WO2022135555A1 - 嘌呤酮类化合物、其制备方法及其在医药上的应用 - Google Patents

嘌呤酮类化合物、其制备方法及其在医药上的应用 Download PDF

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WO2022135555A1
WO2022135555A1 PCT/CN2021/141052 CN2021141052W WO2022135555A1 WO 2022135555 A1 WO2022135555 A1 WO 2022135555A1 CN 2021141052 W CN2021141052 W CN 2021141052W WO 2022135555 A1 WO2022135555 A1 WO 2022135555A1
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cancer
methyl
membered
general formula
compound
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PCT/CN2021/141052
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English (en)
French (fr)
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陆标
沈晓冬
张俊珍
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 WO2022135555A1 publication Critical patent/WO2022135555A1/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
    • A61K31/495—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
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a purinone compound, a preparation method thereof and its application in medicine.
  • the present disclosure relates to a purinone compound represented by the general formula (I), a preparation method thereof and a pharmaceutical composition containing the compound, as well as its use in the preparation of DNA-PK inhibitors and in preparation for treatment and/or use in medicaments for the prevention of cancer.
  • DNA-dependent protein kinase is a serine/hydroxybutyrine protein kinase complex composed of a heterodimer of catalytic subunit DNA-PKcs and Ku protein (Ku70/Ku80), which is involved in the repair of DNA damage. It also plays an important role in maintaining the stability of telomerase, participating in innate immunity and V(D)J recombination, and transcriptional regulation (Curr Opin Allergy Clin Immunol, 2009, 9, 503–509).
  • NER nucleotide excision repair
  • BER base excision repair
  • MMR mismatch repair
  • DSBR double-strand break repair
  • DNA-PK DNA-dependent protein kinase
  • ATM ataxia telangiectasia mutant kinase
  • ATR ATM and Rad3-related kinase
  • the circular Ku70/Ku80 heterodimer recognizes and binds the broken DNA ends, recruiting DNA-PKcs.
  • the recruitment of DNA-PKcs promotes the movement of Ku heterodimers into DNA duplexes, so that DNA-PKcs can serve as tethers to break DNA ends and prevent degradation by exonucleases.
  • the binding to DNA promoted the activation of the catalytic activity of DNA-PKcs, and the main autophosphorylation sites were Ser2056 and Thr2609.
  • DNA-PKcs also leads to phosphorylation of a series of downstream proteins, including Artemis, DNA ligase 4, histone H2A variant (H2AX), etc., which together complete DNA double-strand repair (Nat Rev Clin Oncol., 2019, 81-104) .
  • DNA-PK is highly expressed in various types of tumor tissues and can lead to tumor metastasis by stimulating angiogenesis and tumor cell migration (Clin Cancer Res, 2019, 25, 5623-5637). Moreover, the increase of DNA-PK activity is closely related to chemotherapeutic drug resistance and poor prognosis. Studies have shown that DNA-PK inhibitors can significantly increase the sensitivity of tumor cells to x-ray irradiation (IR) and chemotherapeutic drugs, and increase the tumor suppressive effect of the PAPR inhibitor olaparib (Nat Commun., 2019, 10, 5065-5079 ; Mol Cancer Res., 2019, 17, 2457-2468).
  • IR x-ray irradiation
  • AstraZeneca and Merck have published several patents on DNA-PK inhibitors (WO2019238929A1, WO2018114999A1 and WO2014183850A1, etc.), and there is still room for improvement in both in vitro activity and selectivity of these structural types of compounds.
  • AstraZeneca's small molecule DNA-PK inhibitor entered the first clinical phase in October 2019.
  • No DNA-PK inhibitor drugs are currently approved for marketing, so there is a significant unmet medical need in the relevant patient population.
  • Ring A is a 6- to 14-membered polycyclic heterocyclyl
  • Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy and hydroxyalkyl;
  • R is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;
  • Each R is the same or different, and is each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkane base;
  • n 0, 1, or 2;
  • p 0, 1, 2, 3 or 4.
  • Ring A is selected from 6- to 14-membered spiro heterocyclyl, 6- to 14-membered bridged heterocyclyl and 6- to 14-membered fused heterocyclyl; preferably, Ring A is selected from 6- to 14-membered mono-spiroheterocyclyl, 6- to 14-membered bicyclic bridged heterocyclyl, and 6- to 14-membered bicyclic fused heterocyclyl; more preferably , ring A is a 6- to 14-membered single spiro heterocyclic group or a 6- to 14-membered bicyclic bridged heterocyclic group; further preferably, ring A is a 6- to 14-membered single spiro heterocyclic group containing one oxygen atom or a A 6- to 14-membered bicyclic bridged heterocyclyl group of an oxygen atom; most preferably, Ring A is
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is selected from 6- to 14-membered spiro heterocyclyl, 6- to 14-membered bridged heterocyclyl and 6- to 14-membered fused heterocyclic groups; preferably, Ring A is selected from 6- to 14-membered spiroheterocyclic groups containing 1 oxygen atom, 6- to 14-membered bridged heterocyclic groups containing 1 oxygen atom, and 1- A 6- to 14-membered fused heterocyclic group of oxygen atoms.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is selected from a 6- to 10-membered single spiro heterocyclyl group, a 6- to 10-membered bicyclic bridged heterocyclic group Ring group and 6- to 10-membered bicyclic fused heterocyclic group; preferably, ring A is selected from a 6- to 10-membered mono-spiroheterocyclic group containing 1 oxygen atom, a 6- to 10-membered bicyclic bridged heterocyclic ring containing 1 oxygen atom group and a 6- to 10-membered bicyclic fused heterocyclic group containing 1 oxygen atom; more preferably, Ring A is a 6- to 10-membered mono-spiroheterocyclic group containing 1 oxygen atom or a 6- to 10-membered heterocyclic group containing 1 oxygen atom membered bicyclic bridged heterocyclyl; most preferably, Ring A is a 6 to 10 membered bicyclic bridged heterocyclyl;
  • Ring A is selected from 6- to 8-membered mono-spiroheterocyclyl, 6- to 8-membered bicyclic bridged heterocyclyl Ring group and 6- to 8-membered bicyclic fused heterocyclic group; preferably, ring A is selected from a 6- to 8-membered single spiro heterocyclic group containing 1 oxygen atom, a 6- to 8-membered bicyclic bridged heterocyclic ring containing 1 oxygen atom group and a 6- to 8-membered bicyclic fused heterocyclic group containing 1 oxygen atom; more preferably, Ring A is a 6- to 8-membered mono-spiroheterocyclic group containing 1 oxygen atom or a 6- to 8-membered heterocyclic group containing 1 oxygen atom A membered bicyclic bridged heterocyclyl; most preferably, Ring A is a 6 to 8-membered mono-spiroheterocyclic group containing 1 oxygen atom or a 6- to 8-member
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is a hydrogen atom or a C 1-6 alkyl group; preferably, R 1 is a hydrogen atom .
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Selected from: (which is ), (which is ), Preferably, Selected from: (which is ), (which is )and More preferably, for (which is ).
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from: Preferably, for
  • each R 3 is the same or different, and each is independently selected from hydrogen atom, halogen, cyano and C 1-6 alkyl; preferably, R 3 is a hydrogen atom.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein each R 3 is the same or different, and each is independently selected from halogen, cyano and C 1- 6 alkyl, and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein p is 0 or 1; preferably, p is 0.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein each R 1 is a C 1-6 alkyl group, and p is 0 or 1.
  • Ring A is selected from a 6- to 10-membered spiro heterocyclic group containing 1 oxygen atom, a 6- to 10-membered bicyclic bridged heterocyclic groups containing 1 oxygen atom and 6- to 10-membered bicyclic fused heterocyclic groups containing 1 oxygen atom;
  • R 1 is hydrogen atom;
  • R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl;
  • each R 3 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a cyano group, and a C 1-6 alkyl group; and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is selected from a 6- to 10-membered spiro heterocyclic group containing 1 oxygen atom, a 6- to 10-membered bicyclic bridged heterocyclic group containing 1 oxygen atom and 6- to 10-membered bicyclic fused heterocyclic group containing 1 oxygen atom; p is 0; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl ; each R 3 is the same or different, and each is independently selected from halogen, cyano and C 1-6 alkyl, and n is 0 or 1.
  • Ring A is selected from a 6- to 10-membered spiro heterocyclic group containing 1 oxygen atom, a 6- to 10-membered bicyclic bridged heterocyclic groups containing 1 oxygen atom and 6- to 10-membered bicyclic fused heterocyclic groups containing 1 oxygen atom;
  • R 1 is hydrogen atom;
  • R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl;
  • each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, cyano, and C 1-6 alkyl;
  • n is 0 or 1; and p is 0.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is selected from a 6- to 8-membered spiro heterocyclic group containing 1 oxygen atom, a 6- to 8-membered bicyclic bridged heterocyclic groups containing 1 oxygen atom and 6- to 8-membered bicyclic fused heterocyclic groups containing 1 oxygen atom; p is 0; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl ; each R 3 is the same or different, and each is independently selected from halogen, cyano and C 1-6 alkyl, and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is a 6- to 10-membered spiro heterocyclic group containing 1 oxygen atom or a 1 A 6- to 10-membered bicyclic bridged heterocyclyl group with one oxygen atom; p is 0; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; each R 3 is the same or different, and each is independently selected from halogen, cyano and C 1-6 alkyl, and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is a 6- to 8-membered spiroheterocyclic group containing 1 oxygen atom or a 1- A 6- to 8-membered bicyclic bridged heterocyclyl group with one oxygen atom; p is 0; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; each R 3 is the same or different, and each is independently selected from halogen, cyano and C 1-6 alkyl, and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 6- to 10-membered bicyclic bridged heterocyclic group containing 1 oxygen atom; p is 0; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; each R 3 is the same or different, and each is independently selected from halogen, cyano and C 1-6 alkyl, and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 6- to 8-membered bicyclic bridged heterocyclic group containing 1 oxygen atom; p is 0; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; each R 3 is the same or different, and each is independently selected from halogen, cyano and C 1-6 alkyl, and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Selected from: (which is ), (which is ), R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 is hydrogen atom; and n is 0.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Selected from: (which is ), (which is )and R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; and n is 0.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein preferably
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is selected from any of the following compounds:
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is selected from any of the following compounds:
  • Typical compounds of the present disclosure include, but are not limited to:
  • Example 2 is the structure structure
  • the same name means the same substance, but the drawing method of the structural formula is different.
