WO2021143821A1 - 稠合杂芳基类衍生物、其制备方法及其在医药上的应用 - Google Patents

稠合杂芳基类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2021143821A1
WO2021143821A1 PCT/CN2021/072090 CN2021072090W WO2021143821A1 WO 2021143821 A1 WO2021143821 A1 WO 2021143821A1 CN 2021072090 W CN2021072090 W CN 2021072090W WO 2021143821 A1 WO2021143821 A1 WO 2021143821A1
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group
general formula
enantiomer
pharmaceutically acceptable
cycloalkyl
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PCT/CN2021/072090
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English (en)
French (fr)
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李心
曾长根
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2021143821A1 publication Critical patent/WO2021143821A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B47/00—Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused heteroaryl derivative represented by the general formula (I-1), a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, in particular Use as an ATR kinase inhibitor and use in the preparation of drugs for the treatment and prevention of hyperproliferative diseases.
  • Homologous recombination repair is the main method of repairing DNA double-strand breaks.
  • the homologous sequence of the undamaged sister chromatids is used as its repair template to copy the damaged DNA sequence to accurately repair the DNA.
  • This repair method mainly occurs in the G2 and S phases of the cell.
  • ATR is a key enzyme in the repair pathway of homologous recombination and belongs to the PIKK family.
  • RPA replication protein A
  • ATR is activated and phosphorylates downstream proteins Chk1 and SMARCAL to regulate cell cycle checkpoints and cause cell cycle arrest; guarantee; Stability of damaged DNA; increase the dNTP concentration to promote repair of DNA damage.
  • ATR pathway The repair of DNA damage in the S phase of the cell cycle is mainly completed by the ATR pathway, indicating that ATR is very important to ensure cell proliferation.
  • the analysis results of clinical tumor samples showed that in a variety of tumor tissues, such as gastric cancer, liver cancer, colorectal cancer, ovarian cancer, pancreatic cancer, etc., elevated ATR expression levels were observed. And in patients with ovarian cancer and pancreatic cancer, high levels of ATR are often accompanied by lower survival rates. This shows that ATR is an important tumor treatment target.
  • ATR inhibitors include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889 and WO2014140644.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt:
  • G 1 and G 2 are the same or different, and each independently is CH or N, provided that G 1 and G 2 are not CH at the same time;
  • A is heteroaryl or heterocyclyl
  • Y and Z are the same or different, and are each independently O or NH;
  • R 1 and R 2 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , Heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 1 and R 2 form a cycloalkyl group or a heterocyclic group together with the carbon atom to which they are connected;
  • R 3 and R 4 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , Heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 5 is alkyl or haloalkyl
  • p, q and r are the same or different, and each independently is 0, 1, 2 or 3;
  • n and n are the same or different, and each independently is 0, 1, 2, 3, 4, or 5.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I-1), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt:
  • G 1 and G 2 are the same or different, and each independently is CH or N, provided that G 1 and G 2 are not CH at the same time;
  • A is heteroaryl or heterocyclyl
  • Y and Z are the same or different, and are each independently O or NH;
  • R 1 , R 2 , R 1'and R 2' are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, Cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optional Substituted by one or more selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl Substitution;
  • R 1 and R 2 , R 1'and R 2' together with the connected carbon atoms form a cycloalkyl group or a heterocyclic group;
  • R 3 and R 4 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , Heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 5 is alkyl or haloalkyl
  • p, q and r are the same or different, and each independently is 0, 1, 2 or 3;
  • n and n are the same or different, and each independently is 0, 1, 2, 3, 4, or 5.
  • the compound represented by the general formula (I) or (I-1) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (II) or tautomers, mesoisomers, racemates, Enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • G 1 , G 2 , R 1 , R 2 , R 3 , R 4 , R 5 , Y, Z, m, and n are as defined in the general formula (I) or (I-1).
  • the compound represented by the general formula (I), (I-1) or (II) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (III) or tautomers, mesoisomers, exoisomers Racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R 1 , R 2 , R 3 , Y, Z and n are as defined in the general formula (I), (I-1) or (II).
  • R 1 and R 2 together with the connected carbon atoms form a cycloalkyl group or a heterocyclic group, preferably a 3-6 membered cycloalkyl group, more preferably a cyclopropyl group.
  • R 4 is selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; more preferably, R 4 is a hydrogen atom.
  • the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein G 1 and G 2 are both N; Y and Z are O or NH; R 1 and R 2 are the same or different, and each independently is a hydrogen atom or C 1 -6 alkyl group, or R 1 and R 2 together form a cyclopropyl group; R 3 and R 4 are both hydrogen atoms; R 5 is a C 1-6 alkyl group; m and n are both 1.
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt,
  • X is halogen; preferably Cl;
  • G 1 and G 2 are the same or different, and each independently is CH or N, provided that G 1 and G 2 are not CH at the same time;
  • Y and Z are the same or different, and are independently O or NH;
  • R 1 and R 2 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , Heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 1 and R 2 form a cycloalkyl group or a heterocyclic group together with the carbon atom to which they are connected;
  • R 4 is the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocycle Group, aryl group and heteroaryl group; wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from halogen, alkyl group, alkoxy group , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 5 is alkyl or haloalkyl
  • p, q and r are the same or different, and each independently is 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4, or 5.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (I-1A) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt,
  • X is halogen; preferably Cl;
  • G 1 and G 2 are the same or different, and each independently is CH or N, provided that G 1 and G 2 are not CH at the same time;
  • Y and Z are the same or different, and are independently O or NH;
  • R 1 , R 2 , R 1'and R 2' are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, Cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optional Substituted by one or more selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl Substitution;
  • R 1 and R 2 , R 1'and R 2' together with the connected carbon atoms form a cycloalkyl group or a heterocyclic group;
  • R 4 is the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocycle Group, aryl group and heteroaryl group; wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from halogen, alkyl group, alkoxy group , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 5 is alkyl or haloalkyl
  • p, q and r are the same or different, and each independently is 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4, or 5.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt,
  • X is halogen; preferably Cl;
  • G 1 , G 2 , R 1 , R 2 , R 4 , R 5 , Y, Z, and m are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt,
  • X is halogen; preferably Cl;
  • R 1 , R 2 , Y and Z are as defined in the general formula (III).
  • the general formulas (IA), (I-1A), (IIA) and (IIIA) are intermediates for preparing the compounds of the general formulas (I), (I-1), (II) and (III) of the present disclosure.
  • Typical intermediate compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably Cl;
  • R b is
  • G 1 , G 2 , R 1 , R 2 , R 3 , R 4 , R 5 , Y, Z, A, p, q, r, m, and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably Cl;
  • R b is
  • G 1 , G 2 , R 1 , R 2 , R 1 ' , R 2' , R 3 , R 4 , R 5 , Y, Z, A, p, q, r, m and n are as in the general formula (I- 1) as defined in.
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably Cl;
  • R b is
  • G 1 , G 2 , R 1 , R 2 , R 3 , R 4 , R 5 , Y, Z, m, and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably Cl;
  • R b is
  • R 1 , R 2 , R 3 , Y, Z, and n are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the compound represented by the general formula (I-1) of the present disclosure or its tautomers, mesosomes, racemates, Enantiomers, diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the compound represented by the general formula (I-1) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or its mixture form or The use of the pharmaceutically acceptable salt or the pharmaceutical composition containing the same in the preparation of a medicament for inhibiting ATR kinase.
  • the present disclosure further relates to the compound represented by the general formula (I-1) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or its mixture form or The use of the pharmaceutically acceptable salt or the pharmaceutical composition containing the same in the preparation of a medicament for the treatment or prevention of hyperproliferative diseases.
  • the present disclosure further relates to the compound represented by the general formula (I-1) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or its mixture form or Use of its pharmaceutically acceptable salt or pharmaceutical composition containing it in the preparation of a medicament for treating or preventing tumors.
  • the present disclosure further relates to the compound represented by the general formula (I-1) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or its mixture form or Use of its pharmaceutically acceptable salt or pharmaceutical composition containing it in the preparation of a medicament for treating tumors.
  • the present disclosure also relates to a method for inhibiting ATR kinase, which comprises administering a therapeutically effective amount of a compound represented by the general formula (I-1) or its tautomer, mesosome, and racemate to a desired patient , Enantiomers, diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method for treating or preventing hyperproliferative diseases, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I-1) or its tautomer, meso, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method for treating or preventing tumors, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I-1) or its tautomers, mesosomes, racemics Isomers, enantiomers, diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure further relates to a compound represented by the general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as a medicine.
  • the present disclosure also relates to the compound represented by the general formula (I-1) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or its mixture form or Its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used as an ATR kinase inhibitor.
  • the present disclosure also relates to the compound represented by the general formula (I-1) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or its mixture form or Its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used for the treatment or prevention of hyperproliferative diseases.
