WO2022002243A1 - Dérivé d'imidazopyrimidine, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé d'imidazopyrimidine, son procédé de préparation et son utilisation médicale Download PDF

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Publication number
WO2022002243A1
WO2022002243A1 PCT/CN2021/104227 CN2021104227W WO2022002243A1 WO 2022002243 A1 WO2022002243 A1 WO 2022002243A1 CN 2021104227 W CN2021104227 W CN 2021104227W WO 2022002243 A1 WO2022002243 A1 WO 2022002243A1
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Prior art keywords
alkyl
general formula
enantiomer
pharmaceutically acceptable
tautomer
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PCT/CN2021/104227
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English (en)
Chinese (zh)
Inventor
李心
陈阳
蔡国栋
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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Priority to CN202180045897.8A priority Critical patent/CN115867552A/zh
Publication of WO2022002243A1 publication Critical patent/WO2022002243A1/fr

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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
    • A61K31/495—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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medicine, and relates to an imidazopyrimidine derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an inhibitor of ATR kinase Use of the agent and in the manufacture of a medicament for the treatment and prevention of hyperproliferative diseases.
  • DNA damage occurs thousands of times every day in both normal and tumor cells. This makes DNA damage repair crucial in maintaining genome stability and cell survival. Compared to normal cells, tumor cells are under greater replication stress, carry more endogenous DNA damage, and often exhibit the loss of one or more DNA damage repair pathways. This makes the survival of tumor cells more dependent on the smooth progress of DNA damage repair.
  • Homologous recombination repair is the main repair method for DNA double-strand breaks.
  • the homologous sequence of the undamaged sister chromatid is used as the template for its repair to replicate the DNA sequence at the damaged place, and the DNA is accurately repaired.
  • This repair mode mainly occurs in the G2 and S phases of cells.
  • ATR is a key enzyme in the homologous recombination repair pathway and belongs to the PIKK family. When the ATR/ATRIP complex binds to damaged DNA covered with replication protein A (RPA), ATR is activated and regulates various checkpoints in the cell cycle by phosphorylating downstream proteins Chk1 and SMARCAL, causing cell cycle arrest and ensuring The stability of damaged DNA increases the concentration of dNTPs and promotes the repair of DNA damage.
  • RPA replication protein A
  • DNA damage repair 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.
  • Analysis of clinical tumor samples showed that in various 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 associated with lower survival rates. It can be seen that ATR is an important target for tumor therapy.
  • ATR inhibitors include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889, and WO2014140644, among others.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
  • R 0 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group;
  • R 1 and R 2 are the same or different, each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano , amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl or more substituents;
  • R 3 is selected from hydrogen, halo, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxy Substituted with one or more substituents of alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocycle wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy , substituted with one or more substituents in haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 5 is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;
  • n 0, 1, 2 or 3.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is the compound represented by the general formula (Ia) or its tautomer, meso, racemate, enantiomer, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 0 , R 1 , R 2 , R 3 , R 4 and n are as defined in general formula (I).
  • the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 2 is preferably R 2a is selected from hydrogen atoms, C 1-6 alkyl groups and halogenated C 1-6 alkyl groups; preferably, R 2a is methyl or ethyl.
  • the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or its mixture form or its pharmaceutically acceptable salt wherein R 3 is selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, said pyrazolyl, imidazolyl, pyrrolyl and triazolyl optionally substituted selected from halogen, C 1-6 alkyl and halogenated C 1-6 alkyl group with one or more substituents.
  • the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 3 is preferably R 3a is selected from a hydrogen atom, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group; preferably, R 3a is a hydrogen atom.
  • the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (II) or tautomers, mesomers, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 6 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 7 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • p and q are the same or different, each independently selected from 0, 1, 2 or 3;
  • R 0 , R 1 , R 4 and n are as defined in general formula (I).
  • the compound represented by the general formula (I), (Ia) or (II) or its tautomer, meso, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 0 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cyano group; preferably, R 0 is selected From a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group and a cyano group; more preferably a hydrogen atom or a C 1-6 alkyl group.
  • R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 1 is a hydrogen atom.
  • R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 4 is a hydrogen atom.
  • the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 6 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano , amino and nitro; preferably, R 6 is the same or different, each independently selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; more preferably C 1-6 alkyl ; more preferably methyl.