  • Another aspect of the present disclosure relates to a compound of general formula (IA) or a salt thereof:
  • X is a halogen; preferably a chlorine atom
  • Rings A , R1 and p are as defined in general formula (I).
  • the compound represented by the general formula (IA) of the present disclosure or its salt is selected from any of the following compounds:
  • the compound represented by the general formula (IA) or a salt thereof is selected from any of the following compounds:
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • compound 2e is the structure of and structure
  • the same name means the same substance, but the drawing method of the structural formula is different.
  • Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I) and Table A or a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • a compound of general formula (IA) or a salt thereof is subjected to a coupling reaction with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,
  • X is a halogen; preferably a chlorine atom
  • Ring A, R 1 to R 3 , n and p are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general formula (I) of the present disclosure and a compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts thereof.
  • the present disclosure further relates to the use of the compounds shown in the general formula (I) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a DNA-PK inhibitor.
  • the present disclosure further relates to the use of the compounds shown in the general formula (I) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the preparation of a medicament for the treatment and/or prevention of cancer, preferably in the preparation of Use in a medicament for the treatment and/or prevention of DNA-PK mediated cancer; wherein the cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, uterus Endometrial carcinoma, CNS tumor, dysembryoplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head
  • the present disclosure further relates to a method of inhibiting DNA-PK, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method of treating and/or preventing cancer, preferably a method of treating and/or preventing DNA-PK mediated cancer, comprising administering to a patient in need thereof a therapeutically effective amount of general formula (I) and Table A
  • the present disclosure further relates to a compound represented by the general formula (I) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure further relates to a compound of the general formula (I) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting DNA-PK.
  • the present disclosure further relates to a compound of general formula (I) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used for the treatment and/or prevention of cancer, preferably for the treatment and/or Prevention of DNA-PK mediated cancer; wherein said cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, embryonic development Adverse neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, Liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ova
  • the lymphomas described in the present disclosure are preferably selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma (eg, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma).
  • Hodgkin's lymphoma and non-Hodgkin's lymphoma eg, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma.
  • the lung cancer described in the present disclosure is preferably non-small cell lung cancer (NSCLC) (including lung squamous cell carcinoma, adenocarcinoma, large cell carcinoma, etc.) or small cell lung cancer (SCLC), more preferably non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • the renal cancer described in the present disclosure is preferably selected from renal cell carcinoma, clear cell carcinoma and renal oncocytoma.
  • the leukemia described in the present disclosure is preferably chronic leukemia (eg chronic lymphocytic leukemia) or acute leukemia (eg acute myeloid leukemia).
  • chronic leukemia eg chronic lymphocytic leukemia
  • acute leukemia eg acute myeloid leukemia
  • 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 may also 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 compound is preferably presented in a unit dose 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 may be presented 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 adjuvants, including fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the mode of administration, 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.
  • the aforementioned 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, mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids.
  • 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 following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.
  • the optimal treatment modality such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
  • the compounds of the present disclosure have good pharmacokinetic absorption activity in rats, and have the advantages of pharmacokinetics; they also have good oral pharmacokinetic absorption activities in mice, and oral biological High availability and pharmacokinetic advantages.
  • alkyl refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), and more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • 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
  • 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 base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-Dimethylbutyl, etc.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from deuterium atoms, halogens, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group preferably has 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), and more preferably has 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) 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, the substituents are preferably selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cyclic Alkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , one or more of heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group preferably has 2 to 6 carbon atoms (ie C 2-6 alkenyl).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, it is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , one or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group preferably has 2 to 6 carbon atoms (ie C 2-6 alkynyl).
  • Alkynyl may be substituted or unsubstituted, when substituted it is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , one or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like.
  • the alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of 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 having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 14 (eg 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (ie 3 to 14 membered cycloalkyl), preferably having 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), Most preferably have 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl).
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups 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.
  • a spiro atom a carbon atom shared between the monocyclic rings, which may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 6 to 10 yuan (eg 6, 7, 8, 9 or 10 yuan).
  • spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or poly-spirocycloalkyl groups (eg, bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups or double-spirocycloalkyl groups base.
  • spirocycloalkyl More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 3 yuan/6 yuan, 3 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan 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 6 to 10 yuan (eg 6, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered RMB/6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 5/ 7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan bicycloalkyl.
  • 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 6 to 10 yuan (eg 6, 7, 8, 9 or 10 yuan). According to the number of composing rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl, preferably selected from bicyclic, tricyclic and tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl group (including monocyclic, spirocyclic, fused and bridged rings) as described above fused to an aryl, heteroaryl or heterocyclyl ring, wherein the parent structure is attached at Rings taken together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of 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 having 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 -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • 3 to 14 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) ) is a heteroatom (ie, a 3- to 14-membered heterocyclyl group) (eg, a 4- to 12-membered heterocyclyl group containing at least one oxygen atom); more preferably, has 3 to 8 ring atoms (eg, 3, 4, 5, 6 , 7, and 8), wherein 1-3 are heteroatoms (eg, 1, 2, and 3) (ie, a 3- to 8-membered heterocyclyl group) (eg, a 3- to 8-membered heterocyclyl group containing at least one oxygen atom); or having 6 to 14 ring atoms (e.g.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base and homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, 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.
  • 6 to 14 membered eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered
  • 6 to 14 membered spiroheterocyclyl containing at least one oxygen atom more preferably 6 to 10 membered (eg 6, 7, 8, 9 or 10 membered) (eg 6 to 10 membered spiroheterocyclyl containing at least one oxygen atom), most preferably 6 to 8 membered (eg 6, 7, 8 membered) (eg containing at least one oxygen atom) 6- to 8-membered spiroheterocyclyl with one oxygen atom).
  • spiroheterocyclyls are divided into mono-spiroheterocyclyls or poly-spiroheterocyclyls (such as bis-spiroheterocyclyls), preferably mono-spiroheterocyclyls and bis-spiroheterocyclyls group, more preferably a mono-spiroheterocyclic group (such as a 6- to 10-membered mono-spiro-heterocyclic group containing at least one oxygen atom), most preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 3-membered/6-membered, 3-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered monospiro
  • 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.
  • 6 to 14 membered eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered
  • 6 to 14 membered fused heterocyclic group containing at least one oxygen atom are preferred, and 6 to 10 membered are more preferred (eg 6, 7, 8, 9 or 10 membered) (eg 6 to 10 membered fused heterocyclic group containing at least one oxygen atom), most preferably 6 to 8 membered (eg 6 to 8 membered containing at least one oxygen atom) fused heterocyclyl).
  • bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups preferably bicyclic or tricyclic fused heterocyclic groups, more preferably bicyclic fused heterocyclic groups (such as those containing at least one oxygen atom) 6 to 14-membered bicyclic fused heterocyclic group), most preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan /7-
  • bridged heterocyclyl refers to a 5- to 20-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.
  • 6 to 14 membered eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered
  • 6 to 14 membered bridged heterocyclyl containing at least one oxygen atom more preferably 6 to 10 membered (eg 6 to 10 membered bridged heterocyclyl containing at least one oxygen atom) (eg 6, 7, 8, 9 or 10 membered), most preferably 6 to 8 membered (eg 6 to 8 membered containing at least one oxygen atom) bridged heterocyclyl).
  • bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups, most preferably Bicyclic bridged heterocyclic groups (eg, 6- to 14-membered bicyclic bridged heterocyclic groups containing at least one oxygen atom) are preferred.
  • Bicyclic bridged heterocyclic groups eg, 6- to 14-membered bicyclic bridged heterocyclic groups containing at least one oxygen atom
  • double-bridged heterocyclyl 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, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • 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 may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • 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 a 5- to 10-membered (eg 5, 6, 7, 8, 9 or 10-membered) heteroaryl, more preferably a 5- or 6-membered heteroaryl, eg furyl, thienyl, pyridyl, pyrrolyl , N-alkylpyrrolyl, 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 may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • 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.
  • the derived residues are "cycloalkylene", “heterocyclylene”, “arylene”, “heteroarylene”.
  • amino protecting group refers to a group introduced on an amino group that is easily removed in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and para methoxybenzyl, etc. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy and 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. GMWuts) for hydroxyl protecting groups.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl base, benzoyl, p-nitrobenzoyl, etc.
  • 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 refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate 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.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • tautomer or tautomeric form refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, keto-enol, imine-enamine, lactam-lactam isomerization. An example of a lactam-lactam equilibrium is between A and B as shown below:
  • the compounds of the present disclosure include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with18F -fluorine labeling ( 18F isotope), or enriching with11C- , 13C- , or14C- Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) are replaced by carbon atoms are within the scope of the present 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.
  • deuterated forms of the compounds of the present disclosure mean that 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.
  • Commercially available 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.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 6, 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 compounds of the present disclosure. Such salts are safe and effective when used in mammals, and have due 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.
  • 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 the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • X is a halogen; preferably a chlorine atom
  • Ring A, R 1 to R 3 , n and p are as defined in general formula (I).
  • 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, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride , potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably cesium carbonate.
  • Catalysts used in the above synthesis scheme include but are not limited to tetrakis(triphenylphosphine)palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2 ',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis (Dibenzylphosphorus)dipentyl iron palladium dichloro, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, [1,1'-bis(diphenylphosphino) Ferrocene]dichloropalladium dichloromethane complex and tris(dibenzylideneacetone)dipalladium, etc., preferably methan
  • the reaction of the above steps 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, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate Ester, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and its mixtures.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate Ester, n-hexane
  • 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: 6110/6120Quadrupole 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 1260DAD 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.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • 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 solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: In the dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • Methyl 2,4-dichloropyrimidine-5-carboxylate 1a (400 mg, 1.93 mmol, prepared by the method disclosed in the patent application "WO2013177168A1, P34”) was dissolved in 10 mL of acetonitrile, and 2-oxaspiro[ 3.3] Hept-6-amine hydrochloride 1b (290 mg, 1.94 mmol, Yaoshi) and potassium carbonate (650 mg, 4.70 mmol), stirred for 17 hours. Filtration, washing with ethyl acetate, the resulting organic phase was concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent system A to give the title product 1c (545 mg), yield: 98.2%.
