rectal, vaginal, intraurethral, intraocular, intranasal or intraaural, which includes administration in the form of aqueous suspensions, oily preparations, etc.
  • compositions suitable for administration include compositions wherein the active ingredients are contained in an effective amount to achieve their intended effect.
  • the dosage required for a therapeutically effective amount of the pharmaceutical compositions described in the present disclosure depends on the route of administration, the type of animal, including humans, being treated, and the specific animal under consideration. The dosage may be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medications, and other factors recognized by those skilled in the art of medicine. More specifically, a therapeutically effective amount refers to an amount of the compound that effectively prevents, alleviates, or ameliorates symptoms of a disease, or prolongs the life of the individual being treated. A therapeutically effective amount is well within the practical abilities of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight and type of mammal being treated, the specific compound used and the specific purpose of the compounds used.
  • Those skilled in the art can achieve the purpose of determining effective dosage levels, i.e., the dosage levels necessary for determining the desired effect, using conventional pharmacological methods.
  • human clinical applications of the product are initiated at lower dosage levels, with the dosage level increasing until the desired effect is achieved.
  • acceptable in vitro studies can be used to establish the effective dosage and route of administration of the composition identified by the present method.
  • the dosage range can be relatively wide.
  • the dosage can be about 10 ⁇ g/kg body weight to 1000 mg/kg body weight, and in certain embodiments about 100 ⁇ g/kg body weight to 300 mg/kg body weight.
  • the dosage can be based on and calculated according to the patient's body surface area.
  • the dosage range of the composition administered to the patient can be about 0.5 mg/kg to 1000 mg/kg of the patient's body weight. Depending on the patient's needs, the dosage can be given once or twice or more during one day or several days.
  • the human dosage of the compound has been established due to at least some conditions, the present disclosure will use those same dosages, or a dosage range of about 0.1% to 500% of the determined human dosage, and in certain embodiments, a dosage range of 25% to 250% of the determined human dosage.
  • a suitable human dosage can be inferred from the median value of the half effective dose or the infectious dose, or other suitable values from in vitro or in vivo studies, as quantified in toxicity studies and efficacy studies in animals.
  • the attending physician will know how and when to Terminate, interrupt or adjust administration. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level.
  • the size of the dosage in the treatment of the disease concerned will vary with the severity of the disease state to be treated and the change of the route of administration. For example, the severity of the disease state can be evaluated in part by standard prognostic evaluation methods.
  • the dosage and possible dosage frequency will also vary according to the age, weight, and response of the individual patient. Schemes comparable to the above-discussed schemes can be used in veterinary medicine.
  • the daily dosing regimen for adult patients is, for example, an oral dose of 0.1 mg to 2000 mg of each active ingredient, 1 mg to 2000 mg of each active ingredient in certain embodiments, such as 5 mg to 1500 mg of each active ingredient.
  • the intravenous, subcutaneous or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, 0.1 mg to 1000 mg in certain embodiments, such as 1 mg to 800 mg.
  • the dosage can be calculated according to the free alkali.
  • the composition is administered 1 to 4 times a day.
  • composition described in the present disclosure can be administered by continuous intravenous infusion, and in certain embodiments, the dosage of each active ingredient up to 2000 mg per day is administered.
  • the compounds described in the present disclosure in an amount exceeding or far exceeding the above dosage range in order to effectively and rapidly treat rapidly developing diseases or infections.
  • the compounds are administered during continuous treatment, such as one or several weeks, or several months or years.
  • Dosage and dosing interval can be adjusted individually to provide the plasma level of the active part that is enough to maintain the adjustment effect or minimum effective concentration (MEC).
  • MEC adjustment effect or minimum effective concentration
  • the MEC of each compound is different, but MEC can be assessed from in vitro data.
  • the required dosage reaching MEC depends on individual characteristics and route of administration.
  • HPLC high performance liquid chromatography
  • the MEC value also enables determination of dosing intervals.
  • Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, in certain embodiments 30-90% of the time, and in certain embodiments 50-90% of the time.
  • the effective local concentration of the drug is independent of plasma concentration.
  • composition administered will, of course, be dependent upon the individual being treated, on the individual's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the efficacy and toxicity of the compounds described in the present disclosure can be evaluated using known methods.
  • the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties can be established by determining the toxicity of a cell line in vitro, such as a mammalian cell line and in some embodiments a human cell line.
  • the results of such studies can generally predict toxicity in an animal such as a mammal, or more specifically, in a human.
  • the toxicity of a particular compound in an animal model such as a mouse, rat, rabbit, or monkey can be determined using known methods.
  • the efficacy of a particular compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • the composition can be placed in a package or dispensing device, which can contain one or more unit dosage forms containing active ingredients.
  • the package can, for example, include metal or plastic foil, such as a blister package.
  • the package or dispensing device can carry instructions for administration.
  • the package or dispensing device can also carry precautions associated with the container, which are prescribed by a government agency that manages drug production, use or sales, and which reflect that the drug form has been approved by the agency for human or veterinary administration. Such precautions, for example, can be labels for prescription drugs approved by the State Food and Drug Administration or the U.S. Food and Drug Administration, or approved product instructions.
  • Compositions comprising compounds of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which can also be prepared in suitable containers and placed in compatible pharmaceutical carriers, and marked for use in the treatment of specified disease states.
  • the present disclosure relates to a method for preparing a compound represented by general formula (Ia),
  • X1 and Y1 are each independently selected from amino, thiol or hydroxyl;
  • X and Y are each independently selected from O, S or N;
  • R2 is selected from an optionally substituted hydrocarbon group, an optionally substituted aryl group or an optionally substituted cycloalkyl group.
  • reaction to prepare the compound represented by formula (Ia) is carried out in the presence of a base and a strong oxidant.
  • illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.
  • 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.
  • illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.
  • DIPEA N,N-diisopropylethylamine
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • illustrative examples of strong oxidizing agents that can be used in the present disclosure include, but are not limited to, periodates, dichromates, pyridinium chlorochromates, or any mixture thereof.
  • periodate salts that can be used in the present disclosure include, but are not limited to, sodium periodate, potassium periodate, or any mixture thereof.
  • dichromates that can be used in the present disclosure include, but are not limited to, potassium dichromate, sodium dichromate, or any mixture thereof.
  • the present disclosure relates to a method for preparing a compound represented by general formula (Ib),
  • R1 is selected from halogen, optionally substituted aryl or optionally substituted heteroaryl;
  • B is selected from boric acid or boric acid esters.
  • reaction to prepare the compound represented by formula (Ib) is carried out in the presence of a palladium catalyst and a base.
  • illustrative examples of palladium catalysts that can be used in the present disclosure include, but are not limited to, palladium, Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd(dppf)Cl 2 , or any mixture thereof.
  • illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.
  • 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.
  • illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.
  • DIPEA N,N-diisopropylethylamine
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • borate esters that can be used in the present disclosure include, but are not limited to, bis(pinacolato)diboron (Bpin), Bcat, or any mixture thereof.
  • the present disclosure relates to a method for preparing a compound represented by general formula (Id),
  • the method for preparing the compound represented by formula (Ic) is carried out in the presence of a base.
  • illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.
  • 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.
  • illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.
  • DIPEA N,N-diisopropylethylamine
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • the compound represented by the general formula (Ia) is reacted in the presence of boron bromide to obtain the compound represented by the general formula (Ib).
  • the present disclosure relates to a method for inhibiting tyrosine kinase (TK), which comprises contacting tyrosine kinase with an inhibitory effective amount of a compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • TK tyrosine kinase
  • TKs tyrosine kinases
  • ALK anaplastic lymphoma kinase
  • ROS1 oncogene receptor tyrosine kinase ROS1 oncogene receptor tyrosine kinase
  • EGFR epidermal growth factor receptor
  • PDGF platelet growth factor receptor
  • ABL fibroblast growth factor receptor
  • IRAK interleukin receptor-associated kinase
  • human tyrosine kinase receptor FLT
  • V-raf mouse sarcoma viral oncogene homolog B BRAF
  • KDR vascular endothelial growth factor receptor 2
  • HER2 vascular endothelial growth factor receptor 2
  • HER4 Bruton's tyrosine kinase
  • HER2 human epidermal growth factor receptor 2
  • HER4 human epidermal growth factor receptor 4
  • the present disclosure relates to a method for treating or preventing diseases or disease states mediated by tyrosine kinase (TK), which comprises administering to an individual in need of the method a therapeutically or preventively effective amount of a compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • TK tyrosine kinase
  • illustrative examples of individuals that can be used in the methods of treating or preventing tyrosine kinase (TK)-mediated diseases or disease states disclosed herein include, but are not limited to, mammals.
  • the subject is a human.
  • TKs tyrosine kinases
  • ALK anaplastic lymphoma kinase
  • ROS1 oncogene receptor tyrosine kinase ROS1 oncogene receptor tyrosine kinase
  • EGFR epidermal growth factor receptor
  • PDGF platelet growth factor receptor
  • ABL fibroblast growth factor receptor
  • IRAK interleukin receptor-associated kinase
  • FLT human tyrosine kinase receptor
  • BRAF V-raf mouse sarcoma viral oncogene homolog B
  • KDR vascular endothelial growth factor receptor 2
  • VGFR rearranged kinase by transfection
  • RET Bruton's tyrosine kinase
  • B-lymphoid tyrosine kinase B-lymphoid tyrosine kinase
  • 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, lymphoma, blastoma, sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancies, lung cancer, squamous cell lung carcinoma, peritoneal cancer, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, Bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer,
  • a method for treating or preventing a disease or disease state mediated by tyrosine kinase comprises administering 1 mg-10 g of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual in need of the method.
  • a method for treating or preventing a disease or condition mediated by tyrosine kinase comprises administering 10 mg to 3000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual in need of the method.
  • a method for treating or preventing a disease or condition mediated by tyrosine kinase comprises administering 100 mg to 1000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual in need of said method.
  • a method for treating or preventing a disease or condition mediated by tyrosine kinase comprises administering 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg or 1000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual in need thereof.
  • the methods of treating or preventing tyrosine kinase (TK)-mediated diseases or disease states disclosed herein further comprise administering other active agents to the individual.
  • TK tyrosine kinase
  • examples of active agents 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, nitrogen mustards, aziridines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors, anticancer vaccines, acivicin, aclarubicin, acodazole hydrochloride, aclonine, adolesin, aldesleukin, ambromycin, ametrine acetate , aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, triclinamycin, azacitidine, azatepa, azomycin, batimastat, benzo
  • the present disclosure relates to compounds represented by the general formula (I) of the present disclosure and their pharmaceutically acceptable salts or compounds of the present disclosure and their pharmaceutically acceptable salts for inhibiting tyrosine kinase (TK).
  • TK tyrosine kinase
  • the present disclosure relates to compounds of the general formula (I) of the present disclosure and their pharmaceutically acceptable salts or compounds of the present disclosure and their pharmaceutically acceptable salts for treating or preventing diseases or disease states mediated by tyrosine kinase (TK).
  • TK tyrosine kinase
  • the present disclosure relates to the compounds represented by the general formula (I) of the present disclosure and their pharmaceutically acceptable salts, or the compounds of the present disclosure and their pharmaceutically acceptable salts in the preparation of drugs for inhibiting tyrosine kinase (TK).
  • TK tyrosine kinase
  • the present disclosure relates to the compounds represented by the general formula (I) of the present disclosure and their pharmaceutically acceptable salts, or the compounds of the present disclosure and their pharmaceutically acceptable salts in the preparation of drugs for treating or preventing diseases or disease states mediated by tyrosine kinase (TK).
  • TK tyrosine kinase
  • reagents and equipment used in the examples of the present disclosure are conventional and commercially available. For example:
  • Step a To a mixture of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 17.9 mmol) in THF (60 mL) was added NaH (1.08 g, 27 mmol, 60%), and the mixture was stirred at 0°C for 30 minutes. SEMCl (3.58 g, 3.8 mL, 8.64 mmol) was added to the reaction mixture, which was warmed to room temperature and stirred for 2 hours, and quenched by saturated NH 4 C solution.
  • 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 2 CO 3 (2.764 g, 20 mmol). The reaction was stirred at room temperature overnight. NaIO 4 solution (427.78 mg in 100 mL H 2 O, 20 mol%) was poured into the reaction. TLC showed that 2-amino-4-methoxyphenol was completely consumed. It was extracted with EA. Concentrated and purified by silica gel column to obtain 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, 20 mL, 5 equivalents). The reaction was stirred at room temperature. The reaction was quenched with MeOH until TLC showed no starting material remaining. Concentration and purification by silica gel column gave the desired product F2 (1.88 g, 90%).
  • Step e Pd(dppf)Cl 2 (408.3 mg, 0.5 mmol), K 2 CO 3 (6.91 mg, 50 mmol) and pinacol borane (5.06 g, 20 mmol) were added to a DMF (50 mL) solution of the product of step d (2.83 g, 10 mmol). The nitrogen atmosphere was replaced 3 times, and then the mixture was stirred at 100°C for 4 hours. Extracted with EA, washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column to give the desired product F3 (2.805 g, 85%) as a yellow oil.
  • Step f A 100 mL round-bottom flask was charged with compound F1 (1.9632 g, 4.8 mmol), Pd(PPh 3 ) 2 Cl 2 (280.7 mg, 0.4 mmol), K 2 CO 3 (1.66 g, 12 mmol) and compound F3 (1.346 g, 4.0 mmol) in dioxane/H 2 O (36 mL/4 mL, 0.1 M). Nitrogen was replaced 3 times, and then stirred at 100° C. overnight. Concentration and purification by silica gel column gave the desired intermediate (1.34 g, 69%) as a yellow solid.
  • Step g Compound F2 (0.343 g, 1.32 mmol) and Cs 2 CO 3 (0.643 g, 1.974 mmol) were added to a solution of the product obtained in the previous step (0.32 g, 0.658 mmol) in NMP (3 mL, 0.2 M). The reaction was stirred at 120°C for 4 hours. Extracted with EA, washed with saturated NaCl solution and dried over Na 2 SO 4. Purified with silica gel column to give the desired product (288.8 mg, 62%) as a brown solid.
  • Step h Add DCM/TFA (4 mL/4 mL, 0.1 M) to the product in step g (288.8 mg, 0.406 mmol). The reaction was stirred at room temperature. After 1 hour, TLC showed that no starting material remained. Concentrate to remove most of the DCM and TFA. Add Et2O to obtain the TFA salt of the product. Extract with EA and adjust the pH to 12 to make the compound a free amine. The crude product is further treated with silica gel Column purification gave the title compound YH-I-001 (153.7 mg, 65%) as a white solid.
  • Step i To a solution of compound F1 (0.82 g, 2 mmol) in NMP (4 mL, 0.2 M) was added compound F2 (0.51 g, 2 mmol) and Cs 2 CO 3 (1.629 g, 5 mmol). The reaction was stirred at 120° C. for 4 hours. Extracted with EA, washed with saturated NaCl solution and dried over Na 2 SO 4. Purified with silica gel column to give the desired product (509.8 mg, 40%) as a white solid.
  • Step j To a mixture of 3,5-dimethylpyrrolopinacol (1.11 g, 5.0 mmol) in THF (15 mL) was added NaH (0.30 g, 7.5 mmol, 60%), and the mixture was stirred at 0°C for 30 minutes. SEMCl (2.49 g, 2.66 mL, 6.0 mmol) was added to the reaction mixture, which was warmed to room temperature and stirred for 2 hours, and quenched by saturated NH 4 Cl solution.
  • Step k 3,5-dimethyl-4-bromopyrrole (1.75 g, 10.0 mmol) in DMF (33 mL) was added. To the mixture in , NaH (0.60 g, 15 mmol, 60%) was added, and the mixture was stirred at 0°C for 30 minutes. 4-Sulfonate-Boc piperidine (3.35 g, 12 mmol, 5.32 mL) was added to the reaction mixture, which was warmed to room temperature and stirred for 2 hours, and quenched by saturated NH4Cl solution.
  • Step 1 Pd(OAc) 2 (11.2 mg, 0.05 mmol), KOAc (408.3 mg, 2 mmol) and pinacol borane (0.506 g, 2 mmol) were added to a solution of the product of step k (179.14 mg, 0.5 mmol) in DMA (2 mL). Nitrogen was replaced 3 times, and then stirred at 100° C. for 4 hours. Extracted with EA, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give the desired intermediate (0.108 g, 53%) as a brown oil.
  • test compound Dilute 1 volume of protein culture solution 4 times, and add 50 ⁇ M dithiothreitol as culture solution for standby use. Add different concentrations of the test compound to the 384-well plate (10 ⁇ M as the starting concentration, 3-fold dilution, 10 concentrations, duplicate wells). Seal the 384-well plate to be tested and centrifuge the plate at 1000g for 1 minute. After mixing 2 times ALK protein (test protein) with 1 times protein culture solution, take 2.5 ⁇ L of protein mixture and add it to each well plate, centrifuge the plate at 1000g for 30s, and react at room temperature for 10min. At the same time, mix 2 times substrate and ATP with 1 times protein culture solution and shake well.
  • ALK protein test protein
  • the culture medium was discarded, 150 ⁇ L of dimethyl sulfoxide was added, and the shaking was continued for 15 minutes.
  • the wavelength of 570 nm was selected, and the absorbance value (A value) was measured with an enzyme marker, and the proliferation inhibition rate was calculated.
  • the compound incubation time for Kelly, SH-SY5Y, TGW, and NCIH2228 cells was 72 hours, and the compound incubation time for SUDHL-1, SK-N-SH, and KP-N-RT-BM-1 cells was 120 hours.
  • the compounds disclosed in the present invention were tested for pharmacokinetic properties, and the test operation was as follows: the compound to be tested was dissolved and prepared into a storage solution of the required concentration for standby use. Then, male healthy mice were divided into groups of 3 mice per group. The mice were fasted for one night, allowed to drink water freely, and then fed and administered 4 hours later. The dosage was as shown in the following table. Whole blood samples were collected through the orbital vein at designated time points (0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h), and 30 ⁇ L of the sample was flowed into the sodium heparin anticoagulation tube and centrifuged at 4000rcf/4°C for 5 minutes before taking the upper plasma sample. Finally, LC-MS/MS was used to collect data on the samples, and after data processing, the pharmacokinetic parameters of the compound to be tested were obtained.
  • Tables 5 and 6 show the blood concentration-time data of the compound YH-I-001 of the present disclosure.
  • FIG2 and FIG3 show the blood concentration-time curves of the compound YH-I-001 disclosed in the present invention.
  • KELLY (brain, neuroblastoma, purchased from ECACC, Cat No.: 92110411, Lot No. 14A023) cells were cultured in vitro in monolayers, and the culture conditions were RPMI-1640 medium with 2mM Glutamine, 10% heat-inactivated fetal bovine serum, and cultured at 37°C without CO2 . Digestion and passage were performed with trypsin-EDTA twice a week. When the cells were in the exponential growth phase, the cells were collected, counted, and inoculated.
  • the experimental index is to examine whether tumor growth can be inhibited, delayed or cured.
  • the tumor diameter is measured with a vernier caliper twice a week.
  • the anti-tumor efficacy of the compound is evaluated by T/C (%).
  • T/C% TRTV/CRTV ⁇ 100% (TRTV: RTV of the treatment group; CRTV: negative control group RTV).
  • V1 is the tumor volume measured at the time of cage administration (i.e. Day 1)
  • Vt is the tumor volume measured on the tth day.
  • TGI tumor volume of the control group
  • TGI tumor weight inhibition rate
  • TGI tumor inhibition rate
  • relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any such actual relationship or order between these entities or operations.