  • the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 7 is the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano , amino and nitro; preferably, R 7 is the same or different, each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group; more preferably a hydrogen atom.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 0 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group and a cyano group; R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl group and halogenated C 1-6 alkyl group; R 2 is a five-membered heteroaryl group, and the five-membered heteroaryl group is optionally selected from halogen, C 1 -6 alkyl, C 1-6 alkoxy and one or more substituents in halogenated C 1-6 alkyl; R 3 is a five-membered heteroaryl, and the five-membered heteroaryl can be any optionally substituted by one or more substituent
  • the compound represented by the general formula (Ia) or its tautomer, meso, racemate, enantiomer, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 0 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group and a cyano group; R 1 Selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R 2 is R 2a is selected from hydrogen atom, C 1-6 alkyl and halogenated C 1-6 alkyl; R 3 is R 3a is selected from a hydrogen atom, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group; R 4 is a hydrogen atom; and n is 0 or 1.
  • the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 0 is hydrogen atom or C 1-6 alkyl; R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1- 6 alkyl; R 4 is a hydrogen atom; R 6 is the same or different, each independently selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R 7 is the same or different, each independently is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; n is 0 or 1; p is 1; q is 1.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure pertains to compounds of general formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof,
  • X is a hydrogen atom or halogen; preferably halogen; more preferably Br;
  • R 0 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group;
  • R 1 and R 2 are the same or different, each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano , amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl or more substituents;
  • R 4 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocycle wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy , substituted with one or more substituents in haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 5 is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;
  • n 0, 1, 2 or 3.
  • Another aspect of the present disclosure pertains to a compound of formula (I-aA) or a tautomer, meso, racemate, enantiomer, diastereomer, or tautomer, meso, racemate, or in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • X is a hydrogen atom or halogen; preferably halogen; more preferably Br;
  • R 0 , R 1 , R 2 , R 4 and n are as defined in general formula (Ia).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof,
  • X is a hydrogen atom or halogen; preferably halogen; more preferably Br;
  • R 0 , R 1 , R 4 , R 6 , n and p are as defined in general formula (II).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • a compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction with the compound of general formula (IB) to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • X is halogen; preferably Br;
  • R is a hydrogen atom or an alkyl group
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • X is halogen; preferably Br;
  • R is a hydrogen atom or an alkyl group
  • R 0 , R 1 , R 2 , R 3 , R 4 and n are as defined in general formula (Ia).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • a compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction with the compound of general formula (IIB) to obtain the compound of general formula (II) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • X is halogen; preferably Br;
  • R is a hydrogen atom or an alkyl group
  • R 0 , R 1 , R 4 , R 6 , R 7 , n, p and q are as defined in general formula (II).
  • compositions comprising a compound represented by the general formula (I), (Ia), (II) or Table A of the present disclosure, or a tautomer, internal Racemates, 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 compounds of general formula (I), (Ia), (II), or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired Use of an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting ATR kinase.
  • the present disclosure further relates to compounds of general formula (I), (Ia), (II), or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired Use of an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of a hyperproliferative disease.
  • the present disclosure further relates to compounds represented by general formula (I), (Ia), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired isomers thereof Use of an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating or preventing tumors.
  • the present disclosure further relates to compounds of general formula (I), (Ia), (II), or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired Use of an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating tumors.
  • the present disclosure also relates to a method of inhibiting ATR kinase, comprising administering to a patient in need thereof an inhibitory effective amount of a compound of general formula (I), (Ia), (II) or Table A or a tautomer thereof , meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method of treating or preventing a hyperproliferative disease, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of general formula (I), (Ia), (II) or Table A or Its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same .
  • the present disclosure also relates to a method of treating or preventing tumors, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of general formula (I), (Ia), (II) or Table A or its interconversion Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a compound represented by the general formula (I), (Ia), (II) or Table A or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure also relates to compounds of general formula (I), (Ia), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an ATR kinase inhibitor.
  • the present disclosure also relates to compounds of general formula (I), (Ia), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a hyperproliferative disease.
  • the present disclosure further relates to compounds of general formula (I), (Ia), (II), or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment of tumors.