  • compound 1d (330 mg, 1.22 mmol) was dissolved in 10 mL of N,N-dimethylacetamide, diphenylphosphoryl azide (298 mg, 1.22 mmol) and triethylamine (124 mg, 1.22 mmol) were added successively mmol) and stirred for 1 hour. Heat to 120°C and stir for 17 hours. Poured into water, filtered and washed with water to give the title product 1e (170 mg), yield: 52.1%.
  • compound 2c 250 mg, 0.88 mmol was dissolved in 10 mL of N,N-dimethylacetamide, followed by addition of diphenylphosphoryl azide (215 mg, 0.88 mmol) and triethylamine (90 mg, 0.89 mmol), and after stirring for 1 hour, it was heated to 120° C. and stirred for 17 hours. Poured into water, filtered and washed with water to give the title product 2d (240 mg), yield: 97.1%.
  • Example 2-1 Example 2-1 and Example 2-2
  • Example 3 Example 3-1 and Example 3-2
  • the level of phosphorylated P53 was detected by HTRF method, reflecting the inhibitory effect of the compound on DNA-PK enzyme activity, and the in vitro activity of the compound was evaluated according to the IC50 of the inhibitory effect.
  • Substrate P53 (Eurofins) was diluted with reaction buffer [25mM HEPES (Gibco, #15630-080) pH 8.0, 0.01% Brij-35 (Thermo, #20150), 1% glycerol (Sanko, #A100854-0100)] , #14-952-M) to 500nM; with dilution buffer [25mM HEPES pH8.0, 0.01% Brij-35, 1% glycerol, 5mM DTT (Sankong, #B645939), 1mg/mL BSA (Biyuntian, #ST023)]
  • DNA-PK enzyme (Eurofins, #14-950M) was diluted to 0.16 nM; magnesium acetate (Sigma, #63052) was diluted to 40 mM with dilution buffer followed by ATP (Thermo, #PV3227) to 29.2 ⁇ M.
  • a liquid workstation (PV3227, #SP2-096-0125-03) was used to sequentially add 10 ⁇ L of the prepared compound (the compound was diluted with DMSO), 2.5 ⁇ L of DNA-PK enzyme, and 500 nM P53 bottom in a 384-well plate (Thermo, #267462). 2.5 ⁇ L of ATP and 5 ⁇ L of ATP. After mixing, incubate at 25°C for 1 hour.
  • Stop solution [12.5 mM HEPES pH8.0, 0.005% Brij-35, 0.5% glycerol, 250 mM EDTA (Thermo, #AM9260G)] and detection mixture [50 mM HEPES pH7.0, 150 mM were sequentially added to a 384-well plate using a liquid workstation NaCl (Sankong, #B548121), 267mM KF (Sinopharm, 7789-23-3), 0.1% sodium cholate (Sigma, #C6445), 0.01% Tween 20 (Sigma, #P7949), 0.0125% azide Sodium (Sigma, #S8032), anti-phospho-p53Eu (Cisbio, #61P08KAE) 0.42ng/well and anti-GST-d2 (Cisbio, 61GSTDLF) 25ng/well] 5 ⁇ L each, incubated overnight at 25°C. The absorbance at 665 nm and 620 nm was read using a microplate reader
  • the cytotoxicity of the compounds on non-small cell lung cancer cell line A549 was studied by detecting the intracellular ATP level to reflect the cell activity, and the in vitro activity of the compounds was evaluated according to the IC50 of the killing effect.
  • A549 cells (ATCC, CCL-185) were digested with trypsin (Gibico, 25200-072) at 37°C for 3 min and treated with complete medium [F-12K medium (Gibico, 21127030), 10% FBS (ThermoFisher Scientific, 10099- 141)] were resuspended and counted, 1000 cells were added to each well of a 96-well plate (Corning, 3903), and then placed in a CO 2 constant temperature incubator (Thermo Fisher, HERAcell 240i) for overnight incubation at 37°C.
  • Compounds were prepared (compounds were diluted with DMSO) using Bravo Liquid Workstation (Agilent Technologies, SGS120TH34702), and the prepared compounds were diluted with complete medium for use. Take out the cell culture plate, aspirate 10 ⁇ L of the culture medium, add 5 ⁇ L of the diluted compound, and put it back into the CO 2 constant temperature incubator for 1 hour. Bleomycin (selleck, S1214) was diluted to 20 uM using complete medium and 5 ⁇ L per well (final concentration 500 nM) was added to the plate. Return the culture plate to the CO 2 constant temperature incubator to continue the culture.
  • the disclosed compounds have a good inhibitory effect on the proliferation of DNA-PK cells.
  • LC/MS/MS method was used to determine the drug concentrations in plasma at different times after rats were given the compound of Example 2-2 and the positive control compound by gavage (ig)/intravenous injection (iv).
  • the pharmacokinetic behavior of the disclosed compounds in rats was studied, and their pharmacokinetic characteristics were evaluated.
  • the positive control compound (see the compound in Example 3 of WO2018114999A1, prepared according to this example), has the following structure:
  • Example 2-2 compound and positive control compound administration solution weigh a certain amount of Example 2-2 compound and positive control compound, add 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology) Co., Ltd.) to dissolve it, and then add 90% normal saline to prepare a 0.2 mg/mL clear solution.
  • Example 2-2 Compound Dosing Solution A certain amount of Example 2-2 compound was weighed, and 0.5% CMC-Na was added to make it a homogeneous suspension solution.
  • Oral administration scheme 1 The rats were fasted overnight and then administered by intragastric administration. The dosage was 2.0 mg/kg, and the administration volume was 10.0 mL/kg.
  • Oral administration scheme 2 The rats were fasted overnight and then administered by intragastric administration.
  • the dosage of the compound of Example 2-2 was 60.0 mg/kg, the dosage of the positive control compound was 300 mg/kg, and the administration volume was 10.0 mg/kg. mL/kg.
  • Intravenous injection Intravenous injection in rats, the dosage is 1.0 mg/kg, and the administration volume is 5.0 mL/kg.
  • Rats were administered the compound of Example 2-2 and the positive control compound by gavage. Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the orbit and placed into In an EDTA-K2 anticoagulation test tube, centrifuge at 10,000 rpm for 1 minute (4°C), separate the plasma within 1 hour, and store at -20°C for testing. The blood was collected and centrifuged under ice bath conditions, and food was taken 2 h after administration.
  • Example 2-2 The compound of Example 2-2 and the positive control compound were intravenously injected into rats, and blood was collected from the orbit before administration and 5 minutes after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours. gavage group.
  • Determination of the content of the test compound in rat plasma after drug administration of different concentrations take 25 ⁇ L of rat plasma at each time after administration, add 50 ⁇ L of internal standard solution camptothecin (100 ng/mL) and 200 ⁇ L of acetonitrile, and mix by vortex 5 min, centrifuged for 10 min (3700 g), and 0.5 ⁇ L of the supernatant from the plasma sample was analyzed by LC/MS/MS.
  • the disclosed compounds have good pharmacokinetic absorption activity in rats, and have the advantages of pharmacokinetics.
  • mice Using mice as test animals, the LC/MS/MS method was used to determine the drug concentrations in the plasma at different times after the mice were given the compound of Example 2-2 and the positive control compound by gavage (ig)/intravenous injection (iv). The pharmacokinetic behavior of the disclosed compounds in mice was studied, and their pharmacokinetic characteristics were evaluated.
  • the positive control compound (see the compound in Example 3 of WO2018114999A1, prepared according to this example) has the following structure:
  • mice Female, divided into 4 groups on average, were purchased from Weitong Lihua Laboratory Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2017-0005.
  • Example 2-2 Weigh a certain amount of the compound of Example 2-2 and the positive control compound, add 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then add 90% normal saline to prepare 0.1 mg/ mL clear solution.
  • Oral administration Mice were administered by intragastric administration, the dosage was 2.0 mg/kg, and the administration volume was 20.0 mL/kg.
  • Intravenous injection The mice were administered intravenously, and the dose was 1.0 mg/kg, and the administration volume was 10.0 mL/kg.
  • mice were administered the compound of Example 2-2 and the positive control compound by gavage. Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbit of the eye. In an EDTA-K2 anticoagulation test tube, centrifuge at 10,000 rpm for 1 minute (4°C), separate the plasma within 1 hour, and store at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions.
  • Example 2-2 The compound of Example 2-2 and the positive control compound were intravenously injected into mice, and 0.1 mL of blood was collected from the orbit at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours before administration and 5 minutes after administration.
  • the treatment was the same as the gavage group.
  • Determination of the content of the test compound in mouse plasma after drug administration of different concentrations take 30 ⁇ L of mouse plasma at each time after administration, add 300 ⁇ L of methanol (including internal standard solution camptothecin (10ng/mL)), vortex After mixing for 1 minute, centrifugation for 7 minutes (18000g), 1 ⁇ L of the supernatant of the plasma sample was taken for LC/MS/MS analysis.
  • methanol including internal standard solution camptothecin (10ng/mL)
  • the disclosed compounds have good oral pharmacokinetic absorption activity in mice, high oral bioavailability and pharmacokinetic advantages.