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Abstract

公开了通式(I)所示的化合物，及其药物可接受的盐：其中，R1、R2、X和Y如本公开所定义。

Description

嘧啶并吡咯类似物
相关申请的引用
本公开要求于2022年10月27日向中华人民共和国国家知识产权局提交的申请号为202211339750.2、发明名称为“嘧啶并吡咯类似物”的发明专利申请的全部权益，并通过引用的方式将其全部内容并入本公开。
领域
本公开大体上涉及药物化学领域，更具体地，本公开涉及嘧啶并吡咯类似物。
背景
目前，癌症的发病率越来越高，全球每年约有420万人死于癌症。中国的癌症在2012年的发病个案占全球近一半，高居第一位。治疗癌症的药物主要包括细胞毒性药物(cytotoxic drugs)与分子靶向药物(molecular target drugs)。细胞毒性药物，即传统化疗药物，主要通过杀伤迅速分裂的肿瘤细胞来达到抑制肿瘤生长的目的。然而，细胞毒性药物同时可以危害在正常情况下快速分裂的细胞如：骨髓、胃肠道及毛囊细胞等，导致化疗中常见的副反应：骨髓抑制、粘膜炎、脱发等。靶向药物治疗通过干扰影响肿瘤细胞增生的特定蛋白靶标来实现治疗。一个优秀的蛋白或酶靶标具有肿瘤细胞特异性的突变或其他遗传改变，而在正常组织细胞中则没有，从而实现特异性的细胞选择性。但是，靶向药物往往由于耐药性和靶点分子相关毒副作用等缺陷，导致许多药物候选尽管在动物模型上呈现较好效果，在临床实验中失败。采取靶向抑制剂与细胞毒性药物联合的用药方式，可以通过两种不同的作用机制来提高药效，进而通过降低给药量来获得更佳的药效/毒性窗口。
间变性淋巴瘤激酶(ALK)是一种跨膜蛋白酪氨酸激酶，属于胰岛素受体激酶亚家族。它首次在间变性大细胞淋巴瘤(ALCL)中发现，具有核磷蛋白(NPM)-ALK融合形式，是T-细胞非霍奇金淋巴瘤，通常与染色体易位有关。此后，发现许多癌症与不同形式的ALK融合有关。这些包括非 小细胞肺癌(NSCLC，EML4-ALK)、炎性肌纤维母细胞瘤(IMT、TPM3-ALK)和弥漫性大B细胞淋巴瘤(DLBCL、CLTC-ALK)。此外，ALK基因的扩增和野生型ALK蛋白的突变已在各种肿瘤中报道。
间变性淋巴瘤激酶(ALK)的靶向抑制显着改善了治疗ALK阳性癌症的治疗结果，但不幸的是出现了ALK的获得性耐药突变。因此，提供一类高活性且具有选择性的作用于ALK的嘧啶并吡咯类激酶抑制剂十分重要。目前上市的ALK抑制剂均为I类激酶抑制剂，与ATP竞争结合口袋。
概述
一方面，本公开涉及通式(I)所示的化合物，及其药物可接受的盐：
其中：
R1选自卤素、任意取代的芳基或任意取代的杂芳基；
R2选自任意取代的烃基、任意取代的芳基或任意取代的环烃基；以及
X和Y各自独立地选自O、S或N。
另一方面，本公开涉及化合物，及其药物可接受的盐，其中所述化合物选自：
N-(4-氯苯基)-5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(p-甲苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(4-甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基) 苯并[d]噁唑-2-胺；
5-((6-(4-溴苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-氯苯基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(噻吩-2-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲腈；
N-(4-氯苯基)-5-((6-(4-(三氟甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(2-异丙基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(4-(二甲氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(2-异丙氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(3,5-双(三氟甲基)苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(3,4-二氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并 [2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲氧基)苯基)苯并[d]噁唑-2-胺；
N-(4-异丙基苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-环戊基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-环己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-碘-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-苯基苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(3,5-二甲基-1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(吡咯烷-3-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4- 基)氧基)苯并[d]噁唑-2-胺；
5-((6-(4-(4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基]苯并[d]噁唑-2-胺；
(4-甲基哌嗪-1-基)(4-(4-((4-(三氟甲基)苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲酮；
N-(4-氯苯基)-5-((6-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(1,3-二甲基-1H-吡唑-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
2-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)乙烷-1-醇；
1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)-2-甲基丙-2-醇；以及
1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)丙-2-醇。
又一方面，本公开涉及药物组合物，其包含本公开的通式(I)所示的化合物或其药物可接受的盐，或本公开的化合物或其药物可接受的盐，以及药物可接受的辅料。
再一方面，本公开涉及制备通式(Ia)所示的化合物的方法，
其包括进行如下所示的反应：
其中：
X1和Y1各自独立地选自氨基、巯基或羟基；
X和Y各自独立地选自O、S或N；以及
R2选自任意取代的烃基、任意取代的芳基或任意取代的环烃基。
另一方面，本公开涉及制备通式(Ib)所示的化合物的方法，
其包括进行如下所示的反应：
其中：
R1选自卤素、任意取代的芳基或任意取代的杂芳基；
B选自硼酸或硼酸酯。
又一方面，本公开涉及制备通式(Id)所示的化合物的方法，
其包括将通式(Ic)所示的化合物与通式(Ib)所示的化合物进行反应：
再一方面，本公开涉及抑制酪氨酸激酶(tyrosine kinase,TK)的方法，其包括将酪氨酸激酶与抑制有效量的本公开的通式(I)所示的化合物或其药物可接受的盐、本公开的化合物或其药物可接受的盐或本公开的药物组合物接触。
另一方面，本公开涉及治疗或预防酪氨酸激酶(tyrosine kinase,TK)介 导的疾病或疾病状态的方法，其包括向需要所述方法的个体给予治疗或预防有效量的本公开的通式(I)所示的化合物或其药物可接受的盐、本公开的化合物或其药物可接受的盐或本公开的药物组合物。
又一方面，本公开涉及用于抑制酪氨酸激酶(tyrosine kinase,TK)的本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐。
再一方面，本公开涉及用于治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐。
另一方面，本公开涉及本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐在制备用于抑制酪氨酸激酶(tyrosine kinase,TK)的药物中的用途。
又一方面，本公开涉及本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐在制备用于治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的药物中的用途。
附图简要说明
图1示出了本公开的化合物YH-I-001与ALK相互作用的模式；
图2示出了以1mg·kg-1的剂量静脉给药后本公开的化合物YH-I-001在ICR小鼠中血药浓度-时间曲线；
图3示出了以5mg·kg-1的剂量静脉给药后本公开的化合物YH-I-001在ICR小鼠中血药浓度-时间曲线；
图4示出了KELLY荷瘤鼠的瘤体积变化图；以及
图5示出了KELLY荷瘤鼠的体重变化图。
详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其他方法、部件、材料等的情况下可实现实施方案。
除非本公开中另外要求，在整个说明书和其后的权利要求书中，词语“包括”和“包含”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提及的“一实施方案”或“另一实施方案”或“实施方案”或“某些实施方案”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“一实施方案”或“实施方案”或“另一实施方案”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本公开的说明书和所附的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包含“通式(I)所示的化合物或其药物可接受的盐”的药物组合物包括一种通式(I)所示的化合物或其药物可接受的盐，或两种或多种通式(I)所示的化合物其药物可接受的盐。
定义
因此，除非另有相反的说明，否则说明书及所附权利要求中所用的下列术语具有以下的意思：
本公开中命名的某些化学基团前面所置的简写符号表示在所指示的化学基团存在的碳原子总数。例如，C1-C4烷基描述如下文所定义的具有总共1至4个碳原子的烷基，而C3-C10环烷基描述如下文所定义的具有总共3至10个碳原子的环烷基。简写符号中的碳总数不包含可能存在于所述基团的取代基中的碳。
在本公开中，术语“卤素”系指氟、氯、溴或碘。
在本公开中，术语“羟基”系指-OH基团。
在本公开中，术语“氨基”系指-NH2基团。
在本公开中，术语“氰基”系指-CN基团。
在本公开中，术语“烃基”系指脂肪族烃基团。烃基部分可以是“饱和的烃基”基团，意为其不包含任何烯或炔部分。烃基部分还可以是“不饱和的烃基”部分，意为其包含至少一个烯或炔部分。“烯”部分是指由两至八个碳原子和至少一个碳-碳双键组成的基团，并且由单键与分子的其余 部分连接的直链或支链烃链基团，例如乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等，并且“炔”部分是指由两至八个碳原子和至少一个碳-碳三键组成的基团，并且由单键与分子的其余部分连接的直链或支链烃链基团。烃基部分，无论饱和的或不饱和的，可以是支链的或直链的。
烃基基团可具有1至8个碳原子(在本公开中每次出现时，诸如“1至8”的数值范围是指给定范围中的每一整数；如“1至8”意为所述烃基基团可由1个碳原子、2个碳原子、3个碳原子、4个碳原子等直至并包括8个碳原子，尽管本定义还涵盖未指定数值范围的术语“烃基”的出现)。
烃基基团可以是任意取代的，亦即取代或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：环烃基、芳基、杂芳基、杂脂环基、羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合(isocyanato)、氰硫基、异硫氰酸根合(isothiocyanato)、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。通常烃基基团包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、乙烯基、丙烯基、丁烯基、乙炔基、丙炔基和丁炔基。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