  • the present disclosure further relates to the compound represented by the general formula (I-1) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or its mixture form or Its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used for the treatment of tumors.
  • the tumor described in the present disclosure is selected from melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, nerves Blastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.
  • the active compound can be formulated into a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer in a single dose.
  • the unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.
  • the dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • a suitable unit dose may be 0.1-1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickeners.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure.
  • a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be based on the traditional The treatment plan to verify.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • alkyl group 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently selected from the group consisting of H atom, D atom, halogen, and alkane. Group, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, One or more substituents in the heteroaryl group.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbons Atom, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aromatic
  • substituents in the group heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.
  • alkenyl refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above.
  • Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, and halogenated alkoxy groups.
  • substituents in the group cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl .
  • alkynyl refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, and a halogenated alkoxy group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (E.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 Five-membered and six-membered/6-membered bicyclic alkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro ring, fused ring and bridged ring) fused on an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; indanyl and tetrahydronaphthyl are preferred.
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group.
  • alkoxy refers to -O-(alkyl), where the definition of alkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from D atom, halogen, alkoxy, halogenated alkyl, and halogenated alkoxy Group, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, sulfur, S( O) or S(O) 2 heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • It preferably contains 3 to 12 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (for example, 1, 2, 3, and 4) are hetero Atom; more preferably contains 3 to 8 (such as 3, 4, 5, 6, 7 and 8) ring atoms, of which 1-3 (such as 1, 2 and 3) are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on.
  • Polycyclic heterocyclic groups include spiro, condensed, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur, and S (O) or S(O) 2 heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O) 2 and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms It is a heteroatom selected from nitrogen, oxygen, sulfur, S(O) or S(O) 2 , and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent
  • the rings linked together in the structure are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl.
  • the aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :
  • Aryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 (e.g. 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups have one residue derived by removing one hydrogen atom from the parent ring atom, or two residues derived from the same or two different ring atoms of the parent. Residues derived from three hydrogen atoms, namely "divalent cycloalkyl", “divalent heterocyclic group", “arylene”, and "heteroarylene".
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably tetrahydropyranyl.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • mercapto refers to -SH.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O ) O-, wherein alkyl and cycloalkyl are as defined above.
  • THP is tetrahydropyranyl.
  • the compounds of the present disclosure include isotopic derivatives thereof.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • the present disclosure also includes compounds of general formula in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated compounds of the general formula. Commercially available deuterated starting materials can be used when preparing the deuterated form of the general formula compound, or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated borane. Tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in a group, preferably 1 to 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents.
  • substituents Those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without too much effort.
  • an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure, which is safe and effective when used in mammals, and has due biological activity.
  • the salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • pharmaceutically acceptable refers to these compounds, materials, compositions and/or dosage forms, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or Other problems or complications have a reasonable benefit/risk ratio and are effective for the intended use.
  • the present disclosure adopts the following technical solutions.
  • the preparation method of the salt used includes the following steps:
  • X is halogen; preferably Cl;
  • R b is
  • G 1 , G 2 , R 1 , R 2 , R 3 , R 4 , R 5 , Y, Z, A, p, q, r, m, and n are as defined in the general formula (I).
  • the preparation method of the salt used includes the following steps:
  • X is halogen; preferably Cl;
  • R b is
  • G 1 , G 2 , R 1 , R 2 , R 3 , R 4 , R 5 , Y, Z, m, and n are as defined in the general formula (II).
  • the preparation method of the salt used includes the following steps:
  • X is halogen; preferably Cl;
  • R b is
  • R 1 , R 2 , R 3 , Y, Z, and n are as defined in the general formula (III).
  • the preparation method of the pharmaceutically acceptable salt includes the following steps:
  • X is halogen; preferably Cl;
  • R b is
  • G 1 , G 2 , R 1 , R 2 , R 1 ' , R 2' , R 3 , R 4 , R 5 , Y, Z, A, p, q, r, m and n are as in the general formula (I- 1) as defined in.
  • the reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine.
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate , Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
  • the catalysts described in the above synthesis scheme include, but are not limited to, palladium/carbon, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone) palladium, chlorine (2-dicyclohexylphosphino) -2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, 1,1'- Bis(dibenzylphosphorus)dichloroferrocene palladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1'-bis
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatograph.
  • HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.
  • TLC thin layer chromatography
  • the crude compound 1d (4.9g, 24.1mmol) and urea (4.4g, 72.3mmol) were mixed, heated to 160°C and stirred for 5 hours.
  • the reaction solution was lowered to room temperature, 30 mL of methanol was added, the obtained solid was crushed and spin-dried, and dried in vacuo to obtain the crude title compound 1e (4.77 g), which was directly used in the next step without purification.
  • the crude compound 1e (4.77g, 24.1mmol) was dissolved in 40mL of toluene, 25mL of phosphorus oxychloride and N,N-diisopropylethylamine (3.2g, 48.1mmol) were added, and the mixture was stirred at 120°C for 4 hours.
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • the residue obtained was added dropwise to ice water, and ethyl acetate was added for extraction (50 mL ⁇ 3).
  • Ethyl 1-((3-ethoxy-3-oxopropyl)thio)cyclopropane-1-carboxylate 3b was added to compound 1a (9.79g, 73.0mmol) and 2,4-dibromo-2- Ethyl methyl butyrate 3a (20 g, 73.0 mmol) was dissolved in 300 mL of anhydrous and N,N-dimethylformamide, anhydrous potassium carbonate (20.2 g, 146.0 mmol) was added, and the mixture was stirred for 14 hours.
  • the crude compound 3c (9.1 g, 24.1 mmol) was mixed with urea (8.2 g, 136.5 mmol), and the mixture was heated to 160° C. and stirred for reaction for 5 hours.
  • the reaction solution was cooled to room temperature, 30 mL of methanol was added, the obtained solid was mashed and spin-dried, and dried in vacuo to obtain the crude title compound 3d (8.9 g), which was directly used in the next step without purification.
  • the crude compound 3d (8.9 g, 45.4 mmol) was dissolved in 40 mL of toluene, 42 mL of phosphorus oxychloride and N,N-diisopropylethylamine (17.6 g, 136.2 mmol) were added, and the mixture was stirred at 120°C for 4 hours.
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • the residue obtained was added dropwise to ice water, and ethyl acetate was added for extraction (100 mL ⁇ 3).
  • Test Example 1 The inhibitory effect of the compound of the present disclosure on ATR enzyme
  • ATR enzyme Eurofins Pharma Discovery Services, 14-953-M
  • Microplate reader (BMG, PHERAsta)
  • ATR enzyme 1nM, P53 protein 50nM, 7.435 ⁇ M ATP and different concentrations (first concentration 1 ⁇ M, 3-fold dilution in 11 concentrations, the dilution solvent is 25mM HEPES pH8.0, 0.01% Brij-35, 1% glycerol)
  • the compound of the present disclosure was mixed and incubated at room temperature for 2 hours, and then a stop solution (12.5mM HEPES, 250mM EDTA) was added and mixed, and then 0.42ng/well of labeled europium cryptate anti-phospho-P53 protein antibody and 25ng/well of link d2 were added.
  • Anti-GST antibody After overnight incubation at room temperature, PHERAstar was used to detect the 620nm and 665nm fluorescence signals. The data is processed using GraphPad software.
  • the inhibitory activity of the compounds of the present disclosure on ATR enzyme can be determined by the above test, and the measured IC 50 value is shown in Table 1.
  • the compound of the present disclosure has good inhibitory activity on ATR enzyme.
  • Test Example 2 Selectivity test of the compound of the present disclosure on ATR enzyme
  • Microplate reader (BMG, PHERAsta)
  • the present disclosure of ATM enzyme 1nM, P53 protein 30nM, 11 ⁇ M ATP and different concentrations (initial concentration 10 ⁇ M, 3-fold dilution with 11 concentrations, solvent 25mM HEPES pH8.0, 0.01% Brij-35, 1% glycerol)
  • the compounds were mixed, incubated at room temperature for 2 hours, and then added stop solution (12.5mM HEPES, 250mM EDTA) and mixed well, then 0.42ng/well of labeled europium cryptate anti-phospho-P53 protein antibody and 25ng/well of linked d2 antibody were added. GST antibody. After overnight incubation at room temperature, PHERAstar was used to detect the 620nm and 665nm fluorescence signals. The data is processed using GraphPad software.
  • the inhibitory IC 50 values of the compounds of the present disclosure on ATM enzymes are shown in Table 2.