Abstract

一种通式(I)所示的嘌呤酮类化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是在制备DNA-PK抑制剂中的用途和在制备用于治疗和/或预防癌症的药物中的用途。

Description

嘌呤酮类化合物、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，涉及一种嘌呤酮类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的嘌呤酮类化合物、其制备方法及含有该类化合物的药物组合物，以及其在制备DNA-PK抑制剂中的用途和在制备用于治疗和/或预防癌症的药物中的用途。
背景技术
DNA依赖性蛋白激酶(DNA-PK)是由催化亚基DNA-PKcs和Ku蛋白(Ku70/Ku80)的异二聚体组成的丝氨酸/羟丁氨酸蛋白激酶复合物，是DNA损伤修复过程中的一个重要蛋白(Cancer Discovery,2014,4,1126-1139)，在维持端粒酶的稳定性，参与天然免疫及V(D)J重组，以及转录调节等方面也发挥着重要作用(Curr Opin Allergy Clin Immunol,2009,9,503–509)。
真核生物的DNA修复主要有4种类型：核苷酸切除修复(NER)、碱基切除修复(BER)、错配修复(MMR)和双链断裂修复(DSBR)。NER可切除大片段的DNA损伤，BER可修复个别碱基的损伤，MMR用于修复碱基的错配，而DSBR又包括两种机制：非同源末端连接(NHEJ)和同源重组(HR)。NHEJ直接连接断端而不需要模板，HR需要使用完整的姐妹染色单体作为修复模板。NHEJ是最主要的修复途径，在细胞周期的所有期中均能发生。而HR主要发生在细胞周期的G2/M期(ChemMedChem,2017,12,895–900)。在DNA损伤修复中起主导作用的是三个PI3K相关激酶(PIKK)家族的激酶：DNA依赖性蛋白激酶(DNA-PK)，毛细血管扩张性共济失调症突变激酶(ATM)，以及ATM和Rad3相关激酶(ATR)。DNA-PK主要参与NHEJ途径，ATM主要参与HR途径，而ATR主要修复单链DNA损伤(Nat Rev Clin Oncol.,2019,81-104)。
当DNA双链断裂时，环状Ku70/Ku80异源二聚体识别和结合断裂的DNA末端，招募DNA-PKcs。DNA-PKcs的募集促进了Ku异源二聚体向DNA双链体中的移动，使得DNA-PKcs可用作断裂DNA末端的系链并防止外切核酸酶的降解。同时，与DNA的结合促进了DNA-PKcs催化活性的激活，主要的自磷酸化位点是Ser2056和Thr2609。DNA-PKcs还导致一系列下游蛋白的磷酸化，包括Artemis、DNA连接酶4、组蛋白H2A变体(H2AX)等，共同完成DNA双链修复(Nat Rev Clin Oncol.,2019,81-104)。
DNA-PK在多种类型的肿瘤组织中均有高表达，可以通过刺激血管再生及肿瘤细胞迁移导致肿瘤转移(Clin Cancer Res,2019,25,5623-5637)。而且DNA-PK活性的增加与化疗药的耐药及较差的预后密切相关。研究表明，DNA-PK抑制剂能明显增加肿瘤细胞对x线辐照(IR)及化疗药的敏感性，并增加PAPR抑制剂olaparib 的抑瘤作用(Nat Commun.,2019,10,5065-5079；Mol Cancer Res.,2019,17,2457-2468)。
目前以AstraZeneca和Merck为代表的公司发表了若干DNA-PK抑制剂的专利(WO2019238929A1、WO2018114999A1和WO2014183850A1等)，这些结构类型的化合物无论是体外活性还是选择性都还有提高的空间。其中AstraZeneca的小分子DNA-PK抑制剂于2019年10月进入临床一期。目前还没有DNA-PK抑制剂药物被批准上市，因此相关病患人群中存在重大未满足的医学需求。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
Figure PCTCN2021141052-appb-000001
其中：
环A为6至14元多环杂环基；
各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氧代基、氰基、氨基、硝基、羟基和羟烷基；
R 2选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
各个R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
n为0、1或2；且
p为0、1、2、3或4。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自6至14元螺杂环基、6至14元桥杂环基和6至14元稠杂环基；优选地，环A选自6至14元单螺杂环基、6至14元双环桥杂环基和6至14元双环稠杂环基；更优选地，环A为6至14元单螺杂环基或6至14元双环桥杂环基；进一步优选地，环A为含有1个氧原子的6至14元单螺杂环基或含有1个氧原子的6至14元双环桥杂环基；最优选地，环A为含有1个氧原子的6至14元双环桥杂环基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自6至14元螺杂环基、6至14元桥杂环基和6至14元稠杂环基；优选 地，环A选自含有1个氧原子的6至14元螺杂环基、含有1个氧原子的6至14元桥杂环基和含有1个氧原子的6至14元稠杂环基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自6至10元单螺杂环基、6至10元双环桥杂环基和6至10元双环稠杂环基；优选地，环A选自含有1个氧原子的6至10元单螺杂环基、含有1个氧原子的6至10元双环桥杂环基和含有1个氧原子的6至10元双环稠杂环基；更优选地，环A为含有1个氧原子的6至10元单螺杂环基或含有1个氧原子的6至10元双环桥杂环基；最优选地，环A为含有1个氧原子的6至10元双环桥杂环基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自6至8元单螺杂环基、6至8元双环桥杂环基和6至8元双环稠杂环基；优选地，环A选自含有1个氧原子的6至8元单螺杂环基、含有1个氧原子的6至8元双环桥杂环基和含有1个氧原子的6至8元双环稠杂环基；更优选地，环A为含有1个氧原子的6至8元单螺杂环基或含有1个氧原子的6至8元双环桥杂环基；最优选地，环A为含有1个氧原子的6至8元双环桥杂环基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中R 1为氢原子或C 1-6烷基；优选地，R 1为氢原子。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
Figure PCTCN2021141052-appb-000002
选自：
Figure PCTCN2021141052-appb-000003
(即
Figure PCTCN2021141052-appb-000004
)、
Figure PCTCN2021141052-appb-000005
(即
Figure PCTCN2021141052-appb-000006
)、
Figure PCTCN2021141052-appb-000007
优选地，
Figure PCTCN2021141052-appb-000008
选自：
Figure PCTCN2021141052-appb-000009
(即
Figure PCTCN2021141052-appb-000010
Figure PCTCN2021141052-appb-000011
)、
Figure PCTCN2021141052-appb-000012
(即
Figure PCTCN2021141052-appb-000013
)和
Figure PCTCN2021141052-appb-000014
更优选地，
Figure PCTCN2021141052-appb-000015
为
Figure PCTCN2021141052-appb-000016
(即
Figure PCTCN2021141052-appb-000017
Figure PCTCN2021141052-appb-000018
)。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
Figure PCTCN2021141052-appb-000019
选自：
Figure PCTCN2021141052-appb-000020
优选地，
Figure PCTCN2021141052-appb-000021
为
Figure PCTCN2021141052-appb-000022
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中R 2选自氢原子、卤素和C 1-6烷基；优选地，R 2为氢原子。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中各个R 3相同或不同，且各自独立地选自氢原子、卤素、氰基和C 1-6烷基；优选地，R 3为氢原子。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中各个R 3相同或不同，且各自独立地选自卤素、氰基和C 1-6烷基，且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中p为0或1；优选地，p为0。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中各个R 1为C 1-6烷基，且p为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自含有1个氧原子的6至10元单螺杂环基、含有1个氧原子的6至10元双环桥杂环基和含有1个氧原子的6至10元双环稠杂环基；R 1为氢原子；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、氰基和C 1-6烷基；且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自含有1个氧原子的6至10元单螺杂环基、含有1个氧原子的6至10元双环桥杂环基和含有1个氧原子的6至10元双环稠杂环基；p为0；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自卤素、氰基和C 1-6烷基，且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自含有1个氧原子的6至10元单螺杂环基、含有1个氧原子的6至10元双环桥杂环基和含有1个氧原子的6至10元双环稠杂环基；R 1为氢原子；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、氰基和C 1-6烷基；n为0或1；且p为0。在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自含有1个氧原子的6至8元单螺杂环基、含有1个氧原子的6至8元双环桥杂环基和含有1个氧原子的6至8元双环稠杂环基；p为0；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自卤素、氰基和C 1-6烷基，且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为含有1个氧原子的6至10元单螺杂环基或含有1个氧原子的6至10元双环桥杂环基；p为0；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自卤素、氰基和C 1-6烷基，且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为含有1个氧原子的6至8元单螺杂环基或含有1个氧原子的6至8元双环桥杂环基；p为0；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自卤素、氰基和C 1-6烷基，且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为含有1个氧原子的6至10元双环桥杂环基；p为0；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自卤素、氰基和C 1-6烷基，且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为含有1个氧原子的6至8元双环桥杂环基；p为0；R 2选自氢原子、卤素和C 1-6烷基；各个R 3相同或不同，且各自独立地选自卤素、氰基和C 1-6烷基，且n为0或1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
Figure PCTCN2021141052-appb-000023
选自：
Figure PCTCN2021141052-appb-000024
(即
Figure PCTCN2021141052-appb-000025
)、
Figure PCTCN2021141052-appb-000026
(即
Figure PCTCN2021141052-appb-000027
)、
Figure PCTCN2021141052-appb-000028
R 2选自氢原子、卤素和C 1-6烷基；R 3为氢原子；且n为0。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
Figure PCTCN2021141052-appb-000029
选自：
Figure PCTCN2021141052-appb-000030
(即
Figure PCTCN2021141052-appb-000031
)、
Figure PCTCN2021141052-appb-000032
(即
Figure PCTCN2021141052-appb-000033
)和
Figure PCTCN2021141052-appb-000034
R 2选自氢原子、卤素和C 1-6烷基；且n为0。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
Figure PCTCN2021141052-appb-000035
为
Figure PCTCN2021141052-appb-000036
(即
Figure PCTCN2021141052-appb-000037
)；R 2选自氢原子、卤素和C 1-6烷基；且n为0。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
Figure PCTCN2021141052-appb-000038
优选为
Figure PCTCN2021141052-appb-000039
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,3r,5S))-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,3s,5S))-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮；
(±)7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
(R)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
(S)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,5S,6s)-3-氧杂二环并[3.1.0]己-6-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：
Figure PCTCN2021141052-appb-000040
(即
Figure PCTCN2021141052-appb-000041
)、
Figure PCTCN2021141052-appb-000042
表A本公开的典型化合物包括但不限于：
Figure PCTCN2021141052-appb-000043
Figure PCTCN2021141052-appb-000044