在某些实施方案中，“C1-C4烃基”系指含有一至四个碳原子的上述定义的烃基基团。C1-C4烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C1-C4烃基”可以是C1-C4烷基集团。C1-C4烷基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C1-C6烃基”系指含有一至六个碳原子的上述定义的烃基基团。C1-C6烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C1-C6烃基”可以是C1-C6烷基集团。C1-C6烷基 基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C1-C12烃基”系指含有一至十二个碳原子的上述定义的烃基基团。C1-C12烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C1-C12烃基”可以是C1-C12烷基集团。C1-C12烷基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C2-C6烃基”系指含有二至六个碳原子的上述定义的烃基基团。C2-C6烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C2-C6烃基”可以是C2-C6烷基基团。C2-C6烷基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C2-C6烃基”可以是C2-C6烯基基团。C2-C6烯基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C2-C6烃基”可以是C2-C6炔基基团。C2-C6炔基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C6烃基”系指含有三至六个碳原子的上述定义的烃基。C3-C6烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C6烃基”可以是C3-C6烷基基团。C3-C6烷基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C6烃基”可以是C3-C6烯基基团。C3-C6烯基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C6烃基”可以是C3-C6炔基基团。C3-C6炔基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C12烃基”系指含有三至十二个碳原子的上述定义的烃基。C3-C12烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C12烃基”可以是C3-C12烷基基团。C3-C12烷基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C12烃基”可以是C3-C12烯基基团。C3-C12烯基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C3-C12烃基”可以是C3-C12炔基基团。C3-C12炔基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C6-C12烃基”系指含有六至十二个碳原子的上述定义的烃基。C6-C12烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C6-C12烃基”可以是C6-C12烷基基团。C6-C12烷基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C6-C12烃基”可以是C6-C12烯基基团。C6-C12烯基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C6-C12烃基”可以是C6-C12炔基基团。C6-C12炔基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C7-C12烃基”系指含有七至十二个碳原子的上述定义的烃基。C7-C12烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C7-C12烃基”可以是C7-C12烷基基团。C7-C12烷基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C7-C12烃基”可以是C7-C12烯基基团。C7-C12烯基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C7-C12烃基”可以是C7-C12炔基基团。C7-C12炔基基团可以如对烃基基团定义的那样被任意地取代。
在本公开中，术语“烃基氧基”系指通式-O-烃基，其中烃基如本公开中所定义。烃基氧基的示例性实例包括但不限于甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(异丙氧基)、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基和叔戊氧基。
在本公开中，术语“芳基”是指具有完全离域的Pi电子体系的碳环(全碳)或两个或多个稠合环(共享两个相邻碳原子的环)。芳基基团包括但不限于芴基、苯基及萘基。芳基基团例如可以具有五至十二个碳原子。本公开的芳基基团可以是取代的或未取代的。当被取代时，氢原子被一个或多个独立地选自下列取代基的基团取代：烃基、环烃基、芳基、杂芳基、杂脂环基、羟基、被保护的羟基、烃氧基、芳氧基、巯基、烃硫基、 芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、Ν-硫代氨基甲酰基、C-酰氨基、Ν-酰氨基、S-亚磺酰氨基、Ν-亚磺酰氨基、C-羧基、被保护的C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或被保护的氨基。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
在本公开中，术语“杂芳基”系指是指由一至十七个碳原子和一至十个选自氮、氧及硫的杂原子组成的5元至18元芳族环基。在某些实施方案中，杂芳基可为单环、双环、三环或四环环系统，其可包含经稠合或桥接的环系统；且杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。杂芳基的示例性实例包括但不限于氮杂卓基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并二氧杂环戊烯基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧杂环庚基、1,4-苯并二噁烷基、苯并萘呋喃基、苯并噁唑基、苯并二氧杂环戊烯基、苯并二氧杂环己烯基、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、异噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、异吲哚基、吲哚啉基、异吲哚啉基、异喹啉基、吲哚嗪基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂卓基、噁唑基、环氧乙基、1-苯基-1H-吡咯基、菲嗪基、菲噻嗪基、菲噁嗪基、酞嗪基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、喹唑啉基、喹噁啉基、喹啉基、奎宁环基、异喹啉基、四氢喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基和噻吩基。本公开的杂芳基基团可以是取代的或未取代的。当被取代时，氢原子被一个或多个独立地选自下列取代基的基团取代：烃基、环烃基、芳基、杂芳基、杂脂环基、羟基、被保护的羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、Ν-硫代氨基甲酰基、C-酰氨基、Ν-酰氨基、S-亚磺酰氨基、Ν-亚磺酰氨基、C-羧基、被保护的C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、 甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或被保护的氨基。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
在本公开中，术语“环烃基”系指仅由碳和氢原子组成的，具有三至十五个碳原子的，在某些实施方案中具有三至十二个碳原子的，并且其为饱和或不饱和的，并且通过单键与分子的其余部分相连的稳定的非芳香族单环或双环烃基团，例如环丙基、环丁基、环戊基、环己基、环癸基等。除非本公开中另有明确说明，否则术语“环烃基”旨在包括被一个或多个选自如下取代基的基团所任意取代的上述定义的环烃基：环烃基、芳基、杂芳基、杂脂环基、羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰基氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。
在某些实施方案中，“C3-C6环烃基”系指具有三至六个碳原子的上述定义的环烃基基团。C3-C6环烃基基团可以如对上述环烃基的定义那样被任意地取代。
在某些实施方案中，“C3-C10环烃基”系指具有三至十个碳原子的上述定义的环烃基基团。C3-C10环烃基基团可以如对上述环烃基的定义那样被任意地取代。
在某些实施方案中，“C3-C12环烃基”系指具有三至十二个碳原子的上述定义的环烃基基团。C3-C12环烃基基团可以如对上述环烃基的定义那样被任意地取代。
在本公开中，术语“杂环烃基”系指由碳原子和一至五个选自氮、氧和硫的杂原子组成的稳定的三至十二员的非芳香族环基团。这样的杂环基基团的实例包括但不限于二氧环戊基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、 哌嗪基、4-哌啶酮基、吡咯烷基、吡唑烷基、噻唑烷基、四氢呋喃基、三噻烷基、四氢吡喃基、硫代吗啉基、噻吗啉基、1-氧代-硫代吗啉基和1,1-二氧代-硫代吗啉基。
在本公开中，术语“本公开的化合物或其药物可接受的盐”系指本公开的通式(I)所示的化合物及其药物可接受的盐，以及任何落入通式(I)中的具体化合物及其药物可接受的盐。
在本公开中，术语“哺乳动物”是指包括例如狗、猫、牛、羊、马和人类等的动物。在某些实施方案中，哺乳动物包括人类。
在本公开中，术语“患者”系指动物(例如，人)、伴侣动物(例如，狗、猫或马)和家畜(例如，牛、猪和羊)。在某些实施方案中，患者是包括雄性和雌性的哺乳动物。在某些实施方案中，患者为人类。
在本公开中，术语“药物可接受的”系指必须与制剂的其它成分相容并且不会对其接受者有害的载体、载剂、稀释剂、赋形剂和/或盐。
在本公开中，术语“任意的”或“任意地”意为随后描述的事件或状况可以发生也可以不发生，且说明书包括该事件或状况发生的情况及未发生的情况。
在本公开中，术语“药物可接受的辅料”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
在本公开中，术语“载体”定义为有利于将化合物引入细胞或组织的化合物。例如二甲亚砜(DMSO)通常用作载体，这是因为它易于将某些有机化合物引入生物体的细胞或组织中。
在本公开中，术语“药物可接受的盐”包括“可以接受的酸加合盐”和“可以接受的碱加合盐”。
在本公开中，术语“可以接受的酸加合盐”系指保持游离碱的生物学有效性和性质的那些盐，所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的，所述无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等，所述有机酸例如但不限于乙酸、2,2-二氯乙 酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
在本公开中，术语“可以接受的碱加合盐”系指保持游离酸的生物学有效性和性质的那些盐，所述碱加合盐是在生物学或其它方面合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。在某些实施方案中，无机盐为铵、钠、钾、钙及镁盐。由有机碱衍生的盐包括但不限于伯、仲和叔胺的盐、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂的盐，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。在某些实施方案中，有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
在本公开中，术语“药物组合物”系指本公开中所述的化合物与通常被本领域所接受的将生物活化化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、稀释剂或赋形剂。
在本公开中，术语“治疗有效量”指改善、减弱或消除特定疾病或病况和特定疾病或病况的症状、或者避免或延迟特定疾病或病况或者特定疾病或病况的症状的发病的化合物或化合物组合的量。根据化合物、疾 病状态及其严重性、以及待治疗哺乳动物的年龄、体重等，构成“治疗有效量”的本公开中所述的化合物的量将会不同，但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本公开中所述的化合物的量。
本公开所用的“进行治疗”或“治疗”涵盖患有相关疾病或病症的哺乳动物例如人类中治疗相关的疾病或疾病状态，并且包括：
(i)预防疾病或疾病状态在哺乳动物中发生，尤其是当该哺乳动物易感于所述疾病状态，但尚未被诊断出患有这种疾病状态时；
(ii)抑制疾病或疾病状态，即阻止其发生；或者
(iii)缓解疾病或疾病状态，即使疾病或疾病状态消退或不进展。
在本公开中，术语“预防”指预防疾病或疾病状态，或其一种或多种症状的发作、复发或扩散。
在本公开中，术语“预防有效量”指足以预防疾病或疾病状态、或者预防其复发或扩散的化合物或化合物组合的量。根据化合物、疾病状态及其严重性、以及待治疗哺乳动物的年龄、体重等，构成“预防有效量”的本公开中所述的化合物的量将会不同，但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本公开中所述的化合物的量。
正如本公开所用的那样，术语“疾病”和“疾病状态”可以相互交换使用，或者可以是不同的，因为特殊的疾病或疾病状态可能并没有已知的致病因子(因此不能用病因学解释)，因此其不被公认为是疾病，而是被认为是不期望的疾病状态或病症，其中临床医生已经鉴定出或多或少的特定系列的症状。
具体实施方式
一方面，本公开涉及通式(I)所示的化合物，及其药物可接受的盐：

其中：
R1选自卤素、任意取代的芳基或任意取代的杂芳基；
R2选自任意取代的烃基、任意取代的芳基或任意取代的环烃基；以及
X和Y各自独立地选自O、S或N。
在某些实施方案中，R1选自卤素、未取代的芳基、任意取代的烷基取代的芳基、烷氧基取代的芳基、卤素取代的芳基、氰基取代的芳基、任意取代的氨基取代的芳基、磺酰胺基取代的芳基、未取代的杂芳基、任意取代的烷基取代的杂芳基、烷氧基取代的杂芳基、氰基取代的杂芳基、任意取代的氨基取代的杂芳基或杂环烷基取代的杂芳基。
在某些实施方案中，R1选自卤素、未取代的苯基、任意取代的烷基取代的苯基、任意取代的杂环烷基取代的任意取代的烷基取代的苯基、烷氧基取代的苯基、卤素取代的苯基、氰基取代的苯基、任意取代的氨基取代的苯基、磺酰胺基取代的苯基、未取代的吡啶基、未取代的噻吩基、未取代的嘧啶基、未取代的吡唑基、任意取代的烷基取代的吡唑基、氨基取代的烷基取代的吡唑基、烷基取代的氨基取代的烷基取代的吡唑基、烷氧基取代的吡唑基、氰基取代的吡唑基、杂环烷基取代的氨基取代的吡唑基或杂环烷基取代的吡唑基。
在某些实施方案中，R1选自卤素、未取代的芳基、烷基取代的芳基、卤素取代的烷基取代的芳基、烷氧基取代的芳基、卤素取代的芳基、氰基取代的芳基、烷基取代的杂环烷基取代的烷基取代的芳基、烷基取代的杂环烷基取代的氧代烷基取代的芳基、烷基取代的氨基取代的芳基、任意取代的杂环烷基取代的氨基取代的芳基、磺酰胺基取代的苯基、未取代的杂芳基、任意取代的烷基取代的杂芳基、任意取代的氨基取代的烷基取代的杂芳基、烷氧基取代的杂芳基、氰基取代的杂芳基、杂环烷基取代的氨基取代的杂芳基或杂环烷基取代的杂芳基。
在某些实施方案中，R1选自碘、苯基、甲苯基、异丙基苯基、三氟甲基苯基、4-(4-甲基哌嗪-1-基)甲基苯基、4-(4-甲基哌嗪-1-基)氧代甲基苯基、甲氧基苯基、异丙氧基苯基、溴苯基、氰基取代的苯基、二甲氨 基苯基、2-甲基-4-哌啶基取代的氨基取代的苯基、2-甲基-4-(N-甲基哌啶基)-氨基取代的苯基、2-甲基-4-四氢吡咯基取代的氨基取代的苯基、2-甲基-4-(N-甲基四氢吡咯基)-氨基取代的苯基、2-甲基-4-磺酰胺基取代的苯基、吡啶基、噻吩基、嘧啶基、吡唑基、N-甲基吡唑基、氰基吡唑基、异丙氧基吡唑基、二甲基吡唑基、N-(羟乙基)二甲基吡唑基、N-(2-羟基-2-甲基丙基)二甲基吡唑基、N-(2-羟基丙基)二甲基吡唑基、N-吡喃基氨基取代的N-甲基吡唑基、N-哌啶基取代的吡唑基、N-哌啶基取代的二甲基吡唑基、氰基-氨甲基取代的N-甲基吡唑基、氰基-N-甲氨甲基取代的N-甲基吡唑基或氰基-N-吡喃基氨基取代的N-甲基吡唑基。
在某些实施方案中，R1选自：