  • DNA-PK enzyme Eurofins Pharma Discovery Services, 14-950-M
  • Microplate reader (BMG, PHERAsta)
  • DNA-PK enzyme 0.02nM, P53 protein 50nM, 7.3 ⁇ M ATP and different concentrations (the first concentration is 10 ⁇ M, 3-fold dilution is 11 concentrations, the solvent is 25mM HEPES pH8.0, 0.01% Brij-35, 1% glycerol ), incubate for 1 hour at room temperature, then add stop solution (12.5mM HEPES, 250mM EDTA) and mix well, then add 0.42ng/well of labeled europium cryptate anti-phospho-P53 protein antibody and 25ng/well Anti-GST antibody linked to d2. After overnight incubation at room temperature, PHERAstar was used to detect the 620nm and 665nm fluorescence signals. The data is processed using GraphPad software. The inhibitory IC 50 values of the compounds of the present disclosure on DNA-PK enzyme are shown in Table 2.
  • PIK3CA/PIK3R1 p110alpha/p85alpha kinase (Invitrogen, PV4788)
  • PIP2 PS lipid substrate (Invitrogen, PV5100)
  • Microplate reader (BMG, PHERAstar)
  • the final concentration of PI3K enzyme is 0.625nM, and different concentrations (the initial concentration of 10 ⁇ M, 3-fold dilution of 10 concentrations, the solvent is 10mM Tris-HCL pH 7.5, 50mM NaCl, 3mM MgCl 2 , 0.05% CHAPS, 100 ⁇ M) small molecule compounds
  • the solvent is 10mM Tris-HCL pH 7.5, 50mM NaCl, 3mM MgCl 2 , 0.05% CHAPS, 100 ⁇ M
  • PIP2:PS lipid substrate final concentration 50 ⁇ M
  • 1x ATP final concentration 50 ⁇ M
  • detection reagent ADP-Glo Promega, V9102
  • the detection reagent of the ADP-Glo TM Kinase Assay Kit was added, and incubated for 40 minutes at room temperature.
  • the fluorescence signal was detected by PHERAstar, and the data was processed by GraphPad software. Table 2 shows the IC 50 value
  • MTOR recombinant human protein (Invitrogen, PV4753)
  • the final concentration of mTOR enzyme is 3nM, and the compounds of the present disclosure of different concentrations (the initial concentration of 10 ⁇ M, 3-fold dilution in 10 concentrations, the solvent is 50mM HEPES pH 7.5 , 10mM MgCl 2 , 1mM EGTA, 2mM DTT, 0.01% Tween-20) Mix, then add ATP and ULight-4E-BP1 peptide (final concentration of 10 ⁇ M ATP and 50nM substrate respectively), mix and incubate at room temperature for 2 hours, then add a final concentration of 8mM EDTA stop solution to mix, incubate at room temperature for 5 minutes, add Eu -Anti-phosphorylated-4E-BP1 (Thr37/46) antibody (final concentration 2nM), incubate for 1 hour at room temperature.
  • the EnVision multi-mode detection platform was used to detect HTRF with an excitation wavelength of 320nm and an emission wavelength of 665nm.
  • the data is processed using GraphPad software.
  • the inhibitory IC 50 values of the compounds of the present disclosure on mTOR enzyme are shown in Table 2.
  • the compound of the present disclosure has weak inhibitory activity on ATM enzyme, DNA-PK enzyme, PI3K enzyme and mTOR enzyme. Comparing Test Examples 1 and 2, it can be seen that the compound of the present disclosure is selective for ATR enzyme.
  • LoVo cells are cultured in F-12K medium containing 10% FBS and passaged 2 to 3 times a week, with a passage ratio of 1:3 or 1:5. During passage, the cells were digested with trypsin and transferred to a centrifuge tube, centrifuged at 1200 rpm for 3 minutes, the supernatant medium was discarded, and fresh medium was added to resuspend the cells. Add 90 ⁇ L of cell suspension to the 96-well cell culture plate at a density of 3.88 ⁇ 10 4 cells/mL, and add only 100 ⁇ L of complete medium to the periphery of the 96-well plate. The culture plate was incubated in an incubator for 24 hours (37°C, 5% CO 2 ).
  • the inhibitory activity of the compounds of the present disclosure on the proliferation of LoVo cells can be determined by the above test, and the measured IC 50 values are shown in Table 3.
  • Table 3 Compound disclosed in proliferation inhibition IC 50 pairs of LoVo cells.
  • the compound of the present disclosure has good inhibitory activity on LoVo cell proliferation.
  • the LC/MS/MS method was used to determine the drug in the plasma at different times after the rats were given the compounds 1-A and 1-B of the present disclosure by intragastric administration, the compounds with short retention time, and the compound of Example 2 concentration.
  • SD rats were fasted overnight and then administered by gavage.
  • the dosage was 2 mg/kg and the dosage was 10.0 mL/kg.
  • Rats were intragastrically administered compounds 1-A and 1-B with short retention time, the compound of Example 2, before and after administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, After 24.0 hours, 0.2 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulation test tube, centrifuged at 4°C at 11,000 rpm for 5 minutes to separate the plasma, stored at -20°C, and eaten 2 hours after administration.
  • the compound of the present disclosure has good pharmacokinetic absorption and has obvious pharmacokinetic advantages.

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Abstract

一种稠合杂芳基类衍生物、其制备方法及其在医药上的应用。具体而言，涉及一种通式(I-1)所示的稠合杂芳基类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为ATR激酶抑制剂的用途和用于制备治疗或预防过度增殖性疾病的药物中的用途。通式(I-1)中各基团的定义与说明书中的定义相同。

Description

稠合杂芳基类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种通式(I-1)所示的稠合杂芳基类衍生物、其制备方法、含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为ATR激酶抑制剂的用途和在用于制备治疗和预防过度增殖性疾病的药物中的用途。
背景技术
无论是正常细胞还是肿瘤细胞中，每天都会出现成千上万次DNA的损伤。这使得DNA损伤修复在维持基因组的稳定性和细胞存活方面起到至关重要的作用。相比较于正常细胞，肿瘤细胞承受了更大的复制压力，携带更多的内源性DNA损伤，并且经常出现一个或多个DNA损伤修复通路的缺失。这使得肿瘤细胞的存活更加依赖于DNA损伤修复的顺利进行。
同源重组修复是DNA双链断裂的主要修复方式，以未受损的姐妹染色单体的同源序列作为其修复的模板复制受损处的DNA序列，精确修复DNA。这种修复方式主要发生在细胞的G2期和S期。ATR是同源重组修复通路中的关键酶，属于PIKK家族。当ATR/ATRIP复合物与覆盖了复制蛋白A(RPA)的受损DNA结合后，ATR被激活并通过磷酸化下游蛋白Chk1和SMARCAL等，调节细胞周期各个检查点，引起细胞周期阻滞；保证受损DNA的稳定性；提高dNTP浓度，促使DNA损伤得以修复。细胞周期S期中出现的DNA损伤修复主要由ATR通路完成，说明ATR对于保证细胞增殖非常重要。对于临床肿瘤样品的分析结果表明在多种肿瘤组织中，例如胃癌、肝癌、结直肠癌、卵巢癌、胰腺癌等，均观察到ATR表达水平升高。并且在卵巢癌、胰腺癌病人中，高水平的ATR往往伴随着较低的存活率。由此可见ATR是一个重要的肿瘤治疗的靶标。