Figure PCTCN2021141052-appb-000045
本领域的技术人员可容易得知，实施例2化合物即结构
Figure PCTCN2021141052-appb-000046
结构
Figure PCTCN2021141052-appb-000047
命名相同，即为同一种物质，只是结构式的画法不同。
本公开的另一方面涉及通式(IA)所示的化合物或其盐：
Figure PCTCN2021141052-appb-000048
其中：
X为卤素；优选为氯原子；
环A、R 1和p如通式(I)中所定义。
本公开通式(IA)所示的化合物或其盐，选自以下任一化合物：
2-氯-7-甲基-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,3r,5S))-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,3s,5S))-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮2-氯-7-甲基-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
(R)-2-氯-7-甲基-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
(S)-2-氯-7-甲基-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
9-((1R,5S,6s)-3-氧杂二环并[3.1.0]己-6-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮。
进一步地，所述通式(IA)所示的化合物或其盐，其选自以下任一化合物：
Figure PCTCN2021141052-appb-000049
(即
Figure PCTCN2021141052-appb-000050
)、
Figure PCTCN2021141052-appb-000051
表B本公开的典型中间体化合物包括但不限于：
Figure PCTCN2021141052-appb-000052
Figure PCTCN2021141052-appb-000053
Figure PCTCN2021141052-appb-000054
本领域的技术人员可容易得知，化合物2e即结构
Figure PCTCN2021141052-appb-000055
和结构
Figure PCTCN2021141052-appb-000056
命名相同，即为同一种物质，只是结构式的画法不同。
本公开的另一方面涉及一种制备通式(I)以及表A所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
Figure PCTCN2021141052-appb-000057
通式(IA)的化合物或其盐与通式(IB)的化合物或其盐发生偶联反应，得到通式(I)的化合物或其可药用的盐，
其中：
X为卤素；优选为氯原子；
环A、R 1至R 3、n和p如通式(I)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)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备DNA-PK抑制剂中的用途。
本公开进一步涉及通式(I)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备用于治疗和/或预防癌症的药物中的用途，优选为在制备用于治疗和/或预防DNA-PK介导的癌症的药物中的用途；其中所述的癌症优选选自白血病、多发性骨髓瘤、淋巴瘤、骨髓增生异常综合征、乳腺癌、肺癌、子宫内膜癌、中枢神经***肿瘤、胚胎发育不良性神经上皮肿瘤、多形性成胶质细胞瘤、混合性胶质瘤、成神经管细胞瘤、成视网膜细胞瘤、成神经细胞瘤、生殖细胞瘤、畸胎瘤、胃癌、食道癌、肝癌、胆管细胞癌、结直肠癌、小肠癌、胰腺癌、皮肤癌、黑色素瘤、甲状腺癌、头颈癌、唾液腺癌、***癌、睾丸癌、卵巢癌、***、外阴癌、膀胱癌、肾癌、鳞状细胞癌、肉瘤、胃肠道间质瘤(GIST)和儿科癌症；其中所述的结直肠癌优选为结肠癌或直肠癌；所述的肉瘤优选选自软骨肉瘤、平滑肌肉瘤、软组织肉瘤、尤文氏肉瘤和卡波氏肉瘤。本公开进一步涉及一种抑制DNA-PK的方法，其包括给予所需患者治疗有效量的通式(I)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物。
本公开进一步涉及一种治疗和/或预防癌症的方法，优选为治疗和/或预防DNA-PK介导的癌症的方法，其包括给予所需患者治疗有效量的通式(I)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物；其中所述的癌症优选选自白血病、多发性骨髓瘤、淋巴瘤、骨髓增生异常综合征、乳腺癌、肺癌、子宫内膜癌、中枢神经***肿瘤、胚胎发育不良性神经上皮肿瘤、多形性成胶质细胞瘤、混合性胶质瘤、成神经管细胞瘤、成视网膜细胞瘤、成神经细胞瘤、生殖细胞瘤、畸胎瘤、胃癌、食道癌、肝癌、胆管细胞癌、结直肠癌、小肠癌、胰腺癌、皮肤癌、黑色素瘤、甲状腺癌、头颈癌、唾液腺癌、***癌、睾丸癌、卵巢癌、***、外阴癌、膀胱癌、肾癌、鳞状细胞癌、肉瘤、胃肠道间质瘤(GIST)和儿科癌症；其中所述的结直肠癌优选为结肠癌或直肠癌；所述的肉瘤优选选自软骨肉瘤、平滑肌肉瘤、软组织肉瘤、尤文氏肉瘤和卡波氏肉瘤。
本公开进一步涉及一种通式(I)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物，其用作抑制DNA-PK的药物。
本公开进一步涉及一种通式(I)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物，其用于治疗和/或预防癌症，优选用于治疗和/或预防DNA-PK介导的癌症；其中所述的癌症优选选自白血病、多发性骨髓瘤、淋巴瘤、 骨髓增生异常综合征、乳腺癌、肺癌、子宫内膜癌、中枢神经***肿瘤、胚胎发育不良性神经上皮肿瘤、多形性成胶质细胞瘤、混合性胶质瘤、成神经管细胞瘤、成视网膜细胞瘤、成神经细胞瘤、生殖细胞瘤、畸胎瘤、胃癌、食道癌、肝癌、胆管细胞癌、结直肠癌、小肠癌、胰腺癌、皮肤癌、黑色素瘤、甲状腺癌、头颈癌、唾液腺癌、***癌、睾丸癌、卵巢癌、***、子宫癌、外阴癌、膀胱癌、肾癌、鳞状细胞癌、肉瘤、胃肠道间质瘤(GIST)和儿科癌症；其中所述的结直肠癌优选为结肠癌或直肠癌；所述的肉瘤优选选自软骨肉瘤、平滑肌肉瘤、软组织肉瘤、尤文氏肉瘤和卡波氏肉瘤。
本公开所述的淋巴瘤优选选自霍奇金淋巴瘤和非霍奇金淋巴瘤(例如套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、边缘区B细胞淋巴瘤、淋巴浆细胞淋巴瘤和外周T细胞淋巴瘤)。
本公开所述的肺癌优选为非小细胞肺癌(NSCLC)(包括肺鳞状细胞癌、腺癌和大细胞癌等)或小细胞肺癌(SCLC)，更优选为非小细胞肺癌(NSCLC)。
本公开所述的肾癌优选选自肾细胞癌、透明细胞癌和肾嗜酸细胞瘤。
本公开所述的白血病优选为慢性白血病(例如慢性淋巴细胞白血病)或急性白血病(例如急性髓性白血病)。
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，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药、吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，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现方式可以是片剂、胶囊、扁囊剂、瓶装药水、粉剂、颗粒剂、锭剂、栓剂、再生粉末或液体制剂。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，所述辅料包括填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方式的不同，组合物可含有0.1至99重量％的活性化合物。
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。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐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、***的速率、药物的组合、疾病的严重性等。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。
经药代动力学实验验证，本公开化合物在大鼠体内均具有很好的药代吸收活性，具有药代动力学优势；在小鼠体内也均具有很好的口服药代吸收活性，口服生物利用度高，具有药代动力学优势。
术语说明
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”指饱和的直链或支链脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C 1-12烷基)，更优选具有1至6个碳原子的烷基(即C 1-6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。最优选具有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，其可以在任何可使用的连接点上被取代，取代基优选选自氘原子、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、芳基和杂芳基中的一个或多个。
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20亚烷基)。所述亚烷基，优选具有1至12个碳原子(即C 1-12亚烷基)，更优选具有1至6个碳原子(即C 1-6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，其可以在任何可使用的连接点上被取代，取代基优选选自烯基、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。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上 所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 2-12烯基)。所述烯基优选具有2至6个碳原子(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其优选选自烷氧基、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。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 2-12炔基)。所述炔基优选具有2至6个碳原子(即C 2-6炔基)。炔基可以是取代的或非取代的，当被取代时，其优选选自烷氧基、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。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、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、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基，环烷基环具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即3至20元环烷基)，优选具有3至14个(例如3、4、5、6、7、8、9、10、11、12、13和14个)碳原子(即3至14元环烷基)，优选具有3至8个碳原子(即3至8元环烷基)，最优选具有3至6个碳原子(即3至6元环烷基)。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烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指5至20元，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6至10元(例如6、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或多螺环烷基(如双螺环烷基)，优选为单螺环烷基或双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元、3元/6元、3元/5元、5元/6元或6元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021141052-appb-000058
术语“稠环烷基”指5至20元，***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6至10元(例如6、7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环稠环烷基，优选为双环或三环稠环烷基，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/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021141052-appb-000059
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6至10元(例如6、7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环桥环烷基，优选选自双环、三环和四环桥环烷基，更优选为双环或三环桥环烷基。桥环烷基的非限制性实例包括：
Figure PCTCN2021141052-appb-000060
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
Figure PCTCN2021141052-appb-000061
等；优选
Figure PCTCN2021141052-appb-000062
Figure PCTCN2021141052-appb-000063
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、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、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其具有3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子 为碳。优选具有3至14个(例如3、4、5、6、7、8、9、10、11、12、13和14个)环原子，其中1～4个(例如1、2、3和4个)是杂原子(即3至14元杂环基)(例如含有至少一个氧原子的4至12元杂环基)；更优选具有3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)(即3至8元杂环基)(例如含有至少一个氧原子的3至8元杂环基)；或具有6至14个环原子(例如6、7、8、9、10、11、12、13和14个)，其中1-3是杂原子(例如1、2和3个)(即6至14元杂环基)(例如含有至少一个氧原子的6至14元杂环基)；或者具有6至10个环原子(例如6、7、8、9、10个)，其中1-3是杂原子(例如1、2和3个)(即6至10元杂环基)(例如含有至少一个氧原子的6至10元杂环基)；或者具有6至8个环原子(例如6、7、8个)，其中1-3是杂原子(例如1、2和3个)(即6至8元杂环基)(例如含有至少一个氧原子的6至8元杂环基)；或者具有3至6个环原子，其中1-3个(例如1、2和3个)是杂原子(即3至6元杂环基)(例如含有至少一个氧原子的3至6元杂环基)；或者具有5或6个环原子，其中1-3个是杂原子(即5或6元杂环基)。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、硫代吗啉基和高哌嗪基等。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元，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、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选6至14元(例如6、7、8、9、10、11、12、13和14元)(例如含有至少一个氧原子的6至14元螺杂环基)，更优选6至10元(例如6、7、8、9或10元)(例如含有至少一个氧原子的6至10元螺杂环基)，最优选6至8元(例如6、7、8元)(例如含有至少一个氧原子的6至8元螺杂环基)。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或多螺杂环基(如双螺杂环基)，优选为单螺杂环基和双螺杂环基，更优选为单螺杂环基(例如含有至少一个氧原子的6至10元单螺杂环基)，最优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、3元/6元、3元/5元、5元/6元或6元/6元单螺杂环基。单螺杂环基的非限制性实例包括：