  • the tumor described in the present disclosure is preferably selected from the group consisting of melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, nerve cancer Blastoma, glioma, sarcoma, bone cancer, endometrial cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation.
  • the compounds of the present disclosure can be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure can be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation.
  • a suitable unit dose may be 0.1 to 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 from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the 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.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents. Sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil, or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • 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 which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health of the patient condition, behavior of the patient, diet of the patient, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimal mode of treatment such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 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 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from H atoms, D atoms, halogens, alkyl groups , alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heterocycle One or more substituents in an aryl group.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups 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 -), and the like.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl , one or more substituents of heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms Carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members 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 more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferably
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from H atoms, D atoms, halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • 1 to 4 eg 1, 2, 3 and 4
  • 3 to 8 ring atoms eg 3, 4, 5, 6, 7 and 8
  • 1-3 are heteroatoms
  • 3 to 6 ring atoms of which 1-3 are heteroatoms
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. 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 monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl 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, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 (eg, 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same or two different ring atoms of the parent. Derived residues, namely "divalent cycloalkyl”, “divalent heterocyclyl", “arylene” and “heteroarylene”.
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-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.
  • hydroxyl protecting group is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P.
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy substituted alkyl or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted with C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, t-butyl, benzyl , methoxymethyl (MOM), ethoxyethyl; can be (C 1-10 alkyl or aryl) acyl, such as: formyl, acetyl
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2.
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl, cycloalkyl are as defined above.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • the present disclosure having the structure, except that "deuterium” or “tritium” in place of a hydrogen, fluorine or instead of fluorine-labeled with 18 F- (18 F isotope), or with 11 C- 13 C-, 14 C- or rich, Compounds in which a set of carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) in place of carbon atoms are within the scope of this disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • the present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the salts can be prepared separately during the final isolation and purification of the compounds, 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 non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • solvate refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of the crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • Prodrug means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the preparation method of medicinal salt comprises the following steps:
  • a compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction occurs with the compound of general formula (IB) in the presence of a catalyst under basic conditions to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X is halogen; preferably Br;
  • R is a hydrogen atom or an alkyl group
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • X is halogen; preferably Br;
  • R is a hydrogen atom or an alkyl group
  • R 0 , R 1 , R 2 , R 3 , R 4 and n are as defined in general formula (Ia).
  • the preparation method of medicinal salt comprises the following steps:
  • a compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction occurs with the compound of general formula (IIB) in the presence of a catalyst under basic conditions to obtain the compound of general formula (II) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X is halogen; preferably Br;
  • R is a hydrogen atom or an alkyl group
  • R 0 , R 1 , R 4 , R 6 , R 7 , n, p and q are as defined in general formula (II).
  • the reagents that provide alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium propylamide, lithium bistrimethylsilylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, 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, preferably sodium carbonate or anhydrous sodium carbonate.
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium propylamide, lithium bistrimethylsilylamide, potassium
  • the catalysts described in the above synthetic schemes include but are not limited to palladium/carbon, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino) -2',4',6'-Triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium, [1,1'-bis(diphenylphosphino)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, and the solvent used includes but is 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 solvent used includes but is 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.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS was used for MS determination (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
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • the 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 TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using 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 chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a 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 embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography chromatography and the developing solvent system of the thin layer chromatography adopted for purifying the compound 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 triethyl ether can also be added Basic or acidic reagents such as amines and acetic acid are used for adjustment.
  • TLC thin layer chromatography
  • the crude compound 1c (12 g, 65.5 mmol) was dissolved in toluene (50 mL), phosphorus oxychloride (36 mL, 393.1 mmol) was added, and N,N-diisopropylethylamine (33 mL, 196.5 mmol) was added slowly, at 90° C. React for 2 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure, added dichloromethane (500 mL), stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1d (8 g), which was used in the next reaction without purification.
  • the crude compound 1d (8 g, 39.59 mmol) was dissolved in 80 mL of acetonitrile, N,N-diisopropylethylamine (232.12 mmol, 39 mL) and (R)-3-methylmorpholine (1e) (8 g, 79.0 mmol, Shanghai Bide), react at 75°C for 4 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with water (150 mL), extracted with ethyl acetate (80 mL ⁇ 2), and purified by silica gel column chromatography with eluent system C to obtain the title compound 1f (500 mg, yield: 4.7%).