现已公开的ATR抑制剂的专利申请包括WO2010071837、WO2011154737、WO2016020320、WO2016130581、WO2017121684、WO2017118734、WO2018049400、WO2019050889和WO2014140644等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2021072090-appb-000001
其中：
G 1和G 2相同或不同，各自独立地为CH或N，条件是G 1和G 2不同时为CH；
A为杂芳基或杂环基；
Y和Z相同或不同，各自独立地为O或NH；
R 1和R 2相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或R 1和R 2与所连接的碳原子一起形成环烷基或杂环基；
R 3和R 4相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5为烷基或卤代烷基；
p、q和r相同或不同，各自独立地为0、1、2或3；
m、n相同或不同，各自独立地为0、1、2、3、4或5。
本公开的目的在于提供一种通式(I-1)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2021072090-appb-000002
其中：
G 1和G 2相同或不同，各自独立地为CH或N，条件是G 1和G 2不同时为CH；
A为杂芳基或杂环基；
Y和Z相同或不同，各自独立地为O或NH；
R 1、R 2、R 1’和R 2’相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或R 1和R 2、R 1’和R 2’与所连接的碳原子一起形成环烷基或杂环基；
R 3和R 4相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、 卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5为烷基或卤代烷基；
p、q和r相同或不同，各自独立地为0、1、2或3；
m、n相同或不同，各自独立地为0、1、2、3、4或5。
在本公开的一些实施方案中，所述的通式(I)或(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中A为
Figure PCTCN2021072090-appb-000003
优选为
Figure PCTCN2021072090-appb-000004
R 3可取代在A上的任意可取代位点。
在本公开的一些实施方案中，所述的通式(I)或(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中-A-(R 3) n为
Figure PCTCN2021072090-appb-000005
优选为
Figure PCTCN2021072090-appb-000006
R 3和n如通式(I)或(I-1)中所定义。
在本公开一些优选的实施方案中，所述的通式(I)或(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2021072090-appb-000007
其中：
G 1、G 2、R 1、R 2、R 3、R 4、R 5、Y、Z、m和n如通式(I)或(I-1)中所定义。
在本公开一些优选的实施方案中，所述的通式(I)、(I-1)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中G 1为N和/或G 2为N。
在本公开一些优选的实施方案中，所述的通式(I)、(I-1)或(II)所示的化合物 或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2021072090-appb-000008
其中：R 1、R 2、R 3、Y、Z和n如通式(I)、(I-1)或(II)中所定义。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1和R 2相同或不同，各自独立地为氢原子或烷基；其中所述的烷基任选被选自卤素、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，或R 1和R 2与所连接的碳原子一起形成环烷基或杂环基，优选3-6元环烷基，更优选形成环丙基。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1和R 2相同或不同，各自独立地为氢原子或烷基；其中所述的烷基任选被选自卤素、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；优选地，R 1和R 2为C 1-6烷基，更优选为甲基。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1和R 2与所连接的碳原子一起形成环烷基或杂环基，优选3-6元环烷基，更优选形成环丙基。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1和R 2为甲基，Y和Z为O。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1为氢原子或C 1-6烷基；其中所述的C 1-6烷基任选被选自卤素、C 1-6烷氧基和氰基中的一个或多个取代基所取代；优选地，R 1为C 1-6烷基，更优选为甲基。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合 物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 2为氢原子或C 1-6烷基；其中所述的C 1-6烷基任选被选自卤素、C 1-6烷氧基和氰基中的一个或多个取代基所取代；优选地，R 2为C 1-6烷基，更优选为甲基。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中Y和Z均为O。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中Z为NH且Y为O。
在本公开的一些实施方案中，所述的通式(I)、(I-1)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 3为氢原子，R 5为甲基。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 3选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基、C 1-6羟烷基、氰基和氨基；其中所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基、C 1-6羟烷基、氰基和氨基中的一个或多个取代基所取代；优选地，R 3选自氢原子、卤素和C 1-6烷基；更优选地，R 3为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(I-1)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 4选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基、C 1-6羟烷基、氰基和氨基；其中所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基、C 1-6羟烷基、氰基和氨基中的一个或多个取代基所取代；优选地，R 4选自氢原子、卤素和C 1-6烷基；更优选地，R 4为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(I-1)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 5为C 1-6烷基，优选为甲基。
在本公开的一些实施方案中，所述的通式(I)或(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中p为1。
在本公开的一些实施方案中，所述的通式(I)或(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中r为1。
在本公开的一些实施方案中，所述的通式(I)或(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中q为1。
在本公开的一些实施方案中，所述的通式(I)、(I-1)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中m为1。
在本公开的一些实施方案中，所述的通式(I)、(I-1)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中n为1。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中G 1和G 2均为N；Y和Z为O或NH；R 1和R 2相同或不同，各自独立地为氢原子或C 1-6烷基，或者R 1和R 2一起形成环丙基；R 3和R 4均为氢原子；R 5为C 1-6烷基；m和n均为1。
本公开的典型化合物包括但不限于：
Figure PCTCN2021072090-appb-000009
Figure PCTCN2021072090-appb-000010
本公开的另一方面涉及通式(IA)所示的化合物或其互变异构体、内消旋体、外 消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
Figure PCTCN2021072090-appb-000011
其中：
X为卤素；优选为Cl；
G 1和G 2相同或不同，各自独立地为CH或N，条件是G 1和G 2不同时为CH；
Y和Z相同或不同，独立地为O或NH；
R 1和R 2相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或R 1和R 2与所连接的碳原子一起形成环烷基或杂环基；
R 4相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5为烷基或卤代烷基；
p、q和r相同或不同，各自独立地为0、1、2或3；
m为0、1、2、3、4或5。
本公开的另一方面涉及通式(I-1A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
Figure PCTCN2021072090-appb-000012
其中：
X为卤素；优选为Cl；
G 1和G 2相同或不同，各自独立地为CH或N，条件是G 1和G 2不同时为CH；
Y和Z相同或不同，独立地为O或NH；
R 1、R 2、R 1’和R 2’相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或R 1和R 2、R 1’和R 2’与所连接的碳原子一起形成环烷基或杂环基；
R 4相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5为烷基或卤代烷基；
p、q和r相同或不同，各自独立地为0、1、2或3；
m为0、1、2、3、4或5。
本公开的另一方面涉及通式(IIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
Figure PCTCN2021072090-appb-000013
其中：
X为卤素；优选为Cl；
G 1、G 2、R 1、R 2、R 4、R 5、Y、Z和m如通式(II)中所定义。
本公开的另一方面涉及通式(IIIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
Figure PCTCN2021072090-appb-000014
X为卤素；优选为Cl；
R 1、R 2、Y和Z如通式(III)中所定义。
通式(IA)、(I-1A)、(IIA)和(IIIA)为制备本公开通式(I)、(I-1)、(II)和(III)化合物的中间体。
本公开的典型中间体化合物包括但不限于：
Figure PCTCN2021072090-appb-000015
本公开的另一方面涉及一种制备通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2021072090-appb-000016
通式(IA)的化合物和通式(IB)化合物发生偶联反应，得到通式(I)的化合物，
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000017
G 1、G 2、R 1、R 2、R 3、R 4、R 5、Y、Z、A、p、q、r、m和n如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2021072090-appb-000018
通式(I-1A)的化合物和通式(IB)化合物发生偶联反应，得到通式(I-1)的化合物，
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000019
G 1、G 2、R 1、R 2、R 1’、R 2’、R 3、R 4、R 5、Y、Z、A、p、q、r、m和n如通式(I-1)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2021072090-appb-000020
通式(IIA)的化合物和通式(IIB)化合物发生偶联反应，得到通式(II)的化合物，