在某些实施方案中，R2选自任意取代的烷基、任意取代的芳基、任意取代的杂芳基、任意取代的环烃基或任意取代的芳基并杂环烃基。
在某些实施方案中，R2选自任意取代的烷基、任意取代的芳基、任意取代的杂芳基、任意取代的环烷基或任意取代的苯并杂环烷基。
在某些实施方案中，R2选自未取代的烷基、卤素取代的芳基、任意取代的烷基取代的芳基、任意取代的烷氧基取代的芳基、未取代的环烷基、未取代的苯并杂环烷基或卤素取代的苯并杂环烷基。
在某些实施方案中，R2选自未取代的烷基、卤素取代的苯基、任意取代的烷基取代的苯基、任意取代的烷氧基取代的苯基、任意取代的吡啶基、任意取代的吡咯基、任意取代的吡唑基、任意取代的噻唑基、任意取代的噁唑基、任意取代的噻吩基、未取代的环烷基、未取代的苯并[1,3]二氧戊环基或卤素取代的苯并[1,3]二氧戊环基。
在某些实施方案中，R2选自己基、3,4-二氯苯基、4-氯苯基、4-异丙基的苯基、3,5-三氟甲基苯基、4-三氟甲基苯基、4-三氟甲氧基苯基、环戊烷基或环己烷基。
在某些实施方案中，R2选自：
在某些实施方案中，X为N，Y为O。
在某些实施方案中，X为N，Y为S。
在某些实施方案中，X为O，Y为N。
在某些实施方案中，X为O，Y为S。
另一方面，本公开涉及化合物，及其药物可接受的盐，其中所述化合物选自：
N-(4-氯苯基)-5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(p-甲苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(4-甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(4-溴苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-氯苯基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(噻吩-2-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲腈；
N-(4-氯苯基)-5-((6-(4-(三氟甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(2-异丙基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(4-(二甲氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(2-异丙氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(3,5-双(三氟甲基)苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(3,4-二氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲氧基)苯基)苯并[d]噁唑-2-胺；
N-(4-异丙基苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-环戊基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-环己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-碘-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-苯基苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(3,5-二甲基-1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(2-甲基-4-(吡咯烷-3-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
5-((6-(1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(4-(4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基]苯并[d]噁唑-2-胺；
(4-甲基哌嗪-1-基)(4-(4-((4-(三氟甲基)苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲酮；
N-(4-氯苯基)-5-((6-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
N-(4-氯苯基)-5-((6-(1,3-二甲基-1H-吡唑-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
2-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)乙烷-1-醇；
1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)-2-甲基丙-2-醇；以及
1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)丙-2-醇。
在某些实施方案中，本公开的化合物具有强效抑制ALK的活性。
在某些实施方案中，本公开的化合物具有ALK突变体的抗耐药性。
在某些实施方案中，本公开的化合物具有优异的稳定性。
在某些实施方案中，本公开的化合物具有优异的药效。
又一方面，本公开涉及药物组合物，其包含本公开的通式(I)所示的化合物或其药物可接受的盐，或本公开的化合物或其药物可接受的盐，以及药物可接受的辅料。
药物组合物
在某些实施方案中，药物组合物包含本公开的通式(I)所示的化合物或其药物可接受的盐，或本公开的化合物或其药物可接受的盐，以及药物可接受的辅料。
在某些实施方案中，本公开的本公开的通式(I)所示的化合物或其药物可接受的盐，或本公开的化合物或其药物可接受的盐用于治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态给予哺乳动物时的给药途径可以为肠胃途径或非肠胃途径。
在某些实施方案中，本公开的本公开的通式(I)所示的化合物或其药物可接受的盐，或本公开的化合物或其药物可接受的盐用于酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态给予哺乳动物时的给药途径可以为口服途径。
在某些实施方案中，本公开的本公开的通式(I)所示的化合物或其药物可接受的盐，或本公开的化合物或其药物可接受的盐用于酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态给予哺乳动物时的给药途径可以为直肠内途径。
可以以任何合适的形式如片剂、胶囊剂、粉剂、口服溶液、悬浮液、直肠凝胶、直肠泡沫、直肠灌肠剂或直肠栓剂等获得本公开中所述的化合物。所述的片剂的示例性实例包括但不限于素片、糖衣片和薄膜衣片。
能够用于本公开的药物组合物中的药物可接受的辅料的实例包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗透压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。用于治疗用途的可接受载体或稀释剂在药物领域是公知的，并且例如在Remington’s Pharmaceutical Sciences(雷明顿制药学),18th Ed.,Mack Publishing Co.,Easton,PA(1990))中有描述，本文将其全部内容引入作为参考。
本公开中的药物组合物可以通过任何实现其预期目的的方法被施用。例如，施用可以通过口服、胃肠外、局部、肠内、静脉内、肌内、吸入、鼻、关节内、脊柱内、经气管、经眼、皮下、腹膜内、经皮或口含等途径进行。给药途径可以为非肠胃途径、口服途径以及直肠内途径。所施用的剂量将取决于接受者的年龄、健康状况和体重，如果有并行治疗，还取决于并行治疗的种类、治疗的频率，以及所需效果的性质。
合适的剂型包括但不限于胶囊剂、片剂、小丸、糖锭剂(dragee)、半固体制剂、散剂、颗粒剂、栓剂、软膏剂、乳膏剂、洗剂、吸入剂、注射剂、泥罨剂、凝胶剂、带剂(tape)、滴眼剂、溶液剂、糖浆剂、气雾剂、混悬剂、乳剂，其可以根据本领域已知的方法制备。
特别适合口服施用的是普通片剂(素片)、糖衣片、薄膜衣片、丸剂、胶囊剂、散剂、颗粒剂、糖浆剂、汁液(juice)或滴剂，适合直肠施用的是栓剂，适合胃肠外施用的是溶液剂，也可以是基于油的溶液或水溶液，此外还有混悬剂、乳剂或植入剂，适合局部使用的是软膏剂、乳膏剂或散剂。本公开中的产品也可以被冻干，生成的冻干物用于例如制备注射剂。所给出的制剂可以被灭菌和/或包含辅助剂(assistant)，如润湿剂、防腐剂、稳定剂和/或润湿剂、乳化剂、用于改变渗透压的盐、缓冲物质、染料、矫味剂和/或众多另外的活性成分，例如一种或多种维生素。
在某些实施方案中，本公开中的药物组合物被制备成胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
在药物组合物中可以提供防腐剂、稳定剂、染料、甜味剂、芳香剂、香料等。例如，可加入作为防腐剂的苯甲酸钠、抗坏血酸以及对羟基苯甲酸的酯。另外，可以使用抗氧化剂和混悬剂。
在不同的实施方案中，醇、酯、硫酸化脂族醇等可用作表面活性剂；蔗糖、葡萄糖、乳糖、淀粉、结晶纤维素、甘露醇、轻质无水硅酸盐、铝酸镁、铝酸甲基硅酸镁、合成硅酸铝、碳酸钙、碳酸氢钙、磷酸氢钙、羟甲基纤维素钙等可用作赋形剂；硬脂酸镁、滑石、硬化油等可用作光滑剂；椰子油、橄榄油、麻油、花生油、大豆可用作混悬剂或润滑剂；作为诸如纤维素或糖等糖类的衍生物的醋酞纤维素、或作为聚乙烯的衍生物的乙酸甲酯-异丁烯酸酯共聚物可用作混悬剂；以及诸如酞酸酯等的增塑剂可用作混悬剂。
合适的给药途径可以例如包括口服给药、直肠给药、透膜给药、肠胃外输送、局部给药或肠内给药；肠胃外输送包括肌内注射、皮下注射、静脉注射、髓内注射以及鞘内注射、直接心室内注射、腹膜内注射、鼻内注射或眼内注射。化合物也能够在包括储库型注射(depot injections)、渗透泵、丸剂、透皮(包括电迁移)贴片等在内的缓释或控释的剂型中以预先确定的速率进行延长和/或定时、脉冲给药。
本公开中的药物组合物可按已知的方法进行生产，例如，通过常规的混合、溶解、粒化、制造锭剂、研磨、乳化、包囊、截留或压片等操作方法进行生产。
因此根据本公开，所使用的药物组合物可使用一种或多种包含赋形剂和辅助剂的生理可接受的载体以常规方法配制，该赋形剂和辅助剂有利于将活性化合物处理成为药学可用的制剂。合适的制剂取决于所选的给药途径。可以如本领域中适合的并理解的那样使用任何公知的技术、载体和赋形剂。
能够将注射剂制备成下列常规形式：作为溶液或混悬液，在注射前适合制成溶液或混悬液的固体剂型，或作为乳剂。合适的赋形剂是，例 如水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、盐酸半胱氨酸等。另外，如果需要，注射剂药物组合物可以含有少量无毒的辅助物，例如湿润剂、pH缓冲剂等。生理适合的缓冲剂包括但不限于Hank溶液、Ringer溶液或生理盐水缓冲液。如果需要，可使用吸收增强制剂(例如脂质体)。
对于口服给药，通过组合所述活性化合物与本领域公知的药物可接受的载体，能够容易地组方所述化合物。为了使待治疗患者口服摄取，这样的载体能使本公开的化合物被配制为片剂、丸剂、锭剂、胶囊、液体、凝胶、糖浆、膏剂、混悬液、溶液、粉剂等。能够通过下述方法获得用于口服的药物制剂：将活性化合物与固体赋形剂混合，任意研磨所得混合物并且将加工颗粒混合物，如果需要，在加入合适的辅助剂后进行加工以获得片剂或锭剂核。合适的赋形剂特别是诸如糖等的填充剂，包括乳糖、蔗糖、甘露醇或山梨醇；纤维素制剂，例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯酮(PVP)。如果需要可加入崩解剂，例如交联的聚乙烯吡咯烷酮、琼脂或海藻酸或诸如海藻酸钠的海藻酸盐。对锭剂核进行合适的包被。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶(carbopol gel)、聚乙二醇和/或二氧化钛、紫胶漆溶液以及合适的有机溶剂或溶剂混合物。为了识别或表征活性化合物剂量的不同组合，可向片剂或锭剂包衣中加入染料或色素。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、紫胶漆溶液、以及合适的有机溶剂或溶剂混合物。
能够用于口服的药物制剂包括明胶制成的推入配合胶囊，以及诸如甘油或山梨醇的明胶和增塑剂制成的软的、密封的胶囊。推入配合胶囊能够包含与诸如乳糖的填充剂、诸如淀粉的粘合剂和/或诸如滑石或硬脂酸镁的润滑剂以及任选的稳定剂混合的活性成分。在软胶囊中，活性成分可溶解或悬浮在合适的液体中，例如脂肪油、液状石蜡或液状聚乙二醇。另外，可加入稳定剂。所有口服给药的制剂应该达到适于这种给药 的剂量。
在某些实施方案中，本公开的药物组合物可以包含0.1％-95％的本公开的化合物或其药物可接受的盐。
在某些实施方案中，本公开的药物组合物可以包含1％-70％的本公开的化合物或其药物可接受的盐。
在任何情况下，待施用的组合物或制剂将含有一定量的本公开的化合物、其立体异构体或其药物可接受的盐，其量可有效治疗受治疗的受试对象疾病/病况。
给药方法
可将本公开的至少一种化合物或其药物可接受的盐或包含至少一种本公开的化合物或其药物可接受的盐的药物组合物以任何适宜系统的和/或局部的输送本公开的化合物或其药物可接受的盐的任何方法进行的方法对患者进行给药。给药方法的非限制性实例包括(a)通过口服途径给药，该给药包括以胶囊、片剂、颗粒剂、喷雾剂、糖浆剂或其它这类形式进行给药；(b)通过非口服途径给药，例如直肠、阴道、尿道内、眼内、鼻内或耳内，所述给药包括以水性悬浮液、油性制剂等或以滴剂、喷雾剂、栓剂、药膏、软膏等方式进行给药；(c)经皮下注射、腹膜内注射、静脉内注射、肌内注射、皮内注射、眶内注射、囊内注射、脊柱内注射、胸骨内注射等进行给药，包括输液泵输送；(d)诸如直接在肾脏区域或心脏区域中进行注射的局部(locally)给药，例如通过储库型植入；以及(e)局部(topically)给药；如本领域中技术人员所认为的适当的给药方式是本公开中所述的化合物与活组织接触。
最适合途径取决于被治疗疾病状态的性质与严重性。本领域技术人员也熟悉确定给药方法(口腔、静脉内、吸入、皮下、直肠等)、剂型、适当医药赋形剂及与将化合物、其立体异构体或其药物可接受的盐传递至有需要的对象有关的其它事项。
适于给药的药物组合物包括其中含有有效量的活性成分以达到其预期效果的组合物。本公开中所述的药物组合物的治疗有效量所需的剂量取决于给药途径、包括人在内的被治疗动物的类型以及所考虑的特定动 物的身体特征。可以调整剂量以达到期望的效果，但是这将取决于下列因素：体重、饮食、同时的药物治疗以及其它医学领域的技术人员公认的其它因素。更具体地，治疗有效量指有效阻止、减轻或改善疾病症状，或延长接受治疗个体寿命的化合物的量。本领域技术人员的实际能力可很好地确定治疗有效量，特别是按照本公开所提供的详细公开。
正如本领域技术人员所显而易见的，用于体内给药的剂量和具体的给药方式的变化将取决于年龄、体重和所治疗的哺乳动物的种类、所使用的具体化合物以及所使用的这些化合物的具体用途。本领域技术人员使用常规的药理学方法可达到确定有效剂量水平的目的，即达到确定预期效果所必需的剂量水平的目的。通常，以较低剂量水平开始进行产物的人体临床应用，随着剂量水平的增加直至达到所期望的效果。或者，采用已确立的药理学方法，能够使用可接受的体外研究来建立本方法鉴定的组合物的有效剂量和给药途径。
在非人动物研究中，潜在产物的应用以较高剂量水平开始，随着剂量的减少直至不再实现所期望的效果或者不良副作用消失。取决于预期效果和治疗适应症，剂量范围可较宽泛。通常，剂量可为约10μg/kg体重至1000mg/kg体重，在某些实施方案中为约100μg/kg体重至300mg/kg体重。或者，正如本领域技术人员所理解的，剂量可基于患者的体表面积并且按照其计算。
