WO2022135360A1 - Dérivé de purinone, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé de purinone, son procédé de préparation et son utilisation en médecine Download PDF

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Publication number
WO2022135360A1
WO2022135360A1 PCT/CN2021/139862 CN2021139862W WO2022135360A1 WO 2022135360 A1 WO2022135360 A1 WO 2022135360A1 CN 2021139862 W CN2021139862 W CN 2021139862W WO 2022135360 A1 WO2022135360 A1 WO 2022135360A1
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general formula
cancer
pharmaceutically acceptable
compound
acceptable salt
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PCT/CN2021/139862
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English (en)
Chinese (zh)
Inventor
陆标
王胜蓝
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202180085295.5A priority Critical patent/CN116685323A/zh
Publication of WO2022135360A1 publication Critical patent/WO2022135360A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a purinone derivative, a preparation method thereof and its application in medicine.
  • the present disclosure relates to a purinone derivative represented by the general formula (IG), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a DNA-PK inhibitor in the preparation of a drug for the treatment and/or prevention of cancer use in.
  • IG general formula
  • 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. Recruitment of DNA-PKcs facilitates the movement of Ku heterodimers into DNA duplexes, allowing DNA-PKcs to serve as tethers to break DNA ends and prevent degradation by exonucleases. At the same time, 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.
  • the purpose of this disclosure is to provide a compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof:
  • G 1 , G 2 and G 3 are the same or different, and are each independently CR 2 or a nitrogen atom;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Ring B is cycloalkyl or heterocyclyl
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and Hydroxyalkyl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl ;
  • R is selected from hydrogen atom, alkyl, haloalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, haloalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and Hydroxyalkyl;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, 4 or 5.
  • the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof wherein G 1 is CR 2 or a nitrogen atom; G 2 and G 3 are the same or different, and Each is independently CR 2 ; R 2 is as defined in general formula (IG).
  • the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof wherein G 1 is a nitrogen atom; G 2 and G 3 are the same or different, and are each independently CR 2 ; R 2 is as defined in general formula (IG).
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Ring B is cycloalkyl or heterocyclyl
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and Hydroxyalkyl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl ;
  • R is selected from hydrogen atom, alkyl, haloalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, haloalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and Hydroxyalkyl;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, 4 or 5.
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Ring B is cycloalkyl or heterocyclyl
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and Hydroxyalkyl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl ;
  • R is selected from hydrogen atom, alkyl, haloalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, haloalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and Hydroxyalkyl;
  • n 0, 1 or 2;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, 4 or 5.
  • ring A is 5-6 membered Heteroaryl or 3- to 6-membered heterocyclic group; preferably 5-membered heteroaryl or 5- to 6-membered heterocyclic group; more preferably selected from imidazolyl, pyrazolyl, triazolyl, 1,2,4- Oxadiazol-5(2H)-one, thiazolyl, pyrrolyl, thienyl and furyl.
  • the compound of general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein R 2 is the same or different, and each independently selected from hydrogen atom, halogen, cyano group and C 1-6 alkyl group; preferably, R 2 are the same or different, and each independently selected from hydrogen atom, cyano group and C 1-6 alkyl group; more preferably Typically, R 2 is the same or different, and each is independently a hydrogen atom or a cyano group; more preferably, R 2 is a hydrogen atom.
  • the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof wherein G 1 is CR 2 or a nitrogen atom; G 2 and G 3 are the same or different, and Each independently is CR 2 ; Ring A is a 5-membered heteroaryl or a 5- to 6-membered heterocyclyl; Ring B is R 3 is methyl or cyclopropyl; R 1 is the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl and oxo; R 2 is the same or different, and each is independently selected from hydrogen atom, cyano and C 1-6 alkyl; R 4 is a hydrogen atom; p is 0, 1, 2 or 3; and q is 0 or 1.