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000021
G 1、G 2、R 1、R 2、R 3、R 4、R 5、Y、Z、m和n如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2021072090-appb-000022
通式(IIIA)的化合物和通式(IIB)化合物发生偶联反应，得到通式(III)的化合物，
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000023
R 1、R 2、R 3、Y、Z和n如通式(III)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物 组合物在制备用于抑制ATR激酶的药物中的用途。
本公开进一步涉及通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物组合物在制备用于治疗或预防过度增殖性疾病的药物中的用途。
本公开进一步涉及通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物组合物在制备用于治疗或预防肿瘤的药物中的用途。
本公开进一步涉及通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物组合物在制备治疗肿瘤的药物中的用途。
本公开还涉及一种抑制ATR激酶的方法，其包括给予所需患者治疗有效量的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐，或包含其的药物组合物。
本公开还涉及一种治疗或预防过度增殖性疾病的方法，其包括给予所需患者治疗有效量的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐，或包含其的药物组合物。
本公开还涉及一种治疗或预防肿瘤的方法，其包括给予所需患者治疗有效量的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐，或包含其的药物组合物。
本公开进一步涉及一种通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物，其用作药物。
本公开还涉及通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐，或包含其的药物组合物，其用作ATR激酶抑制剂。
本公开还涉及通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐，或包含其的药物组合物，其用于治疗或预防过度增殖性疾病。
本公开进一步涉及通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐，或包含其的药物组合物，其用于治疗肿瘤。
本公开中所述的肿瘤选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、皮肤癌、神经母细胞瘤、神经胶质瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、B-细胞淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌。
可将活性化合物制成适合于通过任何适当途径给药的形式，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。
本公开治疗方法中所用化合物或组合物的剂量通常将随疾病的严重性、患者的体重和化合物的相对功效而改变。不过，作为一般性指导，合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷 基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。
术语“烯基”指分子中含有碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“炔基”指分子中含有碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个(例如3、4、5、6、7和8个)碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021072090-appb-000024
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021072090-appb-000025
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021072090-appb-000026
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选茚满基和四氢萘基。
环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷 基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个(例如3、4、5、6、7和8个)环原子，其中1-3个(例如1、2和3个)是杂原子；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021072090-appb-000027
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021072090-appb-000028
Figure PCTCN2021072090-appb-000029
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021072090-appb-000030
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021072090-appb-000031
杂环基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021072090-appb-000032
Figure PCTCN2021072090-appb-000033
芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021072090-appb-000034
杂芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
上述环烷基、杂环基、芳基和杂芳基具有1个从母体环原子上除去一个氢原子所衍生的残基，或2个从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为四氢吡喃基。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“巯基”指-SH。术语“羟烷基”指被一个或多个羟基取代的烷基，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羰基”指C＝O。
术语“氧代基”指“＝O”。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基、环烷基如上所定义。
THP为四氢吡喃基。
本公开的化合物包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-、 13C-或者 14C-富集的碳( 11C-、 13C-或者 14C-碳标记； 11C-、 13C-或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。
本公开还包括各种氘化形式的通式化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的通式化合物。在制备氘代形式的通式化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂 环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案。
方案一
本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021072090-appb-000035
通式(IA)的化合物和通式(IB)化合物在催化剂存在下，在碱性条件下发生偶联反应，得到通式(I)的化合物，
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000036
G 1、G 2、R 1、R 2、R 3、R 4、R 5、Y、Z、A、p、q、r、m和n如通式(I)中所定义。
方案二
本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021072090-appb-000037
通式(IIA)的化合物和通式(IIB)化合物在催化剂存在下，在碱性条件下发生偶联反应，得到通式(II)的化合物，
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000038
G 1、G 2、R 1、R 2、R 3、R 4、R 5、Y、Z、m和n如通式(II)中所定义。
方案三
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021072090-appb-000039
通式(IIIA)的化合物和通式(IIB)化合物在催化剂存在下，在碱性条件下发生偶联反应，得到通式(III)的化合物；
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000040
R 1、R 2、R 3、Y、Z和n如通式(III)中所定义。
方案四
本公开通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021072090-appb-000041
通式(I-1A)的化合物和通式(IB)化合物在催化剂存在下，在碱性条件下发生偶联反应，得到通式(I-1)的化合物，
其中：
X为卤素；优选为Cl；
R b为
Figure PCTCN2021072090-appb-000042
G 1、G 2、R 1、R 2、R 1’、R 2’、R 3、R 4、R 5、Y、Z、A、p、q、r、m和n如通式(I-1)中所定义。
以上合成方案中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂。
以上合成方案中所述的催化剂包括但不限于钯/碳、四三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、1,1’-双(二苄基磷)二氯二茂铁钯或三(二亚苄基丙酮)二钯，优选为[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水或N,N-二甲基甲酰胺。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)，waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)，THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
6-氨亚基-7,7-二甲基-4-((R)-3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5,7-二氢噻吩并[3,4-d]嘧啶-6-氧化物1
(S)-6-氨亚基-7,7-二甲基-4-((R)-3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5,7-二氢噻吩并[3,4-d]嘧啶-6-氧化物1-A
(R)-6-氨亚基-7,7-二甲基-4-((R)-3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5,7-二氢噻吩并[3,4-d]嘧啶-6-氧化物1-B
Figure PCTCN2021072090-appb-000043
Figure PCTCN2021072090-appb-000044
第一步
2-((3-乙氧基-3-氧代丙基)硫基)-2-甲基丙酸乙酯1c
将乙醇钠(2.1g，30.9mmol)溶于60mL乙醇中，加入3-巯基丙酸乙酯1a(4.13g，30.8mmol，adamas)、2-溴-2-甲基丙酸乙酯1b(6g，30.8mmol，adamas)，搅拌14小时。反应液过滤，滤液减压浓缩，所得残余物加入100mL二氯甲烷稀释，用水(50mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物1c(7.6g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：249.1[M+1]。
第二步
5,5-二甲基-4-氧代四氢噻吩-3-羧酸乙酯1d
将乙醇钠(4.2g，61.2mmol)溶于四氢呋喃(80mL)，缓慢滴加化合物1c(7.6g，30.6mmol)，加热至60℃搅拌反应14小时。反应液冷却至室温，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取(20mL×3)，收集有机相，用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物1d(4.9g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：203.0[M+1]。