各医师能够根据患者的状况来选择本公开中所述的药物组合物的确切制剂、给药途径和剂量。通常，向患者给药的组合物的剂量范围可以为约0.5mg/kg至1000mg/kg患者体重。根据患者需要，剂量可在一天或数天期间单独一次给予或两次或多次给予。在化合物的人用剂量因至少某些条件已确立的情况下，本公开将使用那些相同的剂量，或剂量范围为约0.1％至500％的确定的人用剂量，在某些实施方案中剂量范围为25％至250％已确定的人用剂量。在没有确定的人用剂量的情况下，如新发现的药物化合物的情况，适宜的人用剂量能够从半数有效量或感染剂量中位数数值，或来自体外或体内研究的其它合适的值进行推断，正如在动物中的毒性研究和效能研究所定量化的。
应当指出，由于毒性和器官功能障碍，主治医师将知道如何且何时 终止、中断或调整给药。相反，如果临床反应不充分(排除毒性)，则主治医生也将知道将治疗调整至较高水平。在所关注病症的治疗中给药剂量的大小将随着待治疗疾病状态的严重性和给药途径的变化而变化。例如部分通过标准的预后评价方法可评价所述疾病状态的严重性。此外，所述剂量和可能的剂量频率也将根据个体患者的年龄、体重、以及反应的变化而变化。与上述讨论方案相当的方案可用于兽医学中。
虽然可基于逐一的药物分析(drug-by-drug)可决定确切的剂量，但是在大多数情况下，能够就药剂进行某些概括。成人患者的日给药方案为，例如口服剂量为0.1mg至2000mg各活性成分，在某些实施方案中为1mg至2000mg各活性成分，例如5mg至1500mg各活性成分。在其它实施方案中，所使用的各活性成分的静脉内、皮下或肌内剂量为0.01mg至1000mg，在某些实施方案中为0.1mg至1000mg，例如1mg至800mg。在给予药物可接受盐的情况下，可按照游离碱来计算剂量。在某些实施方案中，每日1至4次将所述组合物进行给药。或者，本公开中所述的组合物可通过连续的静脉输注进行给药，在某些实施方案中以每日高达2000mg的各活性成分的剂量进行给药。正如本领域技术人员所理解的，在某些情形中，为了有效且迅速地治疗迅速发展的疾病或感染，以超过或远远超过上述剂量范围的量给予本公开中所述的化合物是必要的。在某些实施方案中，将所述化合物在连续治疗期间进行给药，例如一周或数周、或数月或数年。
可以个别地调整剂量和用药间隔以提供足以维持调整效果或最低有效浓度(MEC)的活性部分的血浆水平。每种化合物的MEC不同，但是能够从体外数据评估MEC。达到MEC的所需剂量取决于个体特征和给药途径。然而，能够使用HPLC(高效液相色谱)测定或生物测定来确定血浆浓度。
使用MEC值还能够测定用药间隔。应使用在10-90％的时间内、在某些实施方案中在30-90％的时间内、以及在某些实施方案中在50-90％的时间内将血浆水平维持在MEC以上的治疗方案对组合物进行给药。
在局部给药或选择性吸收的情况下，药物的有效局部浓度与血浆浓度无关。
当然，被给药的组合物的量取决于待治疗的个体，取决于所述个体的体重、痛苦的严重性、给药方式以及开处方医师的判断。
使用已知的方法能够对本公开中所述的化合物的效能和毒性进行评估。例如，通过在体外测定细胞系的毒性可建立特定化合物或共享某些化学部分的该化合物子集的毒理学，所述细胞系例如哺乳动物细胞系并且在某些实施方案中为人的细胞系。这类研究的结果通常可预测诸如哺乳动物等的动物体内的毒性，或更具体地，可预测人体内的毒性。或者，使用已知方法可测定特定化合物在诸如小鼠、大鼠、家兔或猴等动物模型中的毒性。使用若干公认的方法，例如体外方法、动物模型或人体临床试验，可确定特定化合物的效能。几乎对每类疾病状态都存在着公认的体外模型，该疾病状态包括但不限于癌症、心血管疾病和多种免疫机能障碍。类似地，可接受的动物模型可用于确定治疗这些疾病状态的化学药物的效能。当选择模型测定效能时，技术人员能够在本领域现有技术的指导下选择合适的模型、剂量和给药途径以及治疗方案。当然，人体临床试验还能够用于测定化合物在人体内的效能。
如果需要，可将所述组合物置于包装或分配装置中，该包装或分配装置可以包含一种或多种含有活性成分的单位剂型。所述包装可以例如包括金属或塑料箔，例如泡罩包装。所述包装或分配装置可带有给药说明书。所述包装或分配装置还可以带有与所述容器相关的注意事项，该注意事项是由管理药物生产、使用或销售的政府机构规定的，该注意事项反映了所述药物形式已经由该机构批准用于人类或兽类给药。这类注意事项，例如，可以是由国家食品药品监督管理总局或美国食品和药物管理局批准的用于处方药的标签，或者是批准的产品说明书。还可以在合适的容器中制备、放置在相容的药物载体中组方的包含本公开的化合物、其立体异构体或其药物可接受的盐在内的组合物，并对其标记以用于指定的疾病状态的治疗。
再一方面，本公开涉及制备通式(Ia)所示的化合物的方法，
其包括进行如下所示的反应：
其中：
X1和Y1各自独立地选自氨基、巯基或羟基；
X和Y各自独立地选自O、S或N；以及
R2选自任意取代的烃基、任意取代的芳基或任意取代的环烃基。
在某些实施方案中，在碱和强氧化剂的存在下进行制备通式(Ia)所示的化合物的反应。
在某些实施方案中，能够用于本公开的碱的示例性实例包括但不限于碱金属盐、有机碱或其任意混合物。
在某些实施方案中，能够用于本公开的碱金属盐的示例性实例包括但不限于碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、醇锂、醇钠、醇钾或其任意混合物。
在某些实施方案中，能够用于本公开的醇的示例性实例包括但不限于甲醇、乙醇或叔丁醇。
在某些实施方案中，能够用于本公开的有机碱的示例性实例包括但不限于三乙胺、N,N-二异丙基乙胺(DIPEA)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)或其任意混合物。
在某些实施方案中，能够用于本公的强氧化剂的示例性实例包括但不限于高碘酸盐、重铬酸盐、氯铬酸吡啶或其任意混合物。
在某些实施方案中，能够用于本公开的高碘酸盐的示例性实例包括但不限于高碘酸钠、高碘酸钾或其任意混合物。
在某些实施方案中，能够用于本公开的重铬酸盐的示例性实例包括但不限于重铬酸钾、重铬酸钠或其任意混合物。
另一方面，本公开涉及制备通式(Ib)所示的化合物的方法，
其包括进行如下所示的反应：
其中：
R1选自卤素、任意取代的芳基或任意取代的杂芳基；
B选自硼酸或硼酸酯。
在某些实施方案中，在钯催化剂和碱存在下进行制备通式(Ib)所示的化合物的反应。
在某些实施方案中，能够用于本公开的钯催化剂的示例性实例包括但不限于钯、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2、Pd(dppf)Cl2或其任意混合物。
在某些实施方案中，能够用于本公开的碱的示例性实例包括但不限于碱金属盐、有机碱或其任意混合物。
在某些实施方案中，能够用于本公开的碱金属盐的示例性实例包括但不限于碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、醇锂、醇钠、醇钾或其任意混合物。
在某些实施方案中，能够用于本公开的醇的示例性实例包括但不限于甲醇、乙醇或叔丁醇。
在某些实施方案中，能够用于本公开的有机碱的示例性实例包括但不限于三乙胺、N,N-二异丙基乙胺(DIPEA)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)或其任意混合物。
在某些实施方案中，能够用于本公开的硼酸酯的示例性实例包括但不限于双(频哪醇合)二硼(Bpin)、Bcat或其任意混合物。
又一方面，本公开涉及制备通式(Id)所示的化合物的方法，
其包括将通式(Ic)所示的化合物与通式(Ib)所示的化合物进行反应：
在某些实施方案中，在碱的存在下进行制备通式(Ic)所示的化合物的方法。
在某些实施方案中，能够用于本公开的碱的示例性实例包括但不限于碱金属盐、有机碱或其任意混合物。
在某些实施方案中，能够用于本公开的碱金属盐的示例性实例包括但不限于碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、醇锂、醇钠、醇钾或其任意混合物。
在某些实施方案中，能够用于本公开的醇的示例性实例包括但不限于甲醇、乙醇或叔丁醇。
在某些实施方案中，能够用于本公开的有机碱的示例性实例包括但不限于三乙胺、N,N-二异丙基乙胺(DIPEA)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)或其任意混合物。
在某些实施方案中，通式(Ia)所示的化合物在溴化硼的存在下得到通式(Ib)所示的化合物。
再一方面，本公开涉及抑制酪氨酸激酶(tyrosine kinase,TK)的方法，其包括将酪氨酸激酶与抑制有效量的本公开的通式(I)所示的化合物或其药物可接受的盐、本公开的化合物或其药物可接受的盐或本公开的药物组合物接触。
在某些实施方案中，能够用于本公开的酪氨酸激酶(tyrosine kinase,TK)的示例性实例包括但不限于间变性淋巴瘤激酶(ALK)、ROS1癌基因受体酪氨酸激酶(ROS1)、表皮生长因子受体(EGFR)、血小板生长因子受体(PDGF)、ABL酪氨酸激酶、成纤维细胞生长因子受体(FGFR)、白介素受体相关激酶(IRAK)、人络氨酸激酶受体(FLT)、V-raf小鼠肉瘤病毒癌基因同源物B(BRAF)、血管内皮生长因子受体2(KDR)、血管内皮生长因 子(VEGFR)、转染重排激酶(RET)、布鲁顿酪氨酸激酶(BTK)、B-淋巴酪氨酸激酶(BLK)、胞质酪氨酸蛋白激酶(BMX)、人类表皮生长因子受体2(HER2)、人类表皮生长因子受体4(HER4)、异柠檬酸脱氢酶(IDH)、盘状结构域受体1(DDR1)、白介素2诱导的T细胞激酶(ITK)和人蛋白酪氨酸激酶4(TXK)。
另一方面，本公开涉及治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法，其包括向需要所述方法的个体给予治疗或预防有效量的本公开的通式(I)所示的化合物或其药物可接受的盐、本公开的化合物或其药物可接受的盐或本公开的药物组合物。
在某些实施方案中，能够用于本公开的治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法的个体的示例性实例包括但不限于哺乳动物。
在某些实施方案中，个体为人类。
在某些实施方案中，能够用于本公开的酪氨酸激酶(tyrosine kinase,TK)的示例性实例包括但不限于间变性淋巴瘤激酶(ALK)、ROS1癌基因受体酪氨酸激酶(ROS1)、表皮生长因子受体(EGFR)、血小板生长因子受体(PDGF)、ABL酪氨酸激酶、成纤维细胞生长因子受体(FGFR)、白介素受体相关激酶(IRAK)、人络氨酸激酶受体(FLT)、V-raf小鼠肉瘤病毒癌基因同源物B(BRAF)、血管内皮生长因子受体2(KDR)、血管内皮生长因子(VEGFR)、转染重排激酶(RET)、布鲁顿酪氨酸激酶(BTK)、B-淋巴酪氨酸激酶(BLK)、胞质酪氨酸蛋白激酶(BMX)、人类表皮生长因子受体2(HER2)、人类表皮生长因子受体4(HER4)、异柠檬酸脱氢酶(IDH)、盘状结构域受体1(DDR1)、白介素2诱导的T细胞激酶(ITK)和人蛋白酪氨酸激酶4(TXK)。
在某些实施方案中，能够用于本公开的治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法的疾病或疾病状态的示例性实例包括但不限于淋巴瘤、母细胞瘤、肉瘤、神经内分泌肿瘤、类癌肿瘤、胃泌素瘤、胰岛细胞癌、间皮瘤、神经鞘瘤、听神经瘤、脑膜瘤、腺癌、黑素瘤、白血病、淋巴样恶性肿瘤、肺癌、肺鳞癌、腹膜癌、胃癌、肠癌、胰腺癌、成胶质细胞瘤、子宫颈癌、卵巢癌、肝癌、 膀胱癌、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肛门癌、阴茎癌、梅克尔细胞癌、食管癌、胆道肿瘤、头颈部癌和血液恶性肿瘤。
在某些实施方案中，治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法，包括对需要所述方法的个体给予1mg-10g的本公开的化合物或其药物可接受的盐。
在某些实施方案中，治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法，包括对需要所述方法的个体给予10mg-3000mg的本公开的化合物或其药物可接受的盐。
在某些实施方案中，治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法，包括对需要所述方法的个体给予100mg-1000mg的本公开的化合物或其药物可接受的盐。
在某些实施方案中，治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法，包括对需要所述方法的个体给予100mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、650mg、700mg、750mg、800mg、850mg、900mg或1000mg的本公开的化合物或其药物可接受的盐。
在某些实施方案中，本公开的治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法还包括向个体给予其他活性剂。
在某些实施方案中，能够用于本公开的治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法的活性剂的实例包括但不限于氮芥、氮丙啶、甲基蜜胺、磺酸烷基酯、亚硝基脲、三氮烯、叶酸类似物、嘧啶类似物、嘌呤类似物、长春花生物碱、表鬼臼毒素、抗生素、拓扑异构酶抑制剂、抗癌疫苗、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、安波霉素、醋酸阿美蒽醌、氨鲁米特、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林霉素、阿扎胞苷、阿扎替哌、阿佐霉素、巴马司他、苯佐替哌、比卡鲁胺、盐酸比生群、甲磺酸双萘法德、比折来新、硫酸博来霉素、白消安、放线菌素C、卡普睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡柔比星、苯丁酸氮芥、西罗霉素、克拉屈滨、甲磺酸克立那托、环磷酰胺、阿糖 胞苷、达卡巴嗪、放线菌素D、盐酸柔红霉素、地西他宾、多西他塞、多柔比星、盐酸多柔比星、屈洛昔芬、盐酸表柔比星、盐酸依索比星、雌莫司汀、依他消唑、依托泊苷、氟尿苷、氟尿嘧啶、氟西他滨、吉西他宾、盐酸依达比星、异环磷酰胺、白介素II、干扰素α-2a、干扰素α-2b、盐酸依立替康、来曲唑、巯嘌呤、甲氨蝶呤、氯苯氨啶、丝列霉素、米托蒽酮、紫杉醇、丙卡巴肼、赛替哌、长春碱、长春新碱、血管生成抑制剂、喜树碱、地塞米松、阿司匹林、乙酰氨基酚、吲哚美辛、布洛芬、酮洛芬、美洛昔康、皮质类固醇和肾上腺皮质类固醇。
又一方面，本公开涉及用于抑制酪氨酸激酶(tyrosine kinase,TK)的本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐。
再一方面，本公开涉及用于治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐。
另一方面，本公开涉及本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐在制备用于抑制酪氨酸激酶(tyrosine kinase,TK)的药物中的用途。
又一方面，本公开涉及本公开的通式(I)所示的化合物及其药物可接受的盐或本公开的化合物及其药物可接受的盐在制备用于治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的药物中的用途。
下文中，本公开将通过如下实施例进行详细解释以便更好地理解本申请的各个方面及其优点。然而，应当理解，以下的实施例是非限制性的而且仅用于说明本公开的某些实施方案。
实施例
本公开的实施例中使用的试剂和设备均为常规的并且可商购的。例如：