  • the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof wherein G 1 is a nitrogen atom; G 2 and G 3 are the same or different, and are each independently CR 2 ; Ring A is a 5-membered heteroaryl; Ring B is R 3 is methyl; R 1 is C 1-6 alkyl; p is 0 or 1; R 2 is a hydrogen atom; R 4 is a hydrogen atom;
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 5-membered heteroaryl group or a 5- to 6-membered heterocyclic group; ring B for R 3 is methyl or cyclopropyl; R 1 is the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl and oxo; R 2 is the same or different, and each is independently selected from hydrogen atom, cyano and C 1-6 alkyl; R 4 is a hydrogen atom; n is 0 or 1; p is 0, 1, 2 or 3; and q is 0 or 1.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A is a 5-membered heteroaryl group or a 5- to 6-membered heterocyclic group; ring B for R 3 is methyl or cyclopropyl; R 1 is the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl and oxo; p is 0, 1, 2 or 3; R 2 is the same or different , and each is independently selected from a hydrogen atom, a cyano group, and a C 1-6 alkyl group; n is 0 or 1; R 4 is a hydrogen atom; and q is 0 or 1.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A is a 5-membered heteroaryl; ring B is R 3 is methyl; R 1 is C 1-6 alkyl; p is 0 or 1 ; R 2 is a hydrogen atom; n is 0 or 1;
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IG), or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA) or a salt thereof is subjected to a coupling reaction with the compound represented by the general formula (IGB) or a salt thereof to obtain the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof,
  • X is a halogen; preferably a chlorine atom
  • Ring A, Ring B, G 1 , G 2 , G 3 , R 1 , R 3 , R 4 , p and q are as defined in general formula (IG).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, comprising:
  • the compound represented by the general formula (IA) or a salt thereof is subjected to a coupling reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
  • X is a halogen; preferably a chlorine atom
  • Ring A, Ring B, R 1 to R 4 , n, p and q are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof, the method comprising:
  • a compound represented by the general formula (IA) or a salt thereof is subjected to a coupling reaction with a compound represented by the general formula (IIB) or a salt thereof to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
  • X is a halogen; preferably a chlorine atom
  • Ring A, Ring B, R 1 to R 4 , n, p and q are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present disclosure as shown in general formula (IG), general formula (I), general formula (II) and Table A, or a pharmaceutically acceptable compound thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to compounds of general formula (IG), general formula (I), general formula (II), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of compounds for inhibiting DNA- PK in the use of drugs.
  • the present disclosure further relates to compounds of general formula (IG), general formula (I), general formula (II), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation for use in therapy and/or Or use in a medicament for the prevention of cancer, preferably in the preparation of a medicament for the treatment and/or prevention of DNA-PK mediated cancer.
  • said cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysembryoplastic neuroepithelial tumor, pleomorphic Glioblastoma, 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, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, Gastrointestinal stromal tumors (GIST) and pediatric cancers.
  • leukemia multiple myeloma, lymphom
  • said lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein said lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma) and large cell carcinoma, etc.) or small cell lung cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); renal cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma; wherein the sarcoma is preferably selected from From chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma.
  • NSCLC small cell lung cancer
  • renal cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma
  • the sarcoma is preferably selected from From chondrosarcoma, leiomyosarcoma, soft tissue sarcom
  • 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 (IG), general formula (I), general formula (II) and Table A, or alternatives thereof A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same.
  • a method of inhibiting DNA-PK comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (IG), general formula (I), general formula (II) and Table A, or alternatives thereof A pharmaceutically acceptable salt, 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 formula (IG), formula (I), the compound represented by the general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • 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 formula (IG), formula (I), the compound represented by the general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • said cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysembryoplastic neuroepithelial tumor, pleomorphic Glioblastoma, 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, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, Gastrointestinal stromal tumors (GIST) and pediatric cancers.
  • leukemia multiple myeloma, lymphom
  • said lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein said lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma) and large cell carcinoma, etc.) or small cell lung cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); renal cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma; wherein the sarcoma is preferably selected from From chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma.
  • NSCLC small cell lung cancer
  • renal cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma
  • the sarcoma is preferably selected from From chondrosarcoma, leiomyosarcoma, soft tissue sarcom
  • the present disclosure further relates to a compound of general formula (IG), general formula (I), general formula (II) 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 general formula (IG), general formula (I), general formula (II), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an inhibitor Drugs for DNA-PK.
  • the present disclosure further relates to a compound of general formula (IG), general formula (I), general formula (II), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in therapy and/or medicament for preventing cancer, preferably as medicament for treating and/or preventing DNA-PK mediated cancer.
  • said cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysembryoplastic neuroepithelial tumor, pleomorphic Glioblastoma, 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, Ovarian cancer, Cervical cancer, , Vulvar cancer, Bladder cancer, Kidney cancer, Squamous cell carcinoma, Sarcoma , gastrointestinal stromal tumors (GIST) and pediatric cancers.