第三步
7,7-二甲基-5,7-二氢噻吩并[3,4-d]嘧啶-2,4(1H,3H)-二酮1e
将粗品化合物1d(4.9g，24.1mmol)和尿素(4.4g，72.3mmol)混合，加热至160℃搅拌反应5小时。反应液降至室温，加入30mL甲醇，将所得固体捣碎旋干，真空干燥，得到粗品标题化合物1e(4.77g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：199.1[M+1]。
第四步
2,4-二氯-7,7-二甲基-5,7-二氢噻吩并[3,4-d]嘧啶1f
将粗品化合物1e(4.77g，24.1mmol)溶于40mL甲苯中，加入25mL三氯氧磷和N,N-二异丙基乙胺(3.2g,48.1mmol)，120℃搅拌4小时。反应液冷却至室温，减压浓缩，所得残余物滴加至冰水中，加入乙酸乙酯萃取(50mL×3)，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液硅胶拌样，用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物1f(2.3g)，产率：41.3％。
MS m/z(ESI)：234.9[M+1]。
第五步
(R)-4-(2-氯-7,7-二甲基-5,7-二氢噻吩并[3,4-d]嘧啶-4-基)-3-甲基吗啉1g
将化合物1f(235mg，1.25mmol)和三乙胺(253mg，2.5mmol)溶于10mL N,N-二甲基甲酰胺中，放入冰水中冷却，加入化合物(R)-3-甲基吗啉(126mg，1.25mmol，上海毕得)，自然升至室温搅拌反应14小时。加水20mL，二氯甲烷萃取(20mL×3)，饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物1g(320mg)，产率：85.3％。
MS m/z(ESI)：300.0[M+1]。
第六步
2-氯-6-氨亚基-7,7-二甲基-4-((R)-3-甲基吗啉基)-5,7-二氢噻吩并[3,4-d]嘧啶-6-氧化物1h
将化合物1g(300mg，1.0mmol)溶于5mL乙醇，依次加入乙酸铵(308mg，14mmol)和醋酸碘苯(967mg，3mmol)，室温敞口反应2小时。加入饱和碳酸氢钠溶液淬灭，二氯甲烷萃取(20mL×3)，收集有机相，用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物1h(195mg)，产率：85.3％。
MS m/z(ESI):331.1[M+1]。
第七步
6-氨亚基-7,7-二甲基-4-((R)-3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5,7-二氢噻吩并[3,4-d]嘧啶-6-氧化物1
(S)-6-氨亚基-7,7-二甲基-4-((R)-3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5,7-二氢噻吩并[3,4-d]嘧啶-6-氧化物1-A
(R)-6-氨亚基-7,7-二甲基-4-((R)-3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5-7-二氢噻吩并[3,4-d]嘧啶-6-氧化物1-B
将化合物1h(195mg，0.59mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(48mg，0.059mmol)、碳酸钠(125mg，1.17mmol)和4-(4,4,5,5-四甲基 -1,3,2-二氧硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶(187mg，0.76mmol，上海毕得)溶于5.0mL二氧六环中，加入1.0mL水。在氩气氛下，于80℃搅拌反应3小时，反应液冷却至室温。加水20mL，乙酸乙酯萃取(20mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以洗脱剂体系A纯化，得到标题化合物1(36mg)，再进行手性制备(分离条件：手性制备柱CHIRALPAK IF，5.0cm I.D.×25cm L，10μm，流动相：己烷/EtOH＝40/60(V/V)，流速：60mL/min)，收集其相应组分，减压浓缩，得到标题化合物(18mg，18mg)。
单一构型化合物(较短保留时间)：
MS m/z(ESI)：413.1[M+1]。
手性HPLC分析：保留时间6.569分钟，手性纯度：99.2％(色谱柱：CHIRALPAK IF(IF00CE-SL018)，0.46cm I.D.×25cm L，流动相：正己烷/EtOH＝40/60(V/V),流速：1mL/min)。
1H NMR(400MHz,CD 3OD):δ8.25(d,1H),8.00(d,1H),7.47(d,1H),7.37(d,1H),4.43-4.41(m,1H),3.98-3.95(m,3H),3.93-3.90(m,2H),3.81-3.77(m,1H),3.25(t,1H),3.10(s,3H),1.82-1.79(m,2H),1.50-1.46(m,2H),1.39(d,3H)。
单一构型化合物(较长保留时间)：
MS m/z(ESI)：413.1[M+1]。
手性HPLC分析：保留时间8.424分钟，手性纯度：98.7％(色谱柱：CHIRALPAK IF(IF00CE-SL018)，0.46cm I.D.×25cm L，流动相：正己烷/EtOH＝40/60(V/V)，流速：1mL/min)。
1H NMR(400MHz,CDCl 3)δ9.69(s,1H),8.45(s,1H),8.08(s,1H),7.46(d,1H),7.37(s,1H),4.38(td,3H),4.10-3.92(m,2H),3.81(s,2H),3.63(dt,11.6Hz,2H),1.76(d,6H),1.45(dd,3H)。
实施例2
(R)-7,7-二甲基-4-(3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5,7-二氢噻吩并[3,4-d]嘧啶-6,6-二氧化物2
Figure PCTCN2021072090-appb-000045
Figure PCTCN2021072090-appb-000046
第一步
2,4-二氯-7,7-二甲基-5,7-二氢噻吩并[3,4-d]嘧啶-6,6-二氧化物2a
将化合物1f(1.18g，5.02mmol)溶于20mL二氯甲烷中，冰浴下分批加入间氯过氧苯甲酸(2.6g，15.1mmol)，自然升至室温搅拌反应14小时。加入饱和硫代硫酸钠溶液淬灭，二氯甲烷萃取(30mL×3)，收集有机相，用饱和碳酸氢钠(50mL)，饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物2a(1.34g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：267.1[M+1]。
第二步
(R)-2-氯-7,7-二甲基-4-(3-甲基吗啉基)-5,7-二氢噻吩并[3,4-d]嘧啶-6,6-二氧化物2b
将粗品化合物2a(500mg，1.87mmol)和三乙胺(378mg，3.7mmol)溶于10mL N,N-二甲基甲酰胺中，放入冰水中冷却，加入化合物(R)-3-甲基吗啉(189mg，1.87mmol，上海毕得)，自然升至室温搅拌反应14小时。加水20mL，二氯甲烷萃取(20mL×3)，合并有机相，减压浓缩，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物2b(530mg)，产率：85.3％。
MS m/z(ESI)：332.1[M+1]。
第三步
(R)-7,7-二甲基-4-(3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-5,7-二氢噻吩并[3,4-d]嘧啶-6,6-二氧化物2
将化合物2b(150mg，0.45mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(37mg，0.045mmol)、碳酸钠(100mg，0.094mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶(166mg，0.68mmol，上海毕得)溶于5.0mL二氧六环中，加入1.0mL水，氩气氛下，80℃搅拌反应3小时，反应液冷却至室温。加水20mL，乙酸乙酯萃取(20mL×3)，合并有机相，减压浓缩，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，以洗脱剂体系A纯化，得到标题化合物2(82mg)，产率：44％。
MS m/z(ESI)：414.1[M+1]。
1H NMR(400MHz,CDCl 3)δ9.94(s,1H),8.44(s,1H),8.11(s,1H),7.49(d,1H),7.38(s,1H),4.32(q,3H),4.03(dd,2H),3.82(s,2H),3.74-3.51(m,2H),1.77(s,6H),1.47(d,3H)。
实施例3
6'-氨亚基-4'-((R)-3-甲基吗啉基)-2'-(1H-吡咯并[2,3-b]吡啶-4-基)-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]6'-氧化物3
Figure PCTCN2021072090-appb-000047
第一步
1-((3-乙氧基-3-氧代丙基)硫基)环丙烷-1-羧酸乙酯3b将化合物1a(9.79g，73.0mmol)和2,4-二溴-2-甲基丁酸乙酯3a(20g，73.0mmol)溶于300mL无水和N,N-二甲基甲酰胺中，加入无水碳酸钾(20.2g，146.0mmol)，搅拌14小时。冰浴下，向反应液中依次加入四丁基溴化铵(2.1g，7.3mmol)和钠氢(3.2g，80.2mmol)，自然恢复室温反应5小时。冰浴下，加入饱和氯化铵淬灭反应，加入二氯甲烷(100mL×3)萃取，收集有机相，用50mL饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物3b(18.0g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：247.1[M+1]。
第二步
7-氧代-4-硫杂螺[2.4]庚烷-6-羧酸乙酯3c
将乙醇钠(9.9g，145.9mmol)溶于300mL四氢呋喃，缓慢滴加粗品化合物3b(18g，73.0mmol)，加热至60℃搅拌反应14小时。反应液冷却至室温，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取(80mL×3)，收集有机相，用100mL饱和氯化钠 洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物3c(9.1g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：201.1[M+1]。
第三步
1'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]-2',4'(3'H,5'H)-二酮3d
将粗品化合物3c(9.1g，24.1mmol)与尿素(8.2g，136.5mmol)混合，加热至160℃搅拌反应5小时。反应液冷却至室温，加入30mL甲醇，将所得固体捣碎旋干，真空干燥，得到粗品标题化合物3d(8.9g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：197.2[M+1]。
第四步
2',4'-二氯-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]3e
将粗品化合物3d(8.9g，45.4mmol)溶于40mL甲苯中，加入42mL三氯氧磷和N,N-二异丙基乙胺(17.6g,136.2mmol)，120℃搅拌4小时。反应液冷却至室温，减压浓缩，所得残余物滴加至冰水中，加入乙酸乙酯萃取(100mL×3)，收集有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液硅胶拌样，用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物3e(3.75g)，产率：35.4％。
MS m/z(ESI):232.8[M+1]。
第五步
(R)-4-(2'-氯-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]-4'-基)-3-甲基吗啉3f
将化合物3e(430mg，1.8mmol)和三乙胺(280mg，2.7mmol)溶于10mL N,N-二甲基甲酰胺中，放入冰水中冷却，加入化合物(R)-3-甲基吗啉(187mg，1.8mmol，上海毕得)，自然升至室温搅拌反应14小时。加水20mL，二氯甲烷萃取(20mL×3)，合并有机相，减压浓缩，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物3f(240mg)，产率：44.0％。
MS m/z(ESI):298.0[M+1]。
第六步
2'-氯-6'-氨亚基-4'-((R)-3-甲基吗啉基)-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]6'-氧化物3g