制备实施例
制备实施例1
N-(4-氯苯基)-5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-001)的制备
步骤a：向4-氯-6-碘-7H-吡咯并[2,3-d]嘧啶(5.0g，17.9mmol)在THF(60mL)中的混合物中加入NaH(1.08g，27mmol，60％)，混合物在0℃下搅拌30分钟。向反应混合物中加SEMCl(3.58g，3.8mL，8.64mmol)将其温热至室温并搅拌2小时，通过饱NH4C溶液淬灭。用EtOAc(60mL×2)萃取，用Na2SO4干燥，过滤并减压浓缩，得到粗产物，将其通过硅胶柱色谱进一步纯化，得到所需产物F1，为白色固体(5.72g，78％)。
步骤b：向2-氨基-4-甲氧基苯酚(1.39g，10mmol)在THF(100mL)中的混合物中加入对氯异硫氰酸苯酯(2.54g，15mmol)和K2CO3(2.764g，20mmol)。反应在室温下搅拌过夜。将NaIO4溶液(427.78mg在100mL  H2O中，20mol％)倒入反应中。TLC显示2-氨基-4-甲氧基苯酚消耗完毕。用EA萃取。浓缩并通过硅胶柱纯化，得到所需中间体(2.1976g，80％)。
步骤c：向步骤b中的产物(2.1976g，8mmol)在DCM(80mL)中的悬浮液中加入BBr3·DCM(2M，20mL，5倍当量)。将反应在室温搅拌。用MeOH淬灭反应直到TLC显示没有原料剩余。浓缩并通过硅胶柱纯化，得到所需产物F2(1.88g，90％)。
步骤d：向4-溴-3-甲基苯胺(9.30g，50mmol)在DCE(165mL)中的悬浮液中加入1-甲基哌啶-4-酮(7.92g，8.12mL，70mmol)。将STAB(14.84g，70mmol，1.4eq)和HOAc(3g，5mL，50mmol)加入反应体系中。将混合物在室温搅拌过夜。将混合物调节至pH＝8，用DCM萃取，用NaCl(aq.)洗涤，用Na2SO4干燥，过滤并减压浓缩，得到粗产物。通过柱色谱进一步纯化，得到所需产物，为白色固体(10.7g，75％)。
步骤e：在步骤d的产物(2.83g，10mmol)的DMF(50mL)溶液中加入Pd(dppf)Cl2(408.3mg，0.5mmol)、K2CO3(6.91mg，50mmol)和频哪醇硼烷(5.06g，20mmol)。换氮气3次，然后在100℃下搅拌4小时。用 EA萃取，用盐水洗涤，用硫酸钠干燥，浓缩并通过硅胶柱纯化，得到所需产物F3(2.805g，85％)，为黄色油状物。
步骤f：向100mL圆底烧瓶中加入化合物F1(1.9632g，4.8mmol)、Pd(PPh3)2Cl2(280.7mg，0.4mmol)、K2CO3(1.66g，12mmol)和化合物F3(1.346g，4.0mmol)在二噁烷/H2O(36mL/4mL，0.1M)中。换氮气3次，然后在100℃下搅拌过夜。浓缩并通过硅胶柱纯化，得到所需中间体(1.34g，69％)，为黄色固体。
步骤g：向上一步得到的产物(0.32g，0.658mmol)在NMP(3mL，0.2M)中的溶液中加入化合物F2(0.343g，1.32mmol)和Cs2CO3(0.643g，1.974mmol)。将反应在120℃下搅拌4小时。用EA萃取，用饱和NaCl溶液洗涤并用Na2SO4干燥。用硅胶柱纯化，得到所需产物(288.8mg，62％)，为棕色固体。
步骤h：向步骤g中的产物(288.8mg，0.406mmol)中加入DCM/TFA(4mL/4mL，0.1M)。反应在室温下搅拌。1小时后，TLC显示没有原料残留。浓缩去除大部分DCM和TFA。加入Et2O得到产物的TFA盐。用EA萃取，调节pH至12，使该化合物成为游离胺。将粗品进一步用硅胶 柱纯化，得到标题化合物YH-I-001(153.7mg，65％)，为白色固体。
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+)计算值：C32H30ClN7O2[M+H]+:580.2222,测量值：580.2232
制备实施例2
N-(4-氯苯基)-5-((6-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-002)的制备
步骤i：向化合物F1(0.82g，2mmol)的NMP(4mL，0.2M)溶液中加入化合物F2(0.51g，2mmol)及Cs2CO3(1.629g，5mmol)。将反应在120℃下搅拌4小时。用EA萃取，用饱和NaCl溶液洗涤并用Na2SO4干燥。用硅胶柱纯化，得到所需产物(509.8mg，40％)，为白色固体。
然后按照制备实施例1中的步骤f和h获得标题化合物YH-I-002。
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+)计算值：C25H16ClN5O2[M+H]+:454.1065,测量值：454.1073.
制备实施例3
N-(4-氯苯基)-5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-010)的制备
步骤j：向3,5-二甲基吡咯频哪醇(1.11g，5.0mmol)在THF(15mL)中的混合物中加入NaH(0.30g,，7.5mmol，60％)，将混合物在0℃搅拌30分钟。向反应混合物中加SEMCl(2.49g，2.66mL，6.0mmol)，将其温热至室温并搅拌2小时，通过饱和NH4Cl溶液淬灭。用EtOAc(15mL×2)萃取，经Na2SO4干燥，过滤并减压浓缩，得到粗产物，其通过硅胶柱色谱进一步纯化，得到所需中间体，为白色固体(1.26g，71％)。
然后按照制备实施例1中的步骤f、g和h，获得标题化合物YH-I-010。
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+)C24H18ClN7O2[M+H]+:计算值：472.1283,测量值：472.1287
制备实施例4
N-(4-氯苯基)-5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-011)的制备
步骤k：向3,5-二甲基-4-溴吡咯(1.75g，10.0mmol)在DMF(33mL) 中的混合物中加入NaH(0.60g，15mmol，60％)，将混合物在0℃搅拌30分钟。向反应混合物中加4-磺酸酯-Boc哌啶(3.35g，12mmol，5.32mL)，将其温热至室温并搅拌2小时，通过饱和NH4Cl溶液淬灭。用EtOAc(20mL×3)萃取，经Na2SO4干燥，过滤并减压浓缩，得到粗产物，其通过硅胶柱色谱进一步纯化，得到所需中间体，为白色固体(2.11g，59％)。
步骤l:向步骤k的产物(179.14mg，0.5mmol)的DMA(2mL)溶液中加入Pd(OAc)2(11.2mg，0.05mmol)、KOAc(408.3mg，2mmol)和频哪醇硼烷(0.506g，2mmol)。换氮气3次，然后在100℃下搅拌4小时。用EA萃取，用盐水洗涤，用无水硫酸钠干燥，浓缩并通过硅胶柱纯化，得到所需中间体(0.108g，53％)，为棕黄色油状物。
然后按照制备实施例1中的步骤f、g和h，获得标题化合物YH-I-011。
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+)C29H27ClN8O2[M+H]+:计算值：555.2018,测量值：555.2020
制备实施例5
N-(4-氯苯基)-5-((6-(p-甲苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-003)的制备
使用与实施例1类似的方法，用4-甲苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-003。
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+)计算值：C26H18ClN5O2[M+H]+:468.1222,测量值：468.1228
制备实施例6
N-(4-氯苯基)-5-((6-(4-甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-004)的制备
使用与实施例1类似的方法，用4-甲氧基苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-004。
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+)计算值：C26H18ClN5O3[M+H]+:484.1171,测量值：484.1172
制备实施例7
5-((6-(4-溴苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-氯苯基)苯并[d]噁唑-2-胺(化合物YH-I-005)的制备
使用与实施例1类似的方法，用4-溴苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-005。
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+)计算值：C25H15BrClN5O2[M+H]+:532.0170,测量值：532.0170
制备实施例8
N-(4-氯苯基)-5-((6-(噻吩-2-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-006)的制备
使用与实施例1类似的方法，用2-噻吩频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-006。
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+)计算值：C23H14ClN5O2S[M+H]+:460.0629,测量值：460.0636.
制备实施例9
N-(4-氯苯基)-5-((6-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-007)的制备
使用与实施例1类似的方法，用3-吡啶频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-007。
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+)计算值：C24H15ClN6O2[M+H]+:455.1018,测量值：455.1024
制备实施例10
N-(4-氯苯基)-5-((6-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d] 噁唑-2-胺(化合物YH-I-008)的制备
使用与实施例1类似的方法，用4-吡啶频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-008。
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+)计算值：C24H15ClN6O2[M+H]+:455.1018,测量值：455.1024.
制备实施例11
N-(4-氯苯基)-5-((6-(嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-009)的制备
使用与实施例1类似的方法，用5-嘧啶频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-009。
1HNMR(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+)计算值：C23H14ClN7O2[M+H]+:456.0970,测量值：456.0978
制备实施例12
4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲腈(化合物YH-I-012)的制备
使用与实施例1类似的方法，用4-氰基苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-012。
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+)计算值：C26H15ClN6O2[M+H]+:479.1018,测量值： 580.2232
制备实施例13
N-(4-氯苯基)-5-((6-(4-(三氟甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-013)的制备
使用与实施例1类似的方法，用4-三氟甲基苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物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+)计算值：C26H15ClF3N5O2[M+H]+:522.0939,测量值：580.2232
制备实施例14
N-(4-氯苯基)-5-((6-(2-异丙基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-014)的制备
使用与实施例1类似的方法，用2-异丙基苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-014。
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+)计算值：C28H22ClN5O2[M+H]+:496.1535,测量值：580.2232
制备实施例15
N-(4-氯苯基)-5-((6-(4-(二甲氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-015)的制备
使用与实施例1类似的方法，用4-N,N-二甲基胺基苯频哪醇硼烷替 换F3，经过步骤f、g和h，制备获得标题化合物YH-I-015。
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+)计算值：C27H21ClN6O2[M+H]+:497.1487,测量值：580.2232
制备实施例16
N-(4-氯苯基)-5-((6-(2-异丙氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-016)的制备
使用与实施例1类似的方法，用2-异丙氧基苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物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+)计算值：C28H22ClN5O3[M+H]+:512.1484,测量值：580.2232
制备实施例17
N-(4-氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-017)的制备
使用与实施例1类似的方法，用2-甲基-4-(4-氨基哌啶)苯频哪醇硼烷替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-017。
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+)计算值：C31H28ClN7O2[M+H]+:566.2066,测量值：566.2068
制备实施例18
N-(3,5-双(三氟甲基)苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-023)的制备
使用与实施例1类似的方法，用1-三氟甲基-3-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-023。
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+)计算值：C33H27F6N7O2[M+H]+:668.2203,测量值：668.2216
制备实施例19
N-(3,4-二氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-024)的制备
使用与实施例1类似的方法，用1-氯-2-氯-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-024。
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+)计算值：C31H27Cl2N7O2[M+H]+:600.1676,测量值： 600.1683
制备实施例20
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-025)的制备
使用与实施例1类似的方法，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-025。
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+)计算值：C32H28F3N7O2[M+H]+:600.2335,测量值：600.2339
制备实施例21
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲氧基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-026)的制备
使用与实施例1类似的方法，用1-三氟甲氧基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-026。
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+)计算值：C32H28F3N7O3[M+H]+:616.2284,测量值：616.2285
制备实施例22
N-(4-异丙基苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-027)的制备
使用与实施例1类似的方法，用1-异丙基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-027。
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+)计算值：C34H35N7O2[M+H]+:574.2930,测量值：574.2925
制备实施例23
N-环戊基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-028)的制备
使用与实施例1类似的方法，用异硫氰酸环戊烷替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-028。
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+)计算值：C30H33N7O2[M+H]+:524.2774,测量值：524.2771
制备实施例24
N-环己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4- 基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-029)的制备
使用与实施例1类似的方法，用异硫氰酸环己烷替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-029。
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+)计算值：C31H35N7O2[M+H]+:538.2930,测量值：538.2933
制备实施例25
N-己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-030)的制备
使用与实施例1类似的方法，用异硫氰酸己烷替换1-氯-4-异硫氰酸苯，经过步骤b、c、g和h，制备获得标题化合物YH-I-030。
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+)计算值：C31H37N7O2[M+H]+:540.3087,测量值：540.3085
制备实施例26
N-(4-氯苯基)-5-((6-碘-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-031)的制备
使用与实施例1类似的方法，用F1和F2作为原料，经过步骤g和h，制备获得标题化合物YH-I-031。
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+)计算值：C19H11ClIN5O2[M+H]+:503.9724,测量值：503.9725
制备实施例27
5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-苯基苯并[d]噁唑-2-胺(化合物YH-I-040)的制备
使用与实施例1类似的方法，用(2-甲基-4-(哌啶-4-氨基)苯基)频哪醇硼烷替换F3，用异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-040。
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+)计算值：C31H29N7O2[M+H]+:532.2461,测量值：532.2462
制备实施例28
5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-047)的制备
使用与实施例1类似的方法，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、g和h，制备获得标题化合物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+)计算值：C33H30F3N7O2[M+H]+:614.2491,测量值：614.2493
制备实施例29
5-((6-(3,5-二甲基-1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-048)的制备
使用与实施例1类似的方法，用(3,5-二甲基-1-(1-甲基哌啶-4-基)-1H-吡唑-4-频哪醇硼烷替换F3，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-048。
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+)计算值：C31H29F3N8O2[M+H]+:603.2444,测量值：603.2444
制备实施例30
5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-049)的制备
使用与实施例1类似的方法，用(3,5-二甲基-1-(1-哌啶-4-基)-1H-吡唑-4-频哪醇硼烷替换F3，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-049。
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+)计算值：C30H27F3N8O2[M+H]+:589.2287,测量值：589.2286
制备实施例31
5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-050)的制备
使用与实施例1类似的方法，用1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑替换F3，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-050。
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)计算值：C24H16F3N7O2[M+H]+:492.44,测量值：492.46
制备实施例32
5-((6-(2-甲基-4-(吡咯烷-3-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-051)的制备
使用与实施例1类似的方法，用(2-甲基-4-(吡咯烷-3-基氨基)苯基)硼酸替换F3，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-051。
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)计算值：C31H26F3N7O2[M+H]+:586.60,测量值：586.31
制备实施例33
5-((6-(1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-052)的制备
使用与实施例1类似的方法，用(1H-吡唑-4-基)硼酸替换F3，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-052。
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)计算值：C23H14F3N7O2[M+H]+:478.42,测量值：478.51
制备实施例34
N-(4-氯苯基)-5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-053)的制备
使用与实施例1类似的方法，用1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-053。
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)计算值：C23H16ClN7O2[M+H]+:458.89,测量值：458.78
制备实施例35
5-((6-(4-(4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基]苯并[d]噁唑-2-胺(化合物YH-I-079)的制备
使用与实施例1类似的方法，用(4-(4-甲基哌嗪-1-基)甲基)苯基)硼酸替换F3，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-079。
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)计算值：C32H28F3N7O2[M+H]+:600.63,测量值：600.80
制备实施例36
(4-甲基哌嗪-1-基)(4-(4-((4-(三氟甲基)苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲酮(化合物YH-I-080)的制备
使用与实施例1类似的方法，用(4-(4-甲基哌嗪-1-羰基)苯基)硼酸替换F3，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤b、c、f、g和h，制备获得标题化合物YH-I-080。
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)计算值：C32H26F3N7O3[M+H]+:614.61,测量值：614.70
制备实施例37
N-(4-氯苯基)-5-((6-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-081)的制备
使用与实施例1类似的方法，用4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑-1-基)哌啶替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-081。
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)计算值：C27H23ClN8O2[M+H]+:527.99,测量值：528.06
制备实施例38
5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺(化合物YH-I-090)的制备
使用与实施例3类似的方法，用1-三氟甲基-4-异硫氰酸苯替换1-氯-4-异硫氰酸苯经过步骤j、f、g和h，制备获得标题化合物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)计算值：C25H18F3N7O2[M+H]+:506.47,测量值：506.51
制备实施例39
N-(4-氯苯基)-5-((6-(1,3-二甲基-1H-吡唑-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺(化合物YH-I-091)的制备
使用与实施例1类似的方法，用1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-091。
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)计算值：C24H18ClN7O2[M+H]+:472.91,测量值：472.99
制备实施例40
2-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)乙烷-1-醇(化合物YH-I-092)的制备
使用与实施例1类似的方法，用2-(3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑-1-基)乙烷-1-醇替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-092。
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)计算值：C26H22ClN7O3[M+H]+:516.97,测量值：517.21
制备实施例41
1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)-2-甲基丙-2-醇(化合物YH-I-093)的制备
使用与实施例1类似的方法，用1-(3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑-1-基)-2-甲基丙-2-醇替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-093。
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)计算值：C28H26ClN7O3[M+H]+:545.02,测量值：545.11
制备实施例42
1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)丙-2-醇(化合物YH-I-094)的制备
使用与实施例1类似的方法，用1-(3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑-1-基)丙-2-醇替换F3，经过步骤f、g和h，制备获得标题化合物YH-I-094。
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)计算值：C27H24ClN7O3[M+H]+:530.99,测量值：530.90
生物学实施例
生物学实施例1
ALK抑酶活性
将1体积的蛋白培养液进行4倍稀释，并加入50μM的二硫代苏糖醇，作为培养液待用。在384孔板上加入不同浓度的待测化合物(10μM为起始浓度，3倍稀释，10个浓度，复孔)。密封待检测的384孔板，1000g离心孔板1分钟。将2倍的ALK蛋白(测试蛋白)与1倍蛋白培养液混合均匀后，取2.5μL蛋白混合液加入到每个孔板中，1000g离心板30s，室温10min。同时，将2倍的底物和ATP与1倍蛋白培养液混合摇匀。将2.5μL底物、ATP混合液加入到孔板中，1000g离心板30s，密封孔板，室温反应1h。反应结束后，每孔加入5μL ADP-Glo试剂，室温反应40min。之后，加入10μL蛋白检测试剂，室温反应40min。最后，用Envision2104获取荧光数值，并计算出对应的蛋白抑制率。
表1.本公开的化合物对野生型ALK抑酶活性IC50(单位：nM)
表2.本公开的化合物对突变型ALK的抑酶活性IC50(单位：nM)

