WO2024046420A1 - 稠合二环类化合物、其制备方法及其在医药上的应用 - Google Patents

稠合二环类化合物、其制备方法及其在医药上的应用 Download PDF

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WO2024046420A1
WO2024046420A1 PCT/CN2023/116099 CN2023116099W WO2024046420A1 WO 2024046420 A1 WO2024046420 A1 WO 2024046420A1 CN 2023116099 W CN2023116099 W CN 2023116099W WO 2024046420 A1 WO2024046420 A1 WO 2024046420A1
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group
general formula
cancer
pharmaceutically acceptable
acceptable salt
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PCT/CN2023/116099
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English (en)
French (fr)
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李心
董怀德
贺峰
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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 WO2024046420A1 publication Critical patent/WO2024046420A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure belongs to the field of medicine and relates to a fused bicyclic compound, its preparation method and its application in medicine.
  • the present disclosure relates to fused bicyclic compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, as well as their use as PARP1 inhibitors and for treatment and/or prevention Cancer uses.
  • PARP1 Poly(ADP-ribose)polymerase 1
  • PARP1 can catalyze the transfer of ADP ribose residues from NAD+ to the target substrate to build a poly(ADP-ribose), PAR) chain.
  • the formation and clearance of PAR chains occurs in almost all eukaryotic cells.
  • ADP-ribosylation is a post-translational modification of proteins that is widely present in various physiological and pathological processes. It refers to the binding of one or more ADP-ribose units to specific sites on proteins under the catalysis of enzymes.
  • PARP1 is the first member of the PARP superfamily, which consists of proteins with homology to PARP1. There are currently 17 members, four of which (PARP1, PARP2, PARP5A and PARP5B) can synthesize PAR chains. Most other enzymes in the family can only build a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs).
  • PARP1 and PARP2 have been extensively studied for their roles in DNA damage repair.
  • PARP1 is activated by DNA damage and functions to catalyze poly(ADP-ribose) (PAR) strands to target proteins.
  • PAR poly(ADP-ribose)
  • PARPylation This post-translational modification, called poly-ADP-ribosylation (PARylation), mediates the recruitment of other DNA repair factors to DNA damage.
  • PARP auto-PARylation triggers the release of bound PARP from DNA, allowing access to other DNA repair proteins to complete repair. Therefore, the binding of PARP to damaged sites, its catalytic activity and eventual release from DNA are all important steps in the response of cancer cells to DNA damage caused by chemotherapeutic agents and radiotherapy.
  • PARP inhibitors with improved selectivity for PARP1 compared with other PARP1/2 inhibitors with improved efficacy and reduced toxicity.
  • selective strong inhibition of PARP1 will lead to trapping of PARP1 on DNA, leading to DNA double-strand breaks (DSBs) through the collapse of replication forks in S phase.
  • DLBs DNA double-strand breaks
  • PARP1-DNA trapping is an efficient mechanism to selectively kill tumor cells with HRD.
  • Ring A is heteroaryl
  • Ring B is aryl or heteroaryl
  • G 2 is CR 6a or nitrogen atom
  • G 3 is CR 6b or nitrogen atom
  • R 0 , R 1a , R 6a and R 6b are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, -NR 7a R 7b , hydroxyl group, -C(O)R 8a , -C(O)OR 8a , -C(O)NR 7a R 7b , -S(O) p R 8a , cycloalkyl group, heterocyclyl group, aryl group and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, oxo, alkyl, alkoxy Substituted with one or more substituents in , haloalkyl, haloalkoxy, cyano, -NR
  • Each R 2 is the same or different, and each is independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl;
  • Each R 3 is the same or different, and each is independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7e R 7f , hydroxyl, -C(O)R 8b , -C(O)OR 8b , -C(O)NR 7e R 7f , -S(O) q R 8b , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl group , alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9c R 9d , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Substituted by one or more substitu
  • R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 9a , R 9b , R 9c and R 9d are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a ring Alkyl and heterocyclyl, wherein each of the alkyl, cycloalkyl and heterocyclyl is independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl and haloalkoxy Substituted by a substituent; or
  • R 7a and R 7b together with the attached nitrogen atom form a heterocyclyl group
  • R 7c and R 7d together with the attached nitrogen atom form a heterocyclyl group
  • R 7e and R 7f together with the attached nitrogen atom form a heterocyclyl group
  • the formed heterocyclic group is optionally selected from halogen, oxo One or more of base, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by substituents;
  • R 8a and R 8b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are each independently selected Optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;
  • p 0, 1 or 2;
  • q 0, 1 or 2;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • s 0, 1, 2, 3, or 4;
  • t 0, 1, 2 or 3.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom; in some In embodiments, Ring A is selected from pyrazolyl, thienyl, and imidazolyl; in some embodiments, Ring A is pyrazolyl.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein Selected from Preferably, for More preferably, for Wherein, R 2a is selected from hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR 7c R 7d , hydroxyl group and hydroxyalkyl group, R 7c , R 7d , m and n are as follows As defined in general formula (I).