Figure PCTCN2021141052-appb-000064
术语“稠杂环基”指5至20元，***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、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元(例如6、7、8、9、10、11、12、13和 14元)(例如含有至少一个氧原子的6至14元稠杂环基)，更优选6至10元(例如6、7、8、9或10元)(例如含有至少一个氧原子的6至10元稠杂环基)，最优选为6至8元(例如含有至少一个氧原子的6至8元稠杂环基)。根据组成环的数目可以分为双环、三环、四环等多环稠杂环基，优选为双环或三环稠杂环基，更优选为双环稠杂环基(例如含有至少一个氧原子的6至14元双环稠杂环基)，最优选为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/3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、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。双环稠杂环基的非限制性实例包括：
Figure PCTCN2021141052-appb-000065
术语“桥杂环基”指5至20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、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元(例如6、7、8、9、10、11、12、13和14元)(例如含有至少一个氧原子的6至14元桥杂环基)，更优选6至10元(例如含有至少一个氧原子的6至10元桥杂环基)(例如6、7、8、9或10元)，最优选为6至8元(例如含有至少一个氧原子的6至8元桥杂环基)。根据组成环的数目可以分为双环、三环、四环等多环桥杂环基，优选为双环、三环或四环桥杂环基，更优选为双环或三环桥杂环基，最优选为双环桥杂环基(例如含有至少一个氧原子的6至14元双环桥杂环基)。双桥杂环基的非限制性实例包括：
Figure PCTCN2021141052-appb-000066
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 PCTCN2021141052-appb-000067
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、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、芳基和杂芳基中的一个或多个。
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 PCTCN2021141052-appb-000068
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、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、芳基和杂芳基中的一个或多个。
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5至10元(例如5、6、7、8、9或10元)杂芳基，更优选5元或6元杂芳基，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、***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 PCTCN2021141052-appb-000069
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、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、芳基和杂芳基中的一个或多个。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或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“亚环烷基”、“亚杂环基”、“亚芳基”、“亚杂芳基”。
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、乙酰基、苄基、苄氧羰基(Cbz)、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基和硝基中的1-3个取代基所取代。
术语“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅烷基(TBS)、叔丁基二苯基硅基、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。
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“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
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“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”或“氧代”指“＝O”。
术语“羰基”指C＝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-，其中烷基和环烷基如上所定义。
本公开所述化合物的化学结构中，键
Figure PCTCN2021141052-appb-000070
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021141052-appb-000071
可以为
Figure PCTCN2021141052-appb-000072
或者同时包含
Figure PCTCN2021141052-appb-000073
Figure PCTCN2021141052-appb-000074
两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间：
Figure PCTCN2021141052-appb-000075
所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
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，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。
本公开的各种氘化形式的化合物是指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化合物。 在制备氘代形式的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。
“任选地”或“任选”是指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的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1至6个，更优选为1至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(通过实验或理论)确定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。
“可药用的盐”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)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021141052-appb-000076
通式(IA)的化合物或其盐与通式(IB)的化合物或其盐，在碱性条件下，在催化剂存在下，发生偶联反应，得到通式(I)的化合物或其可药用的盐，
其中：
X为卤素；优选为氯原子；
环A、R 1至R 3、n和p如通式(I)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、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯，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、碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；优选为碳酸铯。
以上合成方案中所用的催化剂包括但不限于四(三苯基膦)钯、二氯化钯、醋酸钯、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)、1,1’-双(二苄基磷)二氯二戊铁钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物和三(二亚苄基丙酮)二钯等，优选为甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)。
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、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、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
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 NEO 500M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：6110/6120Quadrupole 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 1260DAD高效液相色谱仪。
高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备色谱法使用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，反应均能够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，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
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮1
Figure PCTCN2021141052-appb-000077
第一步
2-氯-4-(2-氧杂螺[3.3]庚-6-基氨基)嘧啶-5-甲酸甲酯1c
将2,4-二氯嘧啶-5-甲酸甲酯1a(400mg，1.93mmol，采用专利申请“WO2013177168A1，P34”公开的方法制备而得)溶于10mL乙腈中，依次加入2-氧杂螺[3.3]庚-6-胺盐酸盐1b(290mg，1.94mmol，药石)和碳酸钾(650mg，4.70mmol)，搅拌17小时。过滤，乙酸乙酯洗涤，所得有机相减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物1c(545mg)，产率：98.2％。
MS m/z(ESI):283.9[M+1]。
第二步
2-氯-4-(2-氧杂螺[3.3]庚-6-基氨基)嘧啶-5-羧酸1d
将化合物1c(545mg，1.92mmol)溶于8mL四氢呋喃中，加入3mL水和氢氧化锂一水合物(160mg，3.81mmol)，搅拌17小时。减压浓缩，稀盐酸中和至析出固体，过滤，水洗，干燥后得到标题产物1d(330mg)，产率：63.1％。
MS m/z(ESI):270.1[M+1]。
第三步
2-氯-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮1e
在氩气氛下，将化合物1d(330mg，1.22mmol)溶于10mL N,N-二甲基乙酰胺 中，依次加入叠氮磷酸二苯酯(298mg，1.22mmol)和三乙胺(124mg，1.22mmol)，搅拌1小时。加热至120℃，搅拌17小时。倒入水中，过滤，水洗，得到标题产物1e(170mg)，产率：52.1％。
MS m/z(ESI):267.0[M+1]。
第四步
2-氯-7-甲基-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮1f
将化合物1e(160mg，0.60mmol)溶于10mL四氢呋喃和5mL水中，分别加入氢氧化钠(120mg，3.0mmol)和碘甲烷(256mg，1.80mmol)，搅拌17小时。减压浓缩，过滤，水洗，得到标题产物1f(70mg)，产率：41.6％。
MS m/z(ESI):281.1[M+1]。
第五步
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮1
将化合物1f(60mg，0.21mmol)和7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺1g(38mg，0.26mmol，采用专利申请“CN110177791A，P37”公开的方法制备而得)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(20mg，0.022mmol)和碳酸铯(209mg，0.64mmol)溶解于10mL 1,4-二氧六环中，加热至100℃，搅拌17小时。反应液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物1(55mg)，产率：65.6％。
MS m/z(ESI):393.1[M+1]。
1H NMR(500MHz,DMSO-d 6):δ9.02(s,1H),8.61(s,1H),8.40(s,1H),8.12(s,1H),7.75(s,1H),4.64-4.60(m,3H),4.17(s,2H),3.35(s,3H),2.95(t,2H),2.56-2.52(m,2H),2.37(s,3H)。
实施例2
9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮2
Figure PCTCN2021141052-appb-000078
Figure PCTCN2021141052-appb-000079
第一步
4-(((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)氨基)-2-氯嘧啶-5-甲酸甲酯2b
将化合物1a(330mg，1.58mmol，采用专利申请“WO2013177168，P34”公开的方法制备而得)溶于10mL乙腈中，依次加入(1R,5S)-8-氧杂二环[3.2.1]辛-3-胺盐酸盐2a(257mg，1.57mmol，药石)和碳酸钾(445mg，3.22mmol)，搅拌17小时。过滤，乙酸乙酯洗涤，所得有机相减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物2b(545mg)，产率：81.2％。
MS m/z(ESI):297.9[M+1]。
第二步