生物学实施例2
肿瘤细胞生长抑制活性
细胞毒实验(以对Kelly细胞毒性为例)：在供应商推荐的培养基(含10％胎牛血清)中培育Kelly细胞。在96孔培养板中加入细胞1×103/孔，在37℃、5％CO2环境下过夜培养。之后，在每孔中加入含不同浓度的待测试化合物(10μM为起始浓度，3倍稀释，10个浓度，复孔)的培养液，继续培养72h，经台盼蓝染色，活细胞达95％以上。在培养终止前4h，每孔加入MTT溶液(5mg/mL)20μL，继续孵育4h。弃培养液，加入二甲基亚砜150μL，振荡15min。选择570nm波长，用酶标仪测定吸光度值(A值)，并计算增殖抑制率。其中Kelly、SH-SY5Y、TGW、NCIH2228细胞的化合物孵化时间为72小时，SUDHL-1、SK-N-SH、KP-N-RT-BM-1细胞的化合物孵化时间为120小时。
表3. 1μM本公开的化合物的肿瘤细胞生长抑制率

表4.本公开的化合物抗肿瘤细胞生长的半数抑制浓度IC50(nM)
生物学实施例3
药代动力学性质测试
将本公开的化合物进行药代动力学性质测试，测试操作如下：将待测化合物溶解、配置成所需浓度的储液备用。然后，将雄性健康小鼠进行分组，每组3只。小鼠先禁食一晚，自由饮水，之后再进行喂食，4小时后给药。给药剂量如下表。全血样本在指定时间点(0.083h、0.25h、0.5h、1h、2h、4h、8h、24h)经眼眶静脉采集,采取30μL流入肝素钠抗凝管中样本4000rcf/4℃离心5分钟后取上层血浆样本。最后利用LC-MS/MS对样本进行数据采集，经过数据处理后，获得待测化合物的药代动力学参数。
表5和表6给出了本公开的化合物YH-I-001的血药浓度-时间数据。
表5.

注：NA＝Not Applicable
表6.


注：NA＝Not Applicable
NR＝Not Reportable
图2和图3给出了本公开的化合物YH-I-001的血药浓度-时间曲线。
生物学实施例4
体内抗肿瘤测试
将制备得到的化合物YH-I-001、购买得到的抑制剂Crizotinib、Ceritinib的进行体内抗肿瘤活性分析，提供溶剂作为对照组试验。KELLY(brain,neuroblastoma，购买于ECACC,Cat No.:92110411,Lot No.14A023)细胞体外单层培养，培养条件为RPMI-1640培养基中加2mM Glut胺，10％热灭活胎牛血清，37℃无CO2培养。一周两次用胰酶-EDTA进行消化处理传代。当细胞呈指数生长期时，收取细胞，计数，接种。将含5×105个KELLY细胞的0.2mL细胞悬液(细胞悬于1640：Martigel＝1:1)皮下接种于每只小鼠的右后背。在接种后第22天，肿瘤平均体积达到150.50mm3时开始分组给药。
实验指标是考察肿瘤生长是否可以被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5×a×b2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用T/C(％)评价。T/C％＝TRTV/CRTV×100％(TRTV：治疗组RTV；CRTV：阴性对照组 RTV)。相对肿瘤体积RTV的计算公式为RTV＝Vt/V1。其中V1为分笼给药时(即Day 1)测量所得肿瘤体积，Vt为第t天测量时的肿瘤体积。肿瘤体积疗效用TGI评价，TGI(％)＝(1-(TVtreatment-Dn-TVtreatment-D1)/(TVControl-Dn-TVControl-D1))×100％，TVControl：对照组瘤体积，TVTreatment：治疗组瘤体积。肿瘤重量的疗效用TGI％评价，瘤重抑制率(TGI)％＝(TWC-TWT)/TWC×100％，TWC：对照组瘤重，TWT：治疗组瘤重。
表7.药物的配制方法表

表8.KELLY荷瘤鼠肿瘤抑制率(TGI)对比
在本公开中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。
从前述中可以理解，尽管为了示例性说明的目的描述了本公开的具体实施方案，但是在不偏离本公开的精神和范围的条件下，本领域所述技术人员可以作出各种变形或改进。这些变形或修改都应落入本公开所附权利要求的范围。

Claims (38)