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein m is 1 or 2; preferably, m is 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring B is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, Ring B is phenyl or 6-membered heteroaryl; more preferably, ring B is pyridyl.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein G 2 is CR 6a and R 6a is as defined in the general formula (I); and/or G 3 is CR 6b , and R 6b is as defined in general formula (I).
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein s is 0 or 1; preferably, s is 0.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
  • X and Y are the same or different, and are each independently a nitrogen atom or CR 2a ;
  • R 2a is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl;
  • R 0 , R 1a , R 6a , R 6b , R 7c , R 7d , R 3 , n and t are as defined in general formula (I).
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 3 is the same or different, and each is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, -NR 7e R 7f , hydroxyl, - C(O)R 8b , -C(O)OR 8b and -C(O)NR 7e R 7f , R 8b , R 7e and R 7f are as defined in general formula (I); preferably, R 3 is -C(O)NR 7e R 7f , R 7e and R 7f are as defined in general formula (I); more preferably, R 3 is -C(O)NHCH 3 .
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein R 6a is selected from hydrogen atom, halogen, C 1-6 alkyl , C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group and C 1-6 hydroxyalkyl group; preferably, R 6a is selected from hydrogen atom, halogen, C 1-6 alkyl group and C 1-6 haloalkyl; more preferably, R 6a is a hydrogen atom.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein R 6b is selected from hydrogen atom, halogen, C 1-6 alkyl group , C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group and C 1-6 hydroxyalkyl group; preferably, R 6b is selected from hydrogen atom, halogen, C 1-6 alkyl group and C 1-6 haloalkyl; more preferably, R 6b is a hydrogen atom.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof. of salt:
  • X and Y are the same or different, and are each independently a nitrogen atom or CR 2a ;
  • R 2a is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl;
  • R 0 , R 1a , R 7c , R 7d , R 7e , R 7f and n are as defined in general formula (I).
  • each R 2 in is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl group; preferably, each R 2 is the same or different, and each is independently selected from C 1-6 alkyl and C 1-6 hydroxyalkyl.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R 2a is selected from a hydrogen atom, C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; preferably, R 2a is selected from hydrogen atom, C 1-6 Alkyl and C 1-6 hydroxyalkyl; preferably, R 2a is a hydrogen atom.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R 0 is a hydrogen atom or halogen; more preferably, R 0 is halogen; most preferably, R 0 is F.
  • the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein for Preferably, for Wherein, R 2a and n are as defined in general formula (II).
  • R 0 is a hydrogen atom or halogen
  • R 1a is a C 1-6 alkyl group
  • R 6a is selected from Hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl
  • R 6b is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl
  • n is 1
  • X is a nitrogen atom
  • Y is CR 2a
  • R 2a is selected from hydrogen atom, C 1-6 alkyl and C 1-6 hydroxyalkyl
  • t is 1
  • R 3 is -C(O)NR 7e R 7f , and R 7e and R 7f is the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof R 0 is halogen; R 1a is C 1-6 alkyl; n is 1; X is nitrogen atom; Y is CH; and R 7e and R 7f are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group.
  • Typical compounds of the present disclosure include, but are not limited to:
  • R 3 is -C(O)NR 7e R 7f ;
  • t 1, 2 or 3;
  • X, Y, R 7e , R 7f and n are as defined in general formula (II).