4-(((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)氨基)-2-氯嘧啶-5-甲酸2c
将化合物2b(385mg，1.29mmol)溶于8mL四氢呋喃中，加入3mL水和氢氧化锂一水合物(109mg，2.59mmol)，搅拌17小时。减压浓缩，稀盐酸中和至析出固体，过滤，水洗，干燥后得到标题产物2c(250mg)，产率：68.1％。
MS m/z(ESI):284.1[M+1]。
第三步
9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7,9-二氢-8H-嘌呤-8-酮2d
在氩气氛下，将化合物2c(250mg，0.88mmol)溶于10mL N,N-二甲基乙酰胺中，依次加入叠氮磷酸二苯酯(215mg，0.88mmol)和三乙胺(90mg，0.89mmol)，搅拌1小时后，加热至120℃，搅拌17小时。倒入水中，过滤，水洗，得到标题产物2d(240mg)，产率：97.1％。
MS m/z(ESI):281.0[M+1]。
第四步
9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮2e
将化合物2d(240mg，0.85mmol)溶于10mL四氢呋喃和5mL水中，分别加入氢氧化钠(171mg，4.28mmol)和碘甲烷(243mg，1.71mmol)，搅拌17小时。减压浓缩，过滤，水洗，得到标题产物2e(170mg)，产率：67.5％。
MS m/z(ESI):295.1[M+1]。
第五步
9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮2
将化合物2e(170mg，0.58mmol)和化合物1g(94mg，0.63mmol，采用专利申请“CN110177791A，P37”公开的方法制备而得)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(50mg，0.055mmol)和碳酸铯(376mg，1.15mmol)溶解于15mL 1,4-二氧六环中，加热至100℃，搅拌17小时。反应液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物2(130mg)，产率：55.4％。
MS m/z(ESI):407.1[M+1]。
实施例2-1和实施例2-2
9-((1R,3r,5S)-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮2-1
9-((1R,3s,5S)-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮2-2
Figure PCTCN2021141052-appb-000080
第一步
9-((1R,3r,5S))-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮2e-1
9-((1R,3s,5S))-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮2e-2
将化合物2d(960mg，3.42mmol)溶于15mL四氢呋喃和5mL水中，分别加入氢氧化钠(411mg，10.3mmol)和碘甲烷(1.46mg，10.3mmol)，搅拌17小时。减压浓缩，过滤，水洗，粗品经反相柱层析色谱法拆分，得到标题产物2e-1(420mg，产率：41.7％)和标题产物2e-2(300mg，产率：29.7％)。
单一构型化合物2e-1(420mg，产率：41.7％)(较短保留时间)：
LCMS分析：保留时间3.10分钟，色谱柱：Waters Sunfire C18 75*4.6mm，3.5μm；流动相：水(+0.1％三氟乙酸)/乙腈＝35/65。
MS m/z(ESI):295.1[M+1]。
单一构型化合物2e-2(300mg，产率：29.7％)(较长保留时间)：
LCMS分析：保留时间3.29分钟，色谱柱：Waters Sunfire C18 75*4.6mm，3.5μm；流动相：水(+0.1％三氟乙酸)/乙腈＝35/65。
MS m/z(ESI):295.1[M+1]。
第二步
9-((1R,3r,5S))-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮2-1
9-((1R,3s,5S))-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮2-2
将化合物2e-1(420mg，1.43mmol，保留时间：3.10分钟)和化合物1g(222mg，1.49mmol，采用专利申请“CN110177791A，P37”公开的方法制备而得)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(130mg，0.14mmol)和碳酸铯(930mg，2.85mmol)溶解于15mL 1,4-二氧六环中，加热至100℃，搅拌17小时。反应液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物2-1(390mg，产率：67.4％)。
将化合物2e-2(300mg，1.02mmol，保留时间：3.29分钟)和化合物1g(155mg，1.05mmol，采用专利申请“CN110177791A，P37”公开的方法制备而得)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(93mg，0.10mmol)和碳酸铯(664mg，2.04mmol)溶解于15mL 1,4-二氧六环中，加热至100℃，搅拌17小时。反应液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物2-2(120mg，产率：29.1％)。
单一构型化合物2-1(390mg，产率：67.4％)(较短保留时间)：
HPLC分析：保留时间6.77分钟，纯度：99.3％(色谱柱：Waters Sunfire C1875*4.6mm，3.5μm；流动相：水(+0.1％三氟乙酸)/乙腈＝70/30)。
1H NMR(500MHz,DMSO-d 6):δ9.01(s,1H),8.73(s,1H),8.40(s,1H),8.12(s,1H),7.76(s,1H),4.36-4.29(m,3H),3.29(s,3H),2.35(s,3H),2.13-2.11(m,2H),1.94-1.89(m,2H),1.62(t,2H),1.28(d,2H)。
MS m/z(ESI):407.1[M+1]。
单一构型化合物2-2(120mg，产率：29.1％)(较长保留时间)：
HPLC分析：保留时间7.18分钟，纯度：99.7％(色谱柱：Waters Sunfire C1875*4.6mm，3.5μm；流动相：水(+0.1％三氟乙酸)/乙腈＝70/30)。
MS m/z(ESI):407.1[M+1]。
1H NMR(500MHz,DMSO-d 6):δ9.12(s,1H),8.68(s,1H),8.38(s,1H),8.08(s,1H),7.71(s,1H),4.68-4.61(m,1H),4.43(s,2H),3.30(s,3H),2.61-2.56(m,2H),2.40(s,3H),1.91(brs,2H),1.80-1.78(m,2H),1.62-1.59(m,2H)。
实施例3、实施例3-1和实施例3-2
(±)7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3
(R)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3-1
(S)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3-2
Figure PCTCN2021141052-appb-000081
第一步
4-((4-氧杂螺[2.5]辛-7-基)氨基)-2-氯嘧啶-5-甲酸甲酯3a
将2,4-二氯-5-甲酸甲酯1a(1.23g，5.94mmol)溶于80mL乙腈中，加入4-氧杂螺[2.5]辛-7-氨(755mg，5.94mmol，采用专利申请“US2016376283A1，P229” 公开的方法制备而得)和碳酸钾(2.053g，14.8547mmol)，常温搅拌17小时。过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化得到标题产物3a(180mg)，产率：10.2％。
MS m/z(ESI):297.9[M+1]。
第二步
4-((4-氧杂螺[2.5]辛-7-基)氨基)-2-氯嘧啶-5-羧酸3b
将化合物3a(180mg，604.56μmol)溶于15mL四氢呋喃中，加入3mL水和氢氧化锂一水合物(76mg，1.81mmol)，常温搅拌17小时。减压浓缩，稀盐酸中和至析出固体，过滤，水洗，干燥后得到标题产物3b(150mg)，产率：87.4％。
MS m/z(ESI):283.9[M+1]。
第三步
2-氯-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3c
将化合物3b(150mg，528.70μmol)溶于5mL N,N-二甲基乙酰胺中，依次加入叠氮磷酸二苯酯(129mg，530.42μmol，韶远)和三乙胺(54mg，533.65μmol)，常温搅拌1小时，再加热至120℃，搅拌17小时。倒入水中，过滤，水洗，得到标题产物3c(135mg)，产率：90.9％。
MS m/z(ESI):280.9[M+1]。
第四步
2-氯-7-甲基-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3d
将化合物3c(135mg，480.92μmol)溶于15mL四氢呋喃和2mL水中，加入氢氧化钠(96mg，2.4mmol)和碘甲烷(341mg，2.4mmol)，常温搅拌17小时。减压浓缩，加水，过滤，滤饼干燥得到标题产物3d(100mg)，产率：70.5％。
MS m/z(ESI):294.9[M+1]。
第五步
(±)7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3
在氮气氛下，将化合物3d(100mg，339.28μmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺1g(50mg，337.46μmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(62mg，68.32μmol)和碳酸铯(221mg，678.30μmol)溶解于15mL 1,4-二氧六环中，加热至100℃，搅拌17小时。反应液冷却，过滤，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物3(23mg)，产率：16.7％。
MS m/z(ESI):407.0[M+1]。
1H NMR(500MHz,DMSO-d 6):δ9.11(s,1H),8.71(s,1H),8.38(s,1H),8.09(s,1H),7.71(s,1H),4.58-4.51(m,1H),3.89-3.83(m,1H),3.59-3.48(m,1H),3.31(s,3H),3.05-3.00(m,1H),2.59-2.53(m,1H),2.40(s,3H),1.77-1.73(m,1H),1.24-1.22(m, 1H),0.80-0.76(m,1H),0.65-0.60(m,1H),0.56-0.52(m,1H),0.44-0.40(m,1H)。
第六步
(R)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3-1
(S)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮3-2
将化合物3(130mg，0.320mmol)进行手性制备(分离条件：手性制备柱CHIRALPAK IE 20*250mm，5μm；流动相：正己烷：(乙醇：甲醇(+0.1％二乙胺)＝1：4))＝50:50，流速：20mL/分钟)，收集其相应组分，减压浓缩，得到标题产物(30mg，收率：23.0％)和(30mg，收率：23.0％)。
单一构型化合物(30mg，收率：23.0％)(较短保留时间)：
手性HPLC分析：保留时间14.306分钟，手性纯度：100％(色谱柱：CHIRALPAK IE 4.6*150mm，5μm；流动相：正己烷：(乙醇：甲醇(+0.1％二乙胺)＝1：4))＝50:50，流速：1.0mL/分钟)。
MS m/z(ESI):407.0[M+1]。
1H NMR(500MHz,DMSO-d 6):δ9.12(s,1H),8.71(s,1H),8.38(s,1H),8.09(s,1H),7.71(s,1H),4.57-4.52(m,1H),3.89-3.86(m,1H),3.53-3.48(m,1H),3.31(s,3H),3.05-3.00(m,1H),2.59-2.53(m,1H),2.40(s,3H),1.77-1.74(m,1H),1.24-1.22(m,1H),0.79-0.76(m,1H),0.64-0.61(m,1H),0.56-0.53(m,1H),0.44-0.40(m,1H)。
单一构型化合物(30mg，收率：23.0％)(较长保留时间)：
手性HPLC分析：保留时间15.604分钟，手性纯度：96.9％(色谱柱：CHIRALPAK IE 4.6*150mm，5μm；流动相：正己烷：(乙醇：甲醇(+0.1％二乙胺)＝1：4))＝50:50，流速：1.0mL/分钟)。
MS m/z(ESI):407.0[M+1]。
1H NMR(500MHz,DMSO-d 6):δ9.11(s,1H),8.71(s,1H),8.38(s,1H),8.09(s,1H),7.71(s,1H),4.57-4.52(m,1H),3.89-3.86(m,1H),3.53-3.48(m,1H),3.31(s,3H),3.05-3.00(m,1H),2.58-2.53(m,1H),2.40(s,3H),1.77-1.73(m,1H),1.26-1.22(m,1H),0.80-0.76(m,1H),0.64-0.61(m,1H),0.56-0.52(m,1H),0.44-0.40(m,1H)。
实施例4
9-((1R,5S,6s)-3-氧杂二环并[3.1.0]己-6-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮4
Figure PCTCN2021141052-appb-000082
Figure PCTCN2021141052-appb-000083
采用实施例1的合成路线，将第一步原料化合物1b替换为反式-6-氨基-3-氧杂二环[3.1.0]己烷盐酸盐4a(艾康)，制得标题产物4(52mg)，产率：36.6％。
MS m/z(ESI):378.9[M+1]。
1H NMR(500MHz,CDCl 3)δ9.88(s,1H),8.27(s,1H),7.92(s,1H),7.59(s,1H),6.78(s,1H),4.35-4.30(m,2H),3.92-3.90(m,2H),3.43(s,3H),2.86(m,1H),2.55(s,3H),2.42-2.40(m,2H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些测试例并非意味着限制本公开的范围。
测试例1DNA-PK酶学实验方法
1、实验目的
采用HTRF方法检测磷酸化P53的水平，反映化合物对DNA-PK酶活性的抑制作用，根据抑制效应的IC 50评价化合物的体外活性。
2、实验方法
用反应缓冲液[25mM HEPES(Gibco，#15630-080)pH8.0，0.01％Brij-35(Thermo，#20150)，1％甘油(生工，#A100854-0100)]稀释底物P53(Eurofins，#14-952-M)至500nM；用稀释缓冲液[25mM HEPES pH8.0，0.01％Brij-35，1％甘油，5mM DTT(生工，#B645939)，1mg/mL BSA(碧云天，#ST023)]稀释DNA-PK酶(Eurofins，#14-950M)至0.16nM；用稀释缓冲液稀释醋酸镁(Sigma，#63052)至40mM后稀释ATP(Thermo，#PV3227)至29.2μM。用液体工作站(PV3227，#SP2-096-0125-03)在384孔板(Thermo，#267462)中依次加入配制好的化合物(化合物用DMSO稀释)10μL、DNA-PK酶2.5μL、500nM P53底物2.5μL、ATP 5μL。混匀后25℃孵育1小时。