  • leukemia multiple myelom
  • said lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein said lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma) and large cell carcinoma, etc.) or small cell lung cancer (SCLC), preferably non-small cell lung cancer (NSCLC); kidney cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma; wherein said sarcoma is preferably selected from Chondrosarcoma, Leiomyosarcoma, Soft Tissue Sarcoma, Ewing's Sarcoma, and Kaposi's Sarcoma.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • kidney cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma
  • said sarcoma is preferably selected from Chondrosarcoma, Leiomyosarcoma, Soft Tissue
  • Tumors present in the above definition of cancer are malignant tumors.
  • 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 sustained release 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 expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • 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, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • 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 those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • 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.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 1-12 alkyl), more preferably containing 1 to 6 carbon atoms (ie C 1-6 alkyl) .
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl indivual.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 Straight or branched chain groups of up to 20 carbon atoms (ie C 1-20 alkylene), preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 1-12 alkylene), more preferably an alkylene group containing 1 to 6 carbon atoms (ie C 1-6 alkylene).
  • 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.
  • the alkylene group 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 compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups containing from 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms are preferred (ie C 2-12 alkenyl), more preferably 2 Alkenyl to 6 carbon atoms (ie C 2-6 alkenyl).
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy one or more of a radical, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
  • Alkynyl groups containing from 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms are preferred (ie C 2-12 alkynyl groups), more preferably 2-12 alkynyl groups to alkynyl groups of 6 carbon atoms (ie, C 2-6 alkynyl groups).
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy One or more of , heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms (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 3 to 8 carbon atoms ( ie 3 to 8 membered cycloalkyl), more preferably 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 polycyclic group of 5 to 20 members (ie, 5 to 20 membered spirocycloalkyl), and a single carbon atom (called a spiro atom) is shared between the monocyclic rings, which may contain one or more Double bond.
  • a spiro atom is shared between the monocyclic rings, which may contain one or more Double bond.
  • it is 6 to 14 membered (ie 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered spirocycloalkyl).
  • spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan Monospirocycloalkyl.
  • Non-limiting examples of spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members (ie, 5 to 20 membered fused cycloalkyl) in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system , where one or more of the rings may contain one or more double bonds.
  • it is 6 to 14 membered (ie 6 to 14 membered fused cycloalkyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered fused cycloalkyl).
  • bicyclic, tricyclic, tetracyclic and polycyclic fused cycloalkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered (ie, 5- to 20-membered bridged cycloalkyl), all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, which may contain one or Multiple double bonds.
  • it is 6 to 14 membered (ie 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered bridged cycloalkyl).
  • bridged cycloalkyl preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include preferably
  • 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, heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms (ie, 3 to 20 membered heterocyclyl), one or more of which is optional Heteroatoms from nitrogen, oxygen, and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S-, or -S-S-, the remaining ring atoms for carbon.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, 1,2,4-oxadiazol-5(2H)-one, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl , piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered (i.e., 5- to 20-membered spiroheterocyclyl) polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more rings
  • the atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • spiroheterocyclyl 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered spiroheterocyclyl).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl.
  • spiroheterocyclyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan Single spiro heterocyclyl.
  • spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered (i.e., 5- to 20-membered fused heterocyclyl) polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, One or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may be optionally oxo (i.e., to form a sulfoxide or sulfone). ) and the remaining ring atoms are carbon.
  • it is 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered fused heterocyclic group), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered fused heterocyclyl).
  • bicyclic, tricyclic, tetracyclic and polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 20-membered (ie, 5- to 20-membered bridged heterocyclyl), polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more A double bond in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered bridged heterocyclyl).
  • 6 to 14 membered bridged heterocyclyl eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered
  • 7 to 10 membered eg 7, 8, 9 or 10 membered
  • it can be divided into bicyclic, tricyclic, tetracyclic and polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, 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, 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 (ie, a 6- to 14-membered aromatic group), preferably 6 to 10 membered (ie 6 to 10 membered aryl), 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, heteroaryl.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms (eg, 1, 2, 3, and 4), 5 to 14 ring atoms (ie, a 5 to 14 membered heteroaryl), wherein the heteroaryl The atoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered) (ie 5 to 10 membered heteroaryl), more preferably 5 to 6 membered (ie 5 to 6 membered heteroaryl) aryl), most preferably 5-membered (i.e.
  • heteroaryl such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazole base, pyrazolyl, triazolyl, thiazolyl and tetrazolyl, etc.
  • 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, and the substituents are selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "divalent cycloalkyl", "divalent heterocyclic group", “arylene” and "heteroarylene".