将化合物3f(220mg，1.0mmol)溶于10mL乙醇，依次加入乙酸铵(228mg，3.0mmol)和醋酸碘苯(714mg，2.2mmol)，室温敞口反应0.5小时。加入饱和碳酸氢钠溶液淬灭，二氯甲烷萃取(20mL×3)，收集有机相，用50mL饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系C纯化得到标题化合物3g(180mg)产物,产率：74.0％。
MS m/z(ESI)：331.1[M+1]。
第七步
6'-氨亚基-4'-((R)-3-甲基吗啉基)-2'-(1H-吡咯并[2,3-b]吡啶-4-基)-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]6'-氧化物3
将化合物3g(180mg，0.55mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(45mg，0.055mmol)、碳酸钠(116mg，1.10mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶(244mg，0.82mmol，上海毕得)溶于5.0mL二氧六环中，加入1.0mL水，氩气氛下，于80℃搅拌反应3小时，反应液冷却至室温。加水20mL，乙酸乙酯萃取(20mL×3)，合并有机相，减压浓缩，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，以洗脱剂体系A纯化，得到标题化合物3(56mg)，产率：25％。
MS m/z(ESI)：411.1[M+1]。
1H NMR(400MHz,CDCl 3)δ9.80(s,1H),8.39(s,1H),8.04(s,1H),7.45(d,1H),7.26-7.22(m,1H),4.71-4.47(m,2H),4.36(d,1H),4.06(d,2H),3.82(d,2H),3.74-3.63(m,1H),3.63-3.47(m,1H),1.89(d,4H),1.44(d,3H)。
实施例4
(R)-4'-(3-甲基吗啉基)-2'-(1H-吡咯并[2,3-b]吡啶-4-基)-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]6',6'-二氧化物4
Figure PCTCN2021072090-appb-000048
第一步
2',4'-二氯-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]6',6'-二氧化物4a
将化合物3e(70mg，0.30mmol)溶于3mL二氯甲烷中，冰浴下分批加入间氯过氧苯甲酸(160mg，0.90mmol)，自然升至室温搅拌反应14小时。加入饱和硫代硫酸钠溶液淬灭，二氯甲烷萃取(30mL×3)，收集有机相，用饱和碳酸氢钠(50mL)、饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物4a(80mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：264.9[M+1]。
第二步
(R)-2'-氯-4'-(3-甲基吗啉基)-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]6',6'-二氧化物4b
将粗品化合物4a(79mg，0.30mmol)和三乙胺(90mg，0.9mmol)溶于3mL N,N-二甲基甲酰胺中，放入冰水中冷却，加入化合物(R)-3-甲基吗啉(30mg，0.30mmol，上海毕得)，自然升至室温搅拌反应14小时。加水20mL，二氯甲烷萃取(20mL×3)，合并有机相，减压浓缩，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物4b(57mg)，产率：58％。
MS m/z(ESI)：330.0[M+1]。
第三步
(R)-4'-(3-甲基吗啉基)-2'-(1H-吡咯并[2,3-b]吡啶-4-基)-5'H-螺[环丙烷-1,7'-噻吩并[3,4-d]嘧啶]6',6'-二氧化物4
将4b(57mg，0.17mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(14mg，0.017mmol)、碳酸钠(37mg，0.35mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶(55mg，0.23mmol，上海毕得)溶于2.0mL二氧六环中，加入0.4mL水，氩气氛下，80℃搅拌反应3小时，反应液冷却至室温。加水20mL，乙酸乙酯萃取(20mL×3)，合并有机相，减压浓缩，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，以洗脱剂体系A纯化，得到标题化合物4(7mg)，产率：10％。
MS m/z(ESI)：412.1[M+1]。
1H NMR(400MHz,CDCl 3):δ9.18(s,1H),8.42(s,1H),8.02(d,1H),7.44(s,1H),7.24(s,1H),4.52(q,2H),4.37(dd,1H),4.08(d,2H),3.83(s,2H),3.74-3.65(m,1H),3.63-3.53(m,1H),1.99-1.86(m,4H),1.46(d,3H)。
实施例5
(R)-7,7-二甲基-4-(3-甲基吗啉基)-2-(吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-5,7-二氢噻吩并[3,4-d]嘧啶6,6-二氧化物5
Figure PCTCN2021072090-appb-000049
Figure PCTCN2021072090-appb-000050
第一步
2,4,5,6-四氢吡咯并[3,4-c]吡唑5b
将2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯5a(1.0g，4.8mmol，药明康德)溶解在20mL二氯甲烷中，加入2mL三氟乙酸，反应1小时。反应液减压浓缩，得到粗品标题化合物5b(1.06g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：110.0[M+1]。
第二步
(R)-7,7-二甲基-4-(3-甲基吗啉基)-2-(吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-5,7-二氢噻吩并[3,4-d]嘧啶6,6-二氧化物5
将化合物2b(58mg，0.17mmol)和化合物5b(117mg，0.52mmol)溶解在2mL二氧六环中，加入N,N-二异丙基乙胺(113mg，0.87mmol)。微波120℃反应2小时。将反应液减压浓缩，以洗脱剂体系C纯化，得到标题化合物5(28mg)，产率：40％。
MS m/z(ESI)：405.1[M+1]。
1H NMR(400MHz,CDCl 3)δ7.35(s,1H),4.66(s,4H),4.15(q,3H),4.00-3.87(m,1H),3.83-3.67(m,3H),3.61(td,1H),3.41(td,1H),1.61(s,6H),1.36(d,3H)。
生物学评价
测试例1、本公开化合物对ATR酶的抑制效应
以下方法用来测定本公开化合物对ATR酶的抑制效应。实验方法简述如下：
一、实验材料及仪器
1.ATR酶(Eurofins Pharma Discovery Services，14-953-M)
2.GST标签P53蛋白(Eurofins Pharma Discovery Services，14-952-M)
3. 384孔板(Thermo Scientific，267462)
4.U型底96孔板(Corning，3795)
5.标记铕穴状化合物抗磷酸化P53蛋白抗体(cisbio，61P08KAE)
6.链接d2的抗GST抗体(cisbio，61GSTDLF)
7.ATP溶液(Promega，V916B)
8.EDTA(Thermo Scientific，AM9260G)
9.HEPES(Gibco，15630-080)
10.酶标仪(BMG，PHERAsta)
二、实验步骤
ATR酶1nM、P53蛋白50nM、7.435μM的ATP以及不同浓度(首浓度1μM，3倍梯度稀释11个浓度，稀释溶剂为25mM HEPES pH8.0，0.01％Brij-35，1％丙三醇)的本公开化合物混合室温孵育2小时，然后加入终止液(12.5mM HEPES，250mM EDTA)混匀，再加入0.42ng/孔的标记铕穴状化合物抗磷酸化P53蛋白抗体和25ng/孔的链接d2的抗GST抗体。室温孵育过夜后用PHERAstar检测620nm和665nm荧光信号。数据使用GraphPad软件处理。
三、实验数据
本公开化合物对ATR酶的抑制活性可通过以上的试验进行测定，测得的IC 50值见表1。
表1本公开化合物对ATR酶抑制的IC 50
Figure PCTCN2021072090-appb-000051
结论：本公开化合物对ATR酶具有良好的抑制活性。
测试例2、本公开化合物对ATR酶的选择性测试
以下方法分别测定了本公开化合物对ATM酶、DNA-PK酶、mTOR酶和PI3K酶的抑制效应，用以说明本公开化合物对ATR酶具有选择性。
实验方法简述如下：
(一)本公开化合物对ATM酶的抑制效应
一、实验材料及仪器
1、ATM酶(Eurofins Pharma Discovery Services，14-933-M)
2、GST标签P53蛋白(Eurofins Pharma Discovery Services，14-952-M)
3、384孔板(Thermo Scientific，267462)
4、U型底96孔板(Corning，3795)
5、标记铕穴状化合物抗磷酸化P53蛋白抗体(cisbio，61P08KAE)
6、链接d2的抗GST抗体(cisbio，61GSTDLF)
7、ATP溶液(Promega，V916B)
8、EDTA(Thermo Scientific，AM9260G)
9、HEPES(Gibco，15630-080)
10、酶标仪(BMG，PHERAsta)
二、实验步骤
ATM酶1nM、P53蛋白30nM、11μM的ATP以及不同浓度(首浓度10μM，3倍梯度稀释11个浓度，溶剂为25mM HEPES pH8.0，0.01％Brij-35，1％丙三醇)的本公开化合物混合，室温孵育2小时，然后加入终止液(12.5mM HEPES，250mM EDTA)混匀，再加入0.42ng/孔的标记铕穴状化合物抗磷酸化P53蛋白抗体和25ng/孔的链接d2的抗GST抗体。室温孵育过夜后用PHERAstar检测620nm和665nm荧光信号。数据使用GraphPad软件处理。本公开化合物对ATM酶的抑制IC 50值见表2。
(二)本公开化合物对DNA-PK酶的抑制效应
一、实验材料及仪器
1、DNA-PK酶(Eurofins Pharma Discovery Services，14-950-M)
2、GST标签P53蛋白(Eurofins Pharma Discovery Services，14-952-M)
3、384孔板(Thermo Scientific，267462)
4、U型底96孔板(Corning，3795)
5、标记铕穴状化合物抗磷酸化P53蛋白抗体(cisbio，61P08KAE)
6、链接d2的抗GST抗体(cisbio，61GSTDLF)
7、ATP溶液(Promega，V916B)
8、EDTA(Thermo Scientific，AM9260G)
9、HEPES(Gibco，15630-080)
10、酶标仪(BMG，PHERAsta)
二、实验步骤
DNA-PK酶0.02nM、P53蛋白50nM、7.3μM的ATP以及不同浓度(首浓度10μM，3倍梯度稀释11个浓度，溶剂为25mM HEPES pH8.0，0.01％Brij-35，1％丙三醇)的本公开化合物混合，室温孵育1小时，然后加入终止液(12.5mM HEPES，250mM EDTA)混匀，再加入0.42ng/孔的标记铕穴状化合物抗磷酸化P53蛋白抗体和25ng/孔的链接d2的抗GST抗体。室温孵育过夜后用PHERAstar检测620nm和665nm荧光信号。数据使用GraphPad软件处理。本公开化合物对DNA-PK酶的抑制IC 50值见表2。
(三)本公开化合物对PI3K酶的抑制效应
一、实验材料及仪器
1、PIK3CA/PIK3R1(p110alpha/p85alpha)激酶(Invitrogen，PV4788)
2、PIP2:PS脂质底物(Invitrogen，PV5100)
3、DTT(Sigma，43815-1G)
4、Tris-Hcl(1M,pH7.5)(北京天恩泽生物技术有限公司，101205-100)
5、ATP溶液(Promega，V916B)
6、氯化镁六水合物(Sigma，M2393)
7、氯化钠(国药集团化学试剂有限公司，10019318)
8、CHAPS(Sigma，C3023-5G)
9、HEPES(Gibco，15630-080)
10、ADP-Glo TM激酶分析试剂盒(Promega，V9102)
11、384孔板(Thermo Scientific，267462)
12、U型底96孔板(Corning，3795)
13、酶标仪(BMG，PHERAstar)
二、实验步骤