用液体工作站在384孔板中依次加入终止液[12.5mM HEPES pH8.0，0.005％Brij-35，0.5％甘油，250mM EDTA(Thermo，#AM9260G)]和检测混合物[50mM  HEPES pH7.0，150mM NaCl(生工，#B548121)，267mM KF(国药，7789-23-3)，0.1％胆酸钠(Sigma，#C6445)，0.01％吐温20(Sigma，#P7949)，0.0125％叠氮化钠(Sigma，#S8032)，抗磷酸化-p53Eu(Cisbio，#61P08KAE)0.42ng/孔和抗-GST-d2(Cisbio，61GSTDLF)25ng/孔]各5μL，25℃孵育过夜。使用酶标仪(BMG，PHERAstar FS)读取665nm和620nm吸收光的数值。使用Graphpad Prism 6对数据进行分析处理，结果见表1。
表1本公开化合物对DNA-PK酶的抑制活性的IC 50值
实施例编号 IC 50(nM)
1 1.09
2 0.14
2-2 0.07
2-1 0.14
3 0.07
3-1和3-2中保留时间长的单一构型化合物 0.06
3-1和3-2中保留时间短的单一构型化合物 0.07
4 0.31
结论：本公开化合物对DNA-PK酶具有很好的抑制作用。
测试例2DNA-PK细胞增殖抑制实验
1、实验目的
通过检测细胞内ATP水平反应细胞活性，研究化合物对非小细胞肺癌细胞系A549的杀伤作用，根据杀伤效应的IC 50大小评价化合物的体外活性。
2、实验方法
A549细胞(ATCC，CCL-185)使用胰酶(Gibico，25200-072)37℃消化3分钟，用完全培养基[F-12K培养基(Gibico，21127030)，10％FBS(ThermoFisher Scientific，10099-141)]重悬计数，在96孔板(Corning，3903)中每孔加入1000个细胞，放入CO 2恒温培养箱(Thermo Fisher，HERAcell 240i)37℃培养过夜。
使用Bravo液体工作站(Agilent Technologies，SGS120TH34702)配制化合物(化合物用DMSO稀释)，配制好的化合物用完全培养基稀释备用。取出细胞培养板，吸出培液10μL，加入稀释好的化合物5μL，放回CO 2恒温培养箱培养1小时。使用完全培养基稀释博来霉素(selleck，S1214)至20uM，在培养板中每孔加入5μL(终浓度为500nM)。将培养板放回CO 2恒温培养箱继续培养。6天后取出培养板，每孔加入50μL CellTiter-Glo(Promega，G7573)，25℃避光孵育5分钟。使用酶标仪(PerkinElmer，Vector3)检测发光的数值，使用Graphpad Prism 6对数据进行分析处理，结果见表2。
表2本公开化合物对DNA-PK细胞增殖的抑制活性的IC 50值
实施例编号 IC 50(nM)
2 41
2-2 26
2-1 41
3 19
3-1和3-2中保留时间长的单一构型化合物 21
3-1和3-2中保留时间短的单一构型化合物 14
4 87
结论：本公开化合物对DNA-PK细胞增殖具有很好的抑制作用。
测试例3药代动力学评价
一、大鼠实验
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃(ig)/静脉注射(iv)给予实施例2-2化合物和阳性对照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
实施例2-2化合物和阳性对照化合物。阳性对照化合物(见WO2018114999A1实施例3化合物，根据该实施例制备得到)，结构如下：
Figure PCTCN2021141052-appb-000084
2.2试验动物
SD大鼠24只，雌雄各半，平均分成6组，购自维通利华实验动物有限公司，动物生产许可证号：SCXK(沪)2017-0005。
2.3药物配制
0.2mg/mL实施例2-2化合物和阳性对照化合物给药溶液：称取一定量的实施例2-2化合物和阳性对照化合物，加5％体积的DMSO和5％吐温80(上海泰坦科技有限公司)使其溶解，然后加入90％生理盐水配制成0.2mg/mL澄明溶液。
6mg/mL实施例2-2化合物给药溶液：称取一定量的实施例2-2化合物，加0.5％CMC-Na使其成为均一悬浮溶液。
30mg/mL阳性对照化合物给药溶液：称取一定量的阳性对照化合物，分别加5％体积的DMSO，20％PEG400，70％(10％TPGS)和5％(1％HPMCK100LV)使其成为均一悬浮溶液。
2.4给药
灌胃给药方案一：大鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为10.0mL/kg。
灌胃给药方案二：大鼠禁食过夜后灌胃给药，实施例2-2化合物给药剂量为60.0mg/kg，阳性对照化合物给药剂量为300mg/kg，给药体积均为10.0mL/kg。
静脉注射给药：大鼠静脉注射给药，给药剂量均为1.0mg/kg，给药体积均为5.0mL/kg。
3.操作
大鼠灌胃给药实施例2-2化合物和阳性对照化合物，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EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1h内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作，给药后2h进食。
大鼠静脉注射给药实施例2-2化合物和阳性对照化合物，于给药前及给药后5分钟，0.25、0.5、1.0、2.0、4.0、8.0、11.0、24小时由眼眶采血，处理同灌胃组。
测定不同浓度的药物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50μL内标溶液喜树碱(100ng/mL)和乙腈200μL，涡旋混合5分钟，离心10分钟(3700g)，血浆样品取上清液0.5μL进行LC/MS/MS分析。
4、药代动力学参数结果
表3本公开化合物的药代动力学参数如下：
Figure PCTCN2021141052-appb-000085
结论：本公开化合物在大鼠体内均具有很好的药代吸收活性，具有药代动力学优势。
二、小鼠实验
1、摘要
以小鼠为受试动物，应用LC/MS/MS法测定了小鼠灌胃(ig)/静脉注射(iv)给予实施例2-2化合物和阳性对照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小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
实施例2-2化合物和阳性对照化合物。阳性对照化合物(见WO2018114999A1实施例3化合物，根据该实施例制备)，结构如下：
Figure PCTCN2021141052-appb-000086
2.2试验动物
C57小鼠36只，雌性，平均分成4组，购自维通利华实验动物有限公司，动物生产许可证号：SCXK(沪)2017-0005。
2.3药物配制
称取一定量的实施例2-2化合物和阳性对照化合物，加5％体积的DMSO和5％吐温80(上海泰坦科技有限公司)使其溶解，然后加入90％生理盐水配制成0.1mg/mL澄明溶液。
2.4给药
灌胃给药：小鼠灌胃给药，给药剂量均为2.0mg/kg，给药体积均为20.0mL/kg。
静脉注射给药：小鼠静脉注射给药，给药剂量均为1.0mg/kg，给药体积均为10.0mL/kg。
3.操作
小鼠灌胃给药实施例2-2化合物和阳性对照化合物，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0.1mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1h内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。
小鼠静脉注射给药实施例2-2化合物和阳性对照化合物，于给药前及给药后5分钟，0.25、0.5、1.0、2.0、4.0、8.0、11.0、24小时由眼眶采血0.1mL，处理同灌胃组。
测定不同浓度的药物给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆30μL，加入甲醇300μL(含内标溶液喜树碱(10ng/mL))，涡旋混合1分钟，离心7分钟(18000g)，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
表4本公开化合物的药代动力学参数如下：
Figure PCTCN2021141052-appb-000087
结论：本公开化合物在小鼠体内均具有很好的口服药代吸收活性，口服生物利用度高，具有药代动力学优势。

Claims (15)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2021141052-appb-100001
    其中：
    环A为6至14元多环杂环基；
    各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氧代基、氰基、氨基、硝基、羟基和羟烷基；
    R 2选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
    各个R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
    n为0、1或2；且
    p为0、1、2、3或4。
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其中环A选自6至14元螺杂环基、6至14元桥杂环基和6至14元稠杂环基；优选地，环A选自含有1个氧原子的6至14元螺杂环基、含有1个氧原子的6至14元桥杂环基和含有1个氧原子的6至14元稠杂环基。
  3. 根据权利要求1或2中所述的通式(I)所示的化合物或其可药用的盐，其中R 1为氢原子或C 1-6烷基；优选地，R 1为氢原子。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其中
    Figure PCTCN2021141052-appb-100002
    选自：
    Figure PCTCN2021141052-appb-100003
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 2选自氢原子、卤素和C 1-6烷基；优选地，R 2为氢原子。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个R 3相同或不同，且各自独立地选自氢原子、卤素、氰基和C 1-6烷基；优选地，R 3为氢原子。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：
    7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,3r,5S))-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,3s,5S))-8-氧杂二环[3.2.1]辛-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮；
    (±)7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
    (R)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
    (S)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,5S,6s)-3-氧杂二环并[3.1.0]己-6-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2021141052-appb-100004
  9. 一种通式(IA)所示的化合物或其盐：
    Figure PCTCN2021141052-appb-100005
    其中：
    X为卤素；优选为氯原子；
    环A、R 1和p如权利要求1中所定义。
  10. 根据权利要求9所述的通式(IA)所示的化合物或其盐，其选自以下任一化合物：
    2-氯-7-甲基-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,5S)-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,3r,5S))-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,3s,5S))-8-氧杂二环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮
    2-氯-7-甲基-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
    (R)-2-氯-7-甲基-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
    (S)-2-氯-7-甲基-9-(4-氧杂螺[2.5]辛-7-基)-7,9-二氢-8H-嘌呤-8-酮；
    9-((1R,5S,6s)-3-氧杂二环并[3.1.0]己-6-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮。
  11. 根据权利要求9或10所述的通式(IA)所示的化合物或其盐，其选自以下任一化合物：
    Figure PCTCN2021141052-appb-100006
  12. 一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    Figure PCTCN2021141052-appb-100007
    通式(IA)的化合物或其盐与通式(IB)的化合物或其盐发生偶联反应，得到通式(I)的化合物或其可药用的盐，
    其中：
    X为卤素；优选为氯原子；
    环A、R 1至R 3、n和p如权利要求1中所定义。
  13. 一种药物组合物，所述药物组合物含有根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  14. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求13所述的药物组合物在制备DNA-PK抑制剂中的用途。
  15. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求13所述的药物组合物在制备用于治疗和/或预防癌症的药物中的用途；其中所述的癌症优选选自白血病、多发性骨髓瘤、淋巴瘤、骨髓增生异常综合征、乳腺癌、肺癌、子宫内膜癌、中枢神经***肿瘤、胚胎发育不良性神经上皮肿瘤、多形性成胶质细胞瘤、混合性胶质瘤、成神经管细胞瘤、成视网膜细胞瘤、成神经细胞瘤、生殖细胞瘤、畸胎瘤、胃癌、食道癌、肝癌、胆管细胞癌、结直肠癌、小肠癌、胰腺癌、皮肤癌、黑色素瘤、甲状腺癌、头颈癌、唾液腺癌、***癌、睾丸癌、卵巢癌、***、外阴癌、膀胱癌、肾癌、鳞状细胞癌、肉瘤、胃肠道间质瘤和儿科癌症；其中，所述的结直肠癌优选为结肠癌或直肠癌；所述的肉瘤优选选自软骨肉瘤、平滑肌肉瘤、软组织肉瘤、尤文氏肉瘤和卡波氏肉瘤。
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WO2021204111A1 (zh) * 2020-04-10 2021-10-14 南京明德新药研发有限公司 作为dna-pk抑制剂的氨基嘧啶化合物及其衍生物
WO2022017368A1 (zh) * 2020-07-20 2022-01-27 首药控股(北京)股份有限公司 Dna-pk选择性抑制剂及其制备方法和用途

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