  • the crude compound 2b (9.6 g, 48.6 mmol) was dissolved in toluene (80 mL), phosphorus oxychloride (27 mL, 292.1 mmol) was added, N,N-diisopropylethylamine (33 mL, 194.7 mmol) was added slowly, 90 °C for 3 hours.
  • the reaction solution was concentrated under reduced pressure, added with dichloromethane (500 mL), stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2c (10 g), which was used in the next reaction without purification.
  • the crude compound 2c (10 g, 46.3 mmol) was dissolved in 80 mL of acetonitrile, N,N-diisopropylethylamine (185.12 mmol, 32 mL) and compound 1e (23 g, 227.4 mmol) were added, and the reaction was carried out at 75° C. for 1 hour.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with water (150 mL), extracted with ethyl acetate (80 mL ⁇ 2), and purified by silica gel column chromatography with eluent system C to obtain the title compound 2d (1.3 g, yield : 10%).
  • reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution system: ammonium bicarbonate, acetonitrile, water) to obtain the title compound 2 (98 mg, yield: 27.3%).
  • the crude compound 4b (1.0 g, 4.78 mmol) was dissolved in toluene (20 mL), phosphorus oxychloride (3 mL, 35.1 mmol) was added, and the reaction was carried out at 100° C. for 2 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure, added with dichloromethane (500 mL), stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4c (3.2 g), which was used in the next reaction without purification.
  • the crude compound 4f (60 mg, 0.175 mmol) was dissolved in 4 mL of N,N-dimethylformamide, cooled to -78°C, and anhydrous sodium bicarbonate (30 mg, 0.35 mmol) and N-bromosuccinyl were added. imine (35 mg, 0.184 mmol), stirred for 10 minutes.
  • the reaction solution was warmed to room temperature, 10 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined and concentrated under reduced pressure to obtain 4 g (30 mg, yield: 45.4%) of the crude title product, which was not purified by Purification was used directly in the next reaction.
  • Test Example 1 Inhibitory activity of compounds of the present disclosure on ATR enzyme
  • ATR enzyme Eurofins Pharma Discovery Services, 14-953-M
  • Microplate reader (BMG, PHERAsta)
  • the inhibitory activity of the compounds of the present disclosure on ATR enzyme can be determined by the above assay.
  • the blank experimental well without ATR enzyme was set as 100% inhibition, and the inhibition rate of the compound was calculated by the formula 100 ⁇ [1-(compound signal-background signal)/(DMSO well signal-background signal)].
  • Table 1 discloses compounds of the IC 50 of enzyme inhibition ATR
  • Test Example 2 Selectivity test of compounds of the present disclosure to ATR enzyme
  • Microplate reader (BMG, PHERAsta)
  • DNA-PK enzyme Eurofins Pharma Discovery Services, 14-950-M
  • Microplate reader (BMG, PHERAsta)
  • DNA-PK enzyme 50nM P53 protein, 7.3 ⁇ M ATP and different concentrations (10 ⁇ M initial concentration, 11 concentrations of 3-fold serial dilution) of the present disclosure were mixed, incubated at room temperature for 1 hour, and then a stop solution (12.5mM HEPES) was added. , 250mM EDTA) and mix, and then add 0.42ng/well of labeled europium cryptate anti-phosphorylated P53 protein antibody and 25ng/well of d2-linked anti-GST antibody. Fluorescence signals at 620 nm and 665 nm were detected with PHERAstar after overnight incubation at room temperature. Data were processed using GraphPad software. The present disclosure of the compound to inhibit DNA-PK enzyme IC 50 values in Table 2 below.
  • PIK3CA/PIK3R1 p110alpha/p85alpha kinase (Invitrogen, PV4788)
  • PIP2 PS Lipid substrate (Invitrogen, PV5100)
  • Microplate reader (BMG, PHERAstar)
  • the final concentration of PIK3CA/PIK3R1 (p110alpha/p85alpha) kinase was 0.625nM, mixed with the compounds of the present invention at different concentrations (the initial concentration of 10 ⁇ M, 10 concentrations of 3-fold gradient dilution), incubated at room temperature for 30 minutes, and then added PIP2:PS Lipid substrate (final concentration 50 ⁇ M) and 1x ATP (final concentration 50 ⁇ M), mix, incubate at 37°C for 30 minutes, then add detection reagent ADP-Glo (Promega, V9102) and mix well, incubate at room temperature for 40 minutes, add ADP-Glo TM kinase assay The detection reagents of the kit (Promega, V9102) were incubated at room temperature for 40 minutes. Fluorescence signals were detected with PHERAstar and data were processed using GraphPad software. The present disclosure of the compounds to inhibit PI3K enzymes IC 50 values in Table 2 below.