  1. 通式(I)所示的化合物，及其药物可接受的盐：
    其中：
    R1选自卤素、任意取代的芳基或任意取代的杂芳基；
    R2选自任意取代的烃基、任意取代的芳基或任意取代的环烃基；以及
    X和Y各自独立地选自O、S或N。
  2. 如权利要求1所述的通式(I)所示的化合物，及其药物可接受的盐，其中R1选自卤素、未取代的芳基、任意取代的烷基取代的芳基、烷氧基取代的芳基、卤素取代的芳基、氰基取代的芳基、任意取代的氨基取代的芳基、磺酰胺基取代的芳基、未取代的杂芳基、任意取代的烷基取代的杂芳基、烷氧基取代的杂芳基、氰基取代的杂芳基、任意取代的氨基取代的杂芳基或杂环烷基取代的杂芳基。
  3. 如权利要求1或2所述的通式(I)所示的化合物，及其药物可接受的盐，其中R1选自卤素、未取代的苯基、任意取代的烷基取代的苯基、任意取代的杂环烷基取代的任意取代的烷基取代的苯基、烷氧基取代的苯基、卤素取代的苯基、氰基取代的苯基、任意取代的氨基取代的苯基、磺酰胺基取代的苯基、未取代的吡啶基、未取代的噻吩基、未取代的嘧啶基、未取代的吡唑基、任意取代的烷基取代的吡唑基、氨基取代的烷基取代的吡唑基、烷基取代的氨基取代的烷基取代的吡唑基、烷氧基取代的吡唑基、氰基取代的吡唑基、杂环烷基取代的氨基取代的吡唑基或杂环烷基取代的吡唑基。
  4. 如权利要求1至3中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R1选自卤素、未取代的芳基、烷基取代的芳基、卤素取代的烷基取代的芳基、烷基取代的杂环烷基取代的烷基取代的芳基、烷基取代的杂环烷基取代的氧代烷基取代的芳基、烷氧基取代的芳基、卤素取代的芳基、氰基取代的芳基、烷基取代的氨基取代的芳基、任意取代的杂环烷基取代的氨基取代的芳基、磺酰胺基取代的苯基、未取代的杂芳基、任意取代的烷基取代的杂芳基、任意取代的氨基取代的烷基取代的杂芳基、烷氧基取代的杂芳基、氰基取代的杂芳基、杂环烷基取代的氨基取代的杂芳基或杂环烷基取代的杂芳基。
  5. 如权利要求1至4中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R1选自碘、苯基、甲苯基、异丙基苯基、三氟甲基苯基、4-(4-甲基哌嗪-1-基)甲基苯基、4-(4-甲基哌嗪-1-基)氧代甲基苯基、甲氧基苯基、异丙氧基苯基、溴苯基、氰基取代的苯基、二甲氨基苯基、2-甲基-4-哌啶基取代的氨基取代的苯基、2-甲基-4-(N-甲基哌啶基)-氨基取代的苯基、2-甲基-4-四氢吡咯基取代的氨基取代的苯基、2-甲基-4-(N-甲基四氢吡咯基)-氨基取代的苯基、2-甲基-4-磺酰胺基取代的苯基、吡啶基、噻吩基、嘧啶基、吡唑基、N-甲基吡唑基、氰基吡唑基、异丙氧基吡唑基、二甲基吡唑基、N-(羟乙基)二甲基吡唑基、N-(2-羟基-2-甲基丙基)二甲基吡唑基、N-(2-羟基丙基)二甲基吡唑基、N-吡喃基氨基取代的N-甲基吡唑基、N-哌啶基取代的吡唑基、N-哌啶基取代的二甲基吡唑基、氰基-氨甲基取代的N-甲基吡唑基、氰基-N-甲氨甲基取代的N-甲基吡唑基或氰基-N-吡喃基氨基取代的N-甲基吡唑基。
  6. 如权利要求1至5中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R1选自：

  7. 如权利要求1至6中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R2选自任意取代的烷基、任意取代的芳基、任意取代的杂芳基、任意取代的环烃基或任意取代的芳基并杂环烃基。
  8. 如权利要求1至7中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R2选自任意取代的烷基、任意取代的芳基、任意取代的杂芳基、任意取代的环烷基或任意取代的苯并杂环烷基。
  9. 如权利要求1至8中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R2选自未取代的烷基、卤素取代的芳基、任意取代的烷基取代的芳基、任意取代的烷氧基取代的芳基、未取代的环烷基、未取代的苯并杂环烷基或卤素取代的苯并杂环烷基。
  10. 如权利要求1至9中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R2选自未取代的烷基、卤素取代的苯基、任意取代的烷基取代的苯基、任意取代的烷氧基取代的苯基、任意取代的吡啶基、任意取代的吡咯基、任意取代的吡唑基、任意取代的噻唑基、任意取代的噁唑基、任意取代的噻吩基、未取代的环烷基、未取代的苯并[1,3]二氧戊环基或卤素取代的苯并[1,3]二氧戊环基。
  11. 如权利要求1至10中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R2选自己基、3,4-二氯苯基、4-氯苯基、4-异丙基的苯基、3,5-三氟甲基苯基、4-三氟甲基苯基、4-三氟甲氧基苯基、环戊烷基或环己烷基。
  12. 如权利要求1至11中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中R2选自：

  13. 如权利要求1至12中任一权利要求所述的通式(I)所示的化合物，及其药物可接受的盐，其中X为N，Y选自O或S；或者，X为O，Y为N。
  14. 化合物，及其药物可接受的盐，其中所述化合物选自：
    N-(4-氯苯基)-5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(p-甲苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(4-甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    5-((6-(4-溴苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-氯苯基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(噻吩-2-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡 咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲腈；
    N-(4-氯苯基)-5-((6-(4-(三氟甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(2-异丙基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(4-(二甲氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(2-异丙氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(3,5-双(三氟甲基)苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(3,4-二氯苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲氧基)苯基)苯并[d]噁唑-2-胺；
    N-(4-异丙基苯基)-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-环戊基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-环己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-己基-5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-碘-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑 -2-胺；
    5-((6-(2-甲基-4-(哌啶-4-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-苯基苯并[d]噁唑-2-胺；
    5-((6-(2-甲基-4-((1-甲基哌啶-4-基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    5-((6-(3,5-二甲基-1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    5-((6-(3,5-二甲基-1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    5-((6-(2-甲基-4-(吡咯烷-3-基氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    5-((6-(1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    5-((6-(4-(4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基]苯并[d]噁唑-2-胺；
    (4-甲基哌嗪-1-基)(4-(4-((4-(三氟甲基)苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲酮；
    N-(4-氯苯基)-5-((6-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    5-((6-(3,5-二甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-N-(4-(三氟甲基)苯基)苯并[d]噁唑-2-胺；
    N-(4-氯苯基)-5-((6-(1,3-二甲基-1H-吡唑-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯并[d]噁唑-2-胺；
    2-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)乙烷-1-醇；
    1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d] 嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)-2-甲基丙-2-醇；以及
    1-(4-(4-((2-((4-氯苯基)氨基)苯并[d]噁唑-5-基)氧基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基-1H-吡唑-1-基)丙-2-醇。
  15. 药物组合物，其包含权利要求1至13中任一权利要求所述的通式(I)所示的化合物或其药物可接受的盐，或权利要求14所述的化合物或其药物可接受的盐，以及药物可接受的辅料。
  16. 如权利要求15所述的药物组合物，其被制备为胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、凝胶剂、胶囊剂、气雾剂或栓剂。
  17. 制备通式(Ia)所示的化合物的方法，
    其包括进行如下所示的反应：
    其中：
    X1和Y1各自独立地选自氨基、巯基或羟基；
    X和Y各自独立地选自O、S或N；以及
    R2选自任意取代的烃基、任意取代的芳基或任意取代的环烃基。
  18. 如权利要求17所述的方法，其中在碱和强氧化剂的存在下进行所述反应。
  19. 如权利要求18所述的方法，其中所述碱选自碱金属盐、有机碱或其任意混合物；碱金属盐优选碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、醇锂、醇钠、醇钾或其任意混合物，其中醇优选甲醇、乙醇、 叔丁醇；有机碱优选三乙胺、N,N-二异丙基乙胺(DIPEA)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)或其任意混合物。
  20. 如权利要求18或19所述的方法，其中所述强氧化剂选自高碘酸盐、重铬酸盐、氯铬酸吡啶或其任意混合物，优选选自高碘酸钠、高碘酸钾、重铬酸钾、重铬酸钠、氯铬酸吡啶或其任意混合物。
  21. 制备通式(Ic)所示的化合物的方法，
    其包括进行如下所示的反应：
    其中：
    R1选自卤素、任意取代的芳基或任意取代的杂芳基；
    B选自硼酸或硼酸酯。
  22. 如权利要求21所述的方法，其中在钯催化剂和碱存在下进行所述反应。
  23. 如权利要求22所述的方法，其中所述钯催化剂选自钯、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2、Pd(dppf)Cl2或其任意混合物。
  24. 如权利要求22或23所述的方法，其中所述碱选自碱金属盐、有机碱或其任意混合物；碱金属盐优选碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、醇锂、醇钠、醇钾或其任意混合物，其中醇优选甲醇、乙醇、叔丁醇；有机碱优选三乙胺、N,N-二异丙基乙胺(DIPEA)、1,4-二 氮杂二环[2.2.2]辛烷(DABCO)或其任意混合物。
  25. 制备通式(Id)所示的化合物的方法，
    其包括将通式(Ic)所示的化合物与通式(Ib)所示的化合物进行反应：
  26. 如权利要求25所述的方法，其中在碱的存在下进行所述方法。
  27. 如权利要求26所述的方法，其中所述碱选自碱金属盐、有机碱或其任意混合物，优选氢化钠、氢氧化钠、氢氧化钾、磷酸钾、三乙胺、N,N-二异丙基乙胺(DIPEA)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)或其任意混合物。
  28. 抑制酪氨酸激酶(tyrosine kinase,TK)的方法，其包括将酪氨酸激酶与抑制有效量的权利要求1至13中任一权利要求所述的通式(I)所示的化合物或其药物可接受的盐、权利要求14所述的化合物或其药物可接受的盐或权利要求15或16所述的药物组合物接触。
  29. 治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的方法，其包括向需要所述方法的个体给予治疗或预防有效量的权利要求1至13中任一权利要求所述的通式(I)所示的化合物或其药物可接受 的盐、权利要求14所述的化合物或其药物可接受的盐或权利要求15或16所述的药物组合物。
  30. 如权利要求29所述的方法，其中所述个体为哺乳动物，优选人类。
  31. 如权利要求29或30所述的方法，其中所述酪氨酸激酶(tyrosine kinase,TK)选自间变性淋巴瘤激酶(ALK)、ROS1癌基因受体酪氨酸激酶(ROS1)、表皮生长因子受体(EGFR)、血小板生长因子受体(PDGF)、ABL酪氨酸激酶、成纤维细胞生长因子受体(FGFR)、白介素受体相关激酶(IRAK)、人络氨酸激酶受体(FLT)、V-raf小鼠肉瘤病毒癌基因同源物B(BRAF)、血管内皮生长因子受体2(KDR)、血管内皮生长因子(VEGFR)、转染重排激酶(RET)、布鲁顿酪氨酸激酶(BTK)、B-淋巴酪氨酸激酶(BLK)、胞质酪氨酸蛋白激酶(BMX)、人类表皮生长因子受体2(HER2)、人类表皮生长因子受体4(HER4)、异柠檬酸脱氢酶(IDH)、盘状结构域受体1(DDR1)、白介素2诱导的T细胞激酶(ITK)和人蛋白酪氨酸激酶4(TXK)。
  32. 如权利要求29至31中任一权利要求所述的方法，其中所述疾病或疾病状态选自淋巴瘤、母细胞瘤、肉瘤、神经内分泌肿瘤、类癌肿瘤、胃泌素瘤、胰岛细胞癌、间皮瘤、神经鞘瘤、听神经瘤、脑膜瘤、腺癌、黑素瘤、白血病、淋巴样恶性肿瘤、肺癌、肺鳞癌、腹膜癌、胃癌、肠癌、胰腺癌、成胶质细胞瘤、子宫颈癌、卵巢癌、肝癌、膀胱癌、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肛门癌、阴茎癌、梅克尔细胞癌、食管癌、胆道肿瘤、头颈部癌和血液恶性肿瘤。
  33. 如权利要求29至32中任一权利要求所述的方法，其还包括向所述个体给予其他活性剂。
  34. 如权利要求33所述的方法，其中所述活性剂选自氮芥、氮丙啶、甲基蜜胺、磺酸烷基酯、亚硝基脲、三氮烯、叶酸类似物、嘧啶类似物、嘌呤类似物、长春花生物碱、表鬼臼毒素、抗生素、拓扑异构酶抑制剂、抗癌疫苗、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、安波霉素、醋酸阿美蒽醌、氨鲁米特、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林霉素、阿扎胞苷、阿扎替哌、阿佐霉素、巴马司他、苯佐替哌、比卡鲁胺、盐酸比生群、甲磺酸双萘法德、比折来新、硫酸博来霉素、白消安、放线菌素C、卡普睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡柔比星、苯丁酸氮芥、西罗霉素、克拉屈滨、甲磺酸克立那托、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、盐酸柔红霉素、地西他宾、多西他塞、多柔比星、盐酸多柔比星、屈洛昔芬、盐酸表柔比星、盐酸依索比星、雌莫司汀、依他消唑、依托泊苷、氟尿苷、氟尿嘧啶、氟西他滨、吉西他宾、盐酸依达比星、异环磷酰胺、白介素II、干扰素α-2a、干扰素α-2b、盐酸依立替康、来曲唑、巯嘌呤、甲氨蝶呤、氯苯氨啶、丝列霉素、米托蒽酮、紫杉醇、丙卡巴肼、赛替哌、长春碱、长春新碱、血管生成抑制剂、喜树碱、地塞米松、阿司匹林、乙酰氨基酚、吲哚美辛、布洛芬、酮洛芬、美洛昔康、皮质类固醇和肾上腺皮质类固醇。
  35. 用于抑制酪氨酸激酶(tyrosine kinase,TK)的权利要求1至13中任一权利要求所述的通式(I)所示的化合物及其药物可接受的盐或权利要求14所述的化合物及其药物可接受的盐。
  36. 用于治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的权利要求1至13中任一权利要求所述的通式(I)所示的化合物及其药物可接受的盐或权利要求14所述的化合物及其药物可接受的盐。
  37. 权利要求1至13中任一权利要求所述的通式(I)所示的化合物及其药物可接受的盐或权利要求14所述的化合物及其药物可接受的盐在制备用于抑制酪氨酸激酶(tyrosine kinase,TK)的药物中的用途。
  38. 权利要求1至13中任一权利要求所述的通式(I)所示的化合物及其药物可接受的盐或权利要求14所述的化合物及其药物可接受的盐在制备用于治疗或预防酪氨酸激酶(tyrosine kinase,TK)介导的疾病或疾病状态的药物中的用途。
PCT/CN2023/127058 2022-10-27 2023-10-27 嘧啶并吡咯类似物 WO2024088377A1 (zh)

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WO2004085425A1 (en) * 2003-03-21 2004-10-07 Amgen Inc Fused azoles such as 2,5-disubstituted benzimidazoles, benzoxazoles and benzothiazoles as kinase inhibitors
WO2010032461A1 (ja) * 2008-09-17 2010-03-25 武田薬品工業株式会社 含窒素縮合環化合物
CN106459044A (zh) * 2014-06-03 2017-02-22 吉利德科学公司 Tank‑结合激酶抑制剂化合物
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