  • X, Y, R 7e , R 7f and n are as defined in general formula (III).
  • Typical intermediate 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 (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • a nucleophilic substitution reaction occurs between a compound of general formula (Ia) or a salt thereof (preferably a hydrochloride) and a compound of general formula (Ib) to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof;
  • L is halogen, preferably Br
  • G 2 , G 3 , ring A, ring B, R 0 , R 1a , R 2 , R 3 , s, t, m and n 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 nucleophilic substitution reaction occurs between a compound of general formula (IIa) or a salt thereof (preferably a hydrochloride) and a compound of general formula (IIb) to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof;
  • L is halogen, preferably Br
  • X, Y, R 0 , R 1a , R 3 , R 6a , R 6b , t and n are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • a nucleophilic substitution reaction occurs between a compound of general formula (IIIa) or a salt thereof (preferably a hydrochloride) and a compound of general formula (IIIb) to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof;
  • L is halogen, preferably Br
  • X, Y, R 0 , R 1a , R 7e , R 7f and n are as defined in general formula (III).
  • compositions which contains a compound shown in Formula (I), Formula (II) or Formula (III) of the disclosure and Table A or a pharmaceutically acceptable compound thereof. salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the use of compounds shown in Formula (I), Formula (II) or Formula (III) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including them in the preparation of PARP1 inhibitors. use.
  • the present disclosure further relates to compounds shown in general formula (I), general formula (II) or general formula (III) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including the same in the preparation of treatment and/or prevention Diseases or conditions mediated by PARP1 uses in medicines.
  • the present disclosure further relates to compounds shown in general formula (I), general formula (II) or general formula (III) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions including the same for the preparation of treatments and/or Use in medicines to prevent cancer, essential thrombocythemia, or polycythemia vera.
  • the present disclosure further relates to a method for inhibiting PARP1, which includes administering to a patient in need a therapeutically effective amount of a compound shown in Formula (I), Formula (II) or Formula (III) and Table A or a pharmaceutically acceptable amount thereof salts, or pharmaceutical compositions including them.
  • the present disclosure further relates to a method of treating and/or preventing a disease or condition mediated by PARP1, comprising administering to a patient in need thereof an inhibitory effective amount of Formula (I), Formula (II) or Formula (III) and The compound shown in Table A, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.
  • the present disclosure further relates to a method of treating and/or preventing cancer, essential thrombocythemia or polycythemia vera, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II) or Formula (II) or Polycythemia Vera.
  • a method of treating and/or preventing cancer, essential thrombocythemia or polycythemia vera comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II) or Formula (II) or Polycythemia Vera.
  • the present disclosure further relates to a compound shown in general formula (I), general formula (II) or general formula (III) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used as a medicine .
  • the present disclosure further relates to a compound shown in general formula (I), general formula (II) or general formula (III) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used as PARP1 Inhibitors.
  • the present disclosure further relates to a compound shown in general formula (I), general formula (II) or general formula (III) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used for treatment and/or prevent diseases or conditions mediated by PARP1.
  • the present disclosure further relates to a compound shown in general formula (I), general formula (II) or general formula (III) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used for treatment and/or medicines to prevent cancer, essential thrombocythemia, or polycythemia vera.
  • the disease or disorder mediated by PARP1 of the present disclosure is cancer.
  • the cancer described in the present disclosure is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer (such as colon cancer and rectal cancer), lung cancer, kidney cancer, liver cancer (such as hepatocellular carcinoma), Cervical cancer, endometrial cancer, myeloma (such as multiple myeloma), leukemia (such as acute leukemia, chronic leukemia, myelogenous leukemia, myelofibrosis, erythroleukemia), lymphoma (such as diffuse large B-cell lymphoma) , Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoid malignancies of T-cell or B-cell origin, follicular lymphoma), acoustic neuroma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer , bronchial cancer, sarcomas (such as chondrosarcoma, fibro
  • the cancer cells of the cancer described in the present disclosure are BRCA1 or BRCA2 deficient, preferably BRCA2 deficient.
  • the cancer cells of the cancer described in the present disclosure are defective in BRCA1 or BRCA2, preferably BRCA2.