  • the compounds of the present disclosure have weak inhibitory activities on ATM enzyme, DNA-PK enzyme and PI3K enzyme. Comparing Test Examples 1 and 2, it can be seen that the compounds of the present disclosure have selectivity for ATR enzyme.
  • the following method evaluates the inhibitory effect of the compounds of the present disclosure on the proliferation of LoVo cells by detecting the intracellular ATP content according to the IC 50 size.
  • LoVo cells were cultured in F-12K medium containing 10% FBS, passaged 2-3 times a week, and the passage ratio was 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 residue was discarded, and fresh medium was added to resuspend the cells. 90 ⁇ L of cell suspension was added to the 96-well cell culture plate at a density of 3.88 ⁇ 10 4 cells/ml, and only 100 ⁇ L of complete medium was added to the periphery of the 96-well plate. The plates were incubated in an incubator (37°C, 5% CO 2 ) for 24 hours.
  • the compounds to be tested were diluted with DMSO to 2 mM, and diluted 3-fold successively to 10 concentrations, and blank wells (without cells without compound) and control wells (with cells without compound) were set. 5 ⁇ L of the solution of the compound to be tested prepared in a gradient concentration was added to 95 ⁇ L of fresh medium to prepare a compound-containing medium solution. 10 ⁇ L of the above drug-containing medium solution was added to the culture plate. The plates were incubated for 3 days in an incubator (37 °C, 5% CO 2 ).
  • the inhibitory activity of the compounds of the present disclosure on LoVo cell proliferation can be determined by the above assay.
  • the blank well was set as 100% inhibition, and the inhibition rate of the compound was calculated by the formula 100 ⁇ [1-(compound signal-blank well signal)/(control well well signal-blank well signal)].
  • Table 3 discloses compounds on cell proliferation of LoVo IC 50
  • nude mice Taking nude mice as test animals, the drug concentration in plasma at different times after the compound of Example 1 was administered by gavage to nude mice was determined by LC/MS/MS method. The pharmacokinetic behavior of the disclosed compounds in nude mice was studied, and their pharmacokinetic characteristics were evaluated.
  • mice Nine healthy adult nude mice, female, were purchased from Weitong Lihua Laboratory Animal Co., Ltd.
  • Nude mice were fasted overnight and then intragastrically administered. The dosage was 10 mg/kg, and the administration volume was 0.2 mL/10 g.
  • Nude mice were given the compound of Example 1 by gavage, and 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, and placed in an EDTA-K2 anticoagulation test tube at 4°C, 10000 Centrifuge at rpm for 1 minute, separate plasma within 1 hour, store at -20°C for testing, and operate under ice bath conditions until blood is collected until the centrifugation process.
  • Determination of the content of the test compound in the plasma of nude mice after oral administration of different concentrations of drugs take 25 ⁇ L of nude mouse plasma at each time after administration, add 50 ⁇ L of internal standard solution (100 ng/mL camptothecin), 200 ⁇ L of acetonitrile, and vortex. Spin and mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 0.1 ⁇ L of the supernatant from the plasma sample for LC/MS/MS analysis.

Abstract

La présente divulgation concerne un dérivé d'imidazopyrimidine, son procédé de préparation et son utilisation médicale. En particulier, la présente divulgation concerne un dérivé d'imidazopyrimidine tel que représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le dérivé et son utilisation en tant qu'agent thérapeutique, plus particulièrement son utilisation en tant qu'inhibiteur de l'ATR kinase et son utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention de maladies hyperprolifératives.
PCT/CN2021/104227 2020-07-02 2021-07-02 Dérivé d'imidazopyrimidine, son procédé de préparation et son utilisation médicale WO2022002243A1 (fr)

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