PI3K酶终浓度为0.625nM，与不同浓度(首浓度10μM，3倍梯度稀释10个浓度，溶剂为10mM Tris-HCL pH 7.5,50mM NaCl,3mM MgCl 2,0.05％CHAPS，100μM)的小分子化合物混合室温孵育30分钟，再加入PIP2:PS脂质底物(终浓度50μM)和1x ATP(终浓度50μM)，混合37℃孵育30分钟，然后加入检测试剂ADP-Glo(Promega，V9102)混匀室温孵育40分钟后，加入ADP-Glo TM激酶分析试剂盒(Promega，V9102)的检测试剂，室温孵育40分钟。用PHERAstar检测荧光信号，数据使用GraphPad软件处理。本公开化合物对PI3K酶的抑制IC 50值见表2。
(四)本公开化合物对mTOR酶的抑制效应
一、实验材料及仪器
1、MTOR重组人蛋白(Invitrogen，PV4753)
2、ATP溶液(Promega，V916B)
3、EDTA(Thermo Scientific，AM9260G)
4、HEPES(Gibco，15630-080)
5、U型底96孔板(Corning，3795)
6、DTT(Sigma，43815-1G)
7、Tris-Hcl(1M,pH7.5)(北京天恩泽生物技术有限公司，101205-100)
8、氯化镁六水合物(Sigma，M2393)
9、ULIGHT-4E-BP1(THR37/46)(PerkinElmer，TRF0128-D)
10、EU-ANTI-P-4E-BP1(THR37/46)(PerkinElmer，TRF0216-D)
11、21O-LANCE检测缓冲剂(PerkinElmer，CR97-100)
12、384孔板(Corning，4513)
13、EnVision多模式检测平台(PerkinElmer，EnVision)
二、实验步骤
mTOR酶终浓度为3nM，加入不同浓度(首浓度10μM，3倍梯度稀释10个 浓度，溶剂为50mM HEPES pH 7.5，10mM MgCl 2，1mM EGTA，2mM DTT，0.01％Tween-20)的本公开化合物混合，再加入ATP和ULight-4E-BP1肽(终浓度分别为10μM ATP和50nM底物)混合室温孵育2小时，然后加入终浓度为8mM EDTA终止液混匀，室温孵育5分钟后，加入Eu-抗-磷酰化-4E-BP1(Thr37/46)抗体(终浓度2nM)，室温孵育1小时。用EnVision多模式检测平台检测HTRF，激发波长320nm，发射波长665nm。数据使用GraphPad软件处理。本公开化合物对mTOR酶的抑制IC 50值见表2。
表2本公开化合物对ATM酶、DNA-PK酶、PI3K酶和mTOR酶的抑制的IC 50值。
Figure PCTCN2021072090-appb-000052
结论：本公开化合物对ATM酶、DNA-PK酶、PI3K酶和mTOR酶的抑制活性弱，对比测试例1和2可以看出本公开化合物对ATR酶具有选择性。
测试例3、细胞增殖实验
以下方法通过检测细胞内ATP含量，根据IC 50大小评价本公开化合物对LoVo细胞增殖的抑制效果。
实验方法简述如下：
一、实验材料及仪器
1、LoVo，人结肠癌肿瘤细胞(南京科佰，CBP60032)
2、胎牛血清(GIBCO，10091-148)
3、F-12K培养基(Gibco，21127030)
4、CellTite-Glo试剂(Promega，G7573)
5、96孔细胞培养板(corning，3903)
6、胰酶(invitrogen，25200-072)
7、酶标仪(BMG，PHERAsta)
8、细胞计数仪(上海睿钰生物科技有限公司，IC1000)
二、实验步骤
LoVo细胞培养在含10％FBS的F-12K培养基中，一周传代2～3次，传代比列1:3或1:5。传代时，用胰酶消化细胞后转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，加入新鲜培养基重悬细胞。在96孔细胞培养板中加入90μL的细胞悬液，密度为3.88×10 4细胞/mL，96孔板外围只加入100μL的完全培养基。 将培养板在培养箱培养24小时(37℃，5％CO 2)。
将待测样品用DMSO稀释成2mM，并以3倍依次稀释成10个浓度，并设置空白和对照孔。取配制成梯度浓度的待测化合物溶液5μL加入到95μL新鲜培养基中。再向培养板中加入10μL上述含药物的培养基溶液。将培养板在培养箱孵育3天(37℃，5％CO 2)。在96孔细胞培养板中，每孔加入50μL CellTiter-Glo试剂，室温避光放置5-10分钟，在PHERAstar中读取化学发光信号值，数据使用GraphPad软件处理。
三、实验数据
本公开化合物对LoVo细胞增殖的抑制活性可通过以上的试验进行测定，测得的IC 50值见表3。
表3本公开化合物对LoVo细胞增殖抑制的IC 50。
Figure PCTCN2021072090-appb-000053
结论：本公开化合物对LoVo细胞增殖具有良好的抑制活性。
药代动力学评价
测试例4、本公开化合物的药代动力学测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予本公开化合物1-A和1-B中保留时间短的化合物、实施例2化合物后不同时刻血浆中的药物浓度。研究本公开化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
本公开化合物1-A和1-B中保留时间短的化合物、实施例2化合物。
2.2试验动物
健康成年SD大鼠8只，雌雄各半，平均分成2组，每组4只，购自维通利华实验动物有限公司。
2.3药物配制
称取一定量药物，加入5％DMSO、5％吐温80和90％生理盐水配置成无色澄明溶液。
2.4给药
SD大鼠禁食过夜后灌胃给药，给药剂量均为2mg/kg，给药体积均为10.0mL/kg。
3、操作
大鼠灌胃给药化合物1-A和1-B中保留时间短的化合物、实施例2化合物，于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时由眼眶采血0.2mL，置于EDTA-K2抗凝试管中，4℃、11000转/分钟离心5分钟分离血浆，于-20℃保存，给药后2小时进食。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆25μL，加入内标溶液(喜树碱100ng/mL)50μL，乙腈175μL，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液1μL进行LC/MS/MS分析。
4、药代动力学参数结果
本公开化合物的药代动力学参数如下表4所示。
表4本公开化合物的药代动力学参数
Figure PCTCN2021072090-appb-000054
结论：本公开化合物的药代吸收良好，具有明显的药代动力学优势。

Claims (18)

  1. 一种通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2021072090-appb-100001
    其中：
    G 1和G 2相同或不同，各自独立地为CH或N，条件是G 1和G 2不同时为CH；
    A为杂芳基或杂环基；
    Y和Z相同或不同，各自独立地为O或NH；
    R 1、R 2、R 1’和R 2’相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或R 1和R 2、R 1’和R 2’与所连接的碳原子一起形成环烷基或杂环基；
    R 3和R 4相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 5为烷基或卤代烷基；
    p、q和r相同或不同，各自独立地为0、1、2或3；
    m、n相同或不同，各自独立地为0、1、2、3、4或5。
  2. 根据权利要求1中所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中A为
    Figure PCTCN2021072090-appb-100002
    R 3可取代在A上的任意可取代位点。
  3. 根据权利要求1或2中所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的 盐，其为通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2021072090-appb-100003
    其中：
    G 1、G 2、R 1、R 2、R 3、R 4、R 5、Y、Z、m和n如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2021072090-appb-100004
    其中：R 1、R 2、R 3、Y、Z和n如权利要求1中所定义。
  5. 根据权利要求1至4中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1和R 2相同或不同，各自独立地为氢原子或烷基；其中所述的烷基任选被选自卤素、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；优选地，R 1和R 2为C 1-6烷基，更优选为甲基。
  6. 根据权利要求1至4中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1和R 2与所连接的碳原子一起形成环烷基或杂环基，优选3-6元环烷基，更优选形成环丙基。
  7. 根据权利要求1至6中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中Z为NH且Y为O。
  8. 根据权利要求1至6中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中Z和Y均为O。
  9. 根据权利要求1至8中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 3为氢原子，R 5为甲基。
  10. 根据权利要求1至2、5至9中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2021072090-appb-100005
  11. 一种通式(I-1A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    Figure PCTCN2021072090-appb-100006
    其中：
    X为卤素；优选为Cl；
    G 1和G 2相同或不同，各自独立地为CH或N，条件是G 1和G 2不同时为CH；
    Y和Z相同或不同，独立地为O或NH；
    R 1、R 2、R 1’和R 2’相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或R 1和R 2、R 1’和R 2’与所连接的碳原子一起形成环烷基或杂环基；
    R 4相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 5为烷基或卤代烷基；
    p、q和r相同或不同，各自独立地为0、1、2或3；
    m为0、1、2、3、4或5。
  12. 根据权利要求11所述的通式(I-1A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2021072090-appb-100007
  13. 一种制备根据权利要求1所述的通式(I-1)所示的化合物或其互变异构体、 内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
    Figure PCTCN2021072090-appb-100008
    通式(I-1A)的化合物和通式(IB)化合物发生偶联反应，得到通式(I-1)的化合物，
    其中：
    X为卤素；优选为Cl；
    R b为
    Figure PCTCN2021072090-appb-100009
    G 1、G 2、R 1、R 2、R 1’、R 2’、R 3、R 4、R 5、Y、Z、A、p、q、r、m和n如权利要求1中所定义。
  14. 一种药物组合物，所述药物组合物含有根据权利要求1至10中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  15. 根据权利要求1至10中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求14所述的药物组合物在制备用于抑制ATR激酶的药物中的用途。
  16. 根据权利要求1至10中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求14所述的药物组合物在制备用于治疗或预防过度增殖性疾病的药物中的用途。
  17. 根据权利要求1至10中任一项所述的通式(I-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求14所述的药物组合物在制备用于治疗或预防肿瘤的药物 中的用途。
  18. 根据权利要求17所述的用途，其中所述的肿瘤选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、皮肤癌、神经母细胞瘤、神经胶质瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、B-细胞淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌。
PCT/CN2021/072090 2020-01-17 2021-01-15 稠合杂芳基类衍生物、其制备方法及其在医药上的应用 WO2021143821A1 (zh)

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