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • hydroxy protecting group refers to a hydroxy derivative commonly used to block or protect a hydroxy group while reacting on other functional groups of a compound.
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silyl (TBS), tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy Substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl , benzyl, methoxymethyl (MOM), ethoxyethyl
  • MOM methoxy
  • 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, 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 or both and Two configurations.
  • the bond is not specified, i.e. it can be either the Z configuration or the E configuration, or both.
  • 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.
  • “deuterium” or “tritium” is used in place of hydrogen
  • 18F -fluorine label 18F isotope
  • 18F isotope is used in place of fluorine, or11C- , 13C- , or14C -enriched
  • Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) in place of carbon atoms are within the scope of this disclosure.
  • each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize the compound of formula (I) in deuterated form.
  • 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 not necessarily 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 or cyano substitution.
  • Substituted means that one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity.
  • the compounds can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate 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 (IG) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises:
  • X is a halogen; preferably a chlorine atom
  • Ring A, Ring B, G 1 , G 2 , G 3 , R 1 , R 3 , R 4 , p and q are as defined in general formula (IG).
  • the compound represented by the general formula (I) of the present disclosure or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
  • X is a halogen; preferably a chlorine atom
  • Ring A, Ring B, R 1 to R 4 , n, p and q are as defined in general formula (I).
  • the compound represented by the general formula (II) of the present disclosure, or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
  • X is a halogen; preferably a chlorine atom
  • Ring A, Ring B, R 1 to R 4 , n, p and q are as defined in general formula (II).
  • the reagents that provide alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, Lithium isopropylamide, 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 hydrogenation Sodium, 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, 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.
  • HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • 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 to 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 Chemicals and other 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
  • compound 2c (100 mg, 0.49 mmol) was dissolved in 15 mL of methanol, 10% Pd/C (80 mg) was added, and the mixture was stirred at room temperature for 1 hour. Celite was filtered, washed with methanol once, and the filtrate was spin-dried to obtain compound 2d (80 mg), yield: 93.8%.
  • the level of phosphorylated P53 was detected by HTRF method, which reflected 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.
  • reaction buffer [25mM HEPES (Gibco, Cat. No.: 15630-080), pH 8.0, 0.01% Brij-35 (Thermo, Cat. No.: 20150), 1% glycerol (Sanko, Cat. No. A100854-0100)] P53 (Eurofins, Cat. No. 14-952-M) to 500 nM; with dilution buffer [25 mM HEPES pH8.0, 0.01% Brij-35, 1% glycerol, 5 mM DTT (Sanko, Cat. No. B645939), 1 mg/ mL BSA (Biyuntian, Cat.
  • the stop solution [12.5mM HEPES pH8.0, 0.005% Brij-35, 0.5% glycerol, 250mM EDTA (Thermo, Cat. No. AM9260G)] and detection mixture [50mM HEPES pH7.0, 150mM] were sequentially added to a 384-well plate using a liquid workstation.
  • NaCl Sudong, Item No.: B548121
  • 267mM KF Seopharm, 7789-23-3
  • 0.1% sodium cholate (Sigma, Item No.: C6445)
  • 0.01% Tween 20 (Sigma, Item No.: P7949), 0.0125% Sodium azide (Sigma, Cat.
  • 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 formulated using Bravo Liquid Workstation (Agilent Technologies, SGS120TH34702), and the formulated 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) is diluted to 20 ⁇ M with complete medium, and is added to the culture plate every time. 5 ⁇ L (final concentration 500 nM) was added to the well. Return the culture plate to the CO 2 constant temperature incubator to continue the culture.
  • Bravo Liquid Workstation Align Technologies, SGS120TH34702
  • the disclosed compounds have a good inhibitory effect on the proliferation of DNA-PK cells.
  • the Lantha Screen method was used to detect the change of ATP level, and the inhibitory effect of the compound on TTK enzyme activity was reflected, and the selectivity of the compound was evaluated according to the IC50 of the inhibitory effect.
  • Reaction buffer [50 mM HEPES (Gibco, #11344-041) pH 7.5, 10 mM MgCl2 (Sigma, #M2670), 2 mM DTT (Sigma, #D0632), 0.01% Triton X-100 (Sigma, #T9284) ] TTK enzyme (Invitrogen, #PR7264B), substrates Luciferin-Poly GAT (Invitrogen, #PV3611) and ATP (ADP-Glo Kinase Assay Kit, Promega, #V9102) were diluted respectively.
  • the disclosed compounds have weak inhibitory effect on TTK enzyme, but have good selective inhibitory effect on DNA-PK enzyme.
  • the LC/MS/MS method was used to determine the drug concentrations in the plasma of C57 mice at different times after intragastric (i.g.)/intravenous (i.v.) administration of the compound of Example 9 and positive control example 1 .
  • the pharmacokinetic behavior of the disclosed compounds in C57 mice was studied, and their pharmacokinetic characteristics were evaluated.
  • Positive control example 1 see the compound in Example 3 of WO2018114999A1
  • the structure is as follows:
  • mice Thirty-six C57 mice, female, were divided into 4 groups and purchased from Weitong Lihua Laboratory Animal Co., Ltd.
  • Example 9 Weigh a certain amount of the compound of Example 9 and positive control example 1, add 5% volume DMSO + 5% volume Tween 80 + 90% volume physiological saline, dissolve them, and prepare a 0.1 mg/mL clear solution.
  • Gavage administration group the administration dose was 2.0 mg/kg, and the administration volume was 0.2 mL/10 g.
  • Intravenous administration group the administration dose was 1.0 mg/kg, and the administration volume was 0.1 mL/10 g.
  • Gavage administration group 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10,000 rpm for 5 minutes (4°C), The plasma was separated within 1 hour and stored at -80°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions.
  • Intravenous administration group 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, and the same treatment was performed as the gavage group.
  • Determination of the content of the test compound in mouse plasma after drug administration of different concentrations Take 25 ⁇ L of mouse plasma samples at each time after administration, add 200 ⁇ L of acetonitrile and 50 ⁇ L of internal standard solution camptothecin (100 ng/mL), vortex After mixing for 5 minutes, centrifugation for 10 minutes (4000 rpm), 0.1 ⁇ L of the supernatant of the plasma sample was taken for LC/MS/MS analysis.
  • the disclosed compounds have good pharmacokinetic absorption activity in C57 mice, high oral bioavailability and pharmacokinetic advantages.
  • the LC/MS/MS method was used to determine the drug concentrations in plasma at different times after the beagle dogs were given the compound of Example 9 and the positive control example 1 by gavage (i.g.)/intravenous injection (i.v.) .
  • gavage i.g.
  • intravenous injection i.v.
  • the pharmacokinetic behavior of the disclosed compounds in beagle dogs was studied, and their pharmacokinetic characteristics were evaluated.
  • Example 9 Weigh a certain amount of the compound of Example 9 and positive control example 1, add 5% volume DMSO+20% volume PG+20% volume PEG400+55% volume normal saline, and prepare 0.4mg/mL clear solution (gavage administration). group) and 0.25 mg/mL clear solution (intravenous administration group).
  • Gavage administration group the administration dose was 2.0 mg/kg, and the administration volume was 5.0 mL/kg.
  • Intravenous administration group the administration dose was 0.5 mg/kg, and the administration volume was 2.0 mL/kg.
  • Gavage administration group Before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration, 1.0 mL of blood was collected from jugular vein or forelimb vein, and EDTA-K2 anticoagulation test tube was placed , centrifuge at 10,000 rpm for 5 minutes (4°C), separate plasma within 1 hour, and store at -80°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions. Eat 3 hours after dosing.
  • Intravenous injection group blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, and 24 hours before administration and 5 minutes after administration, and the treatment was the same as the intragastric administration group.
  • Determination of the content of the compound to be tested in Beagle plasma after administration of different concentrations of drugs take 20 ⁇ L of Beagle plasma samples at each time after administration, add 400 ⁇ L methanol (containing 100 ng/mL internal standard solution) for protein precipitation, Vortex for 1 minute, centrifuge at 18,000 g for 7 minutes, and 1 ⁇ L of the supernatant from plasma samples was analyzed by LC/MS/MS.
  • the disclosed compounds have good pharmacokinetic absorption activity in beagle dogs, high oral bioavailability and pharmacokinetic advantages.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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Abstract

L'invention concerne un dérivé de purinone représenté par la formule générale (IG), son procédé de préparation, une composition pharmaceutique contenant ledit dérivé, et ses utilisations en tant qu'agent thérapeutique, en particulier une utilisation en tant qu'inhibiteur d'ADN-PK et une utilisation dans la préparation d'un produit pharmaceutique pour le traitement et/ou la prévention d'un cancer ; les groupes de formule générale (IG) étant tels que définis dans la description.
PCT/CN2021/139862 2020-12-21 2021-12-21 Dérivé de purinone, son procédé de préparation et son utilisation en médecine WO2022135360A1 (fr)

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