  • the active compounds may be prepared in a form suitable for administration by any appropriate route and the compositions of the present disclosure may be formulated by conventional means using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure may also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
  • dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
  • the active compounds are preferably in unit dosage form, or in such form that the patient may self-administer a single dose.
  • the unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • auxiliary materials 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 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 may 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 carrier or oil vehicle.
  • Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredient in vegetable oil, or mineral oil. Oil suspensions may contain thickening agents. Sweetening and flavoring agents as described above 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 oil phase may be vegetable oil, or mineral oil or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles or solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.
  • Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase.
  • injectable solutions or microemulsions may be injected into the patient's bloodstream by local mass injection.
  • solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the present disclosure.
  • continuous intravenous drug delivery devices can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent.
  • sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used.
  • fatty acids are also prepared as injectables.
  • the compounds of the present disclosure may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug.
  • compositions of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules.
  • These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.
  • the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's health, and the patient's behavior. , patient's diet, administration time, administration method, excretion rate, combination of drugs, severity of disease, etc.; in addition, the best treatment method such as treatment mode, daily dosage of compounds or pharmaceutically acceptable salts Types can be verified based on traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e. C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, 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-methyl Pentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhe
  • the alkyl 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 the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 alkylene group).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 alkylene group ).
  • Non-limiting examples include: -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH 2 CH (CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • the alkenyl 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 the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, 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, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic in alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), and more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group). ), most preferably cycloalkyl groups having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl groups).
  • Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic system in which one carbon atom (called a spiro atom) is shared between the rings.
  • the ring may contain one or more double bonds, or the ring may contain one or more atoms selected from nitrogen, Heteroatoms of oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxoated, that is, to form sulfoxide or sulfone, but does not include -O-O-, -O-S - or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl group), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). membered spirocycloalkyl).
  • the spirocycloalkyl group includes a single spirocycloalkyl group and a multi-spirocycloalkyl group (such as a double spirocycloalkyl group, etc.), preferably a single spirocycloalkyl group or a double spirocycloalkyl group, and more preferably a 3-membered/4-membered, 3-membered or 3-membered spirocycloalkyl group.
  • Non-limiting examples include:
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with a heterocyclic cycloalkyl group.
  • One or more of the cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on a single-ring cycloalkyl group, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the fused ring alkyl group is preferably a fused ring alkyl group having 6 to 14 ring atoms (ie, a 6 to 14-membered fused ring alkyl group), and more preferably a fused ring alkyl group having 7 to 10 ring atoms (ie, a 7 to 10 membered ring alkyl group). fused ring alkyl group).
  • the fused cycloalkyl group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6- to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl group). bridged cycloalkyl).
  • the bridged cycloalkyl group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • Cycloalkyl 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 atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic system (i.e., polycyclic heterocyclyl), which contains at least one ring (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxogenated, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), and having 3 to 20 (e.g.
  • the heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclyl group); further preferably a heterocyclyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclyl group) ); more preferably a heterocyclyl group with 3 to 6 ring atoms (i.e. a 3 to 6 membered heterocyclyl group); most preferably a heterocyclyl group with 5 or 6 ring atoms (i.e. a 5 or 6 membered heterocyclyl group).
  • Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl and homopiperazinyl, etc.
  • the polycyclic heterocyclyl group includes spiroheterocyclyl group, fused heterocyclyl group and bridged heterocyclyl group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic system in which the rings share one atom (called a spiro atom).
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, But does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclyl group and the point of attachment is on the monocyclic heterocyclyl group, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie, 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroheterocyclyl group), and more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclyl group).
  • 1-membered spiroheterocyclyl 1-membered spiroheterocyclyl
  • the spiroheterocyclyl group includes a single spiroheterocyclyl group and a polyspiroheterocyclyl group (such as a double spiroheterocyclyl group, etc.), preferably a single spiroheterocyclyl group or a double spiroheterocyclyl group, more preferably 3-membered/4-membered, 3-membered or 3-membered spiroheterocyclyl.
  • Non-limiting examples include:
  • fused heterocyclyl refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between the rings.
  • the ring may contain one or more double bonds, and the ring may contain at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not Including -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl fused with one or more monocyclic heterocyclyl groups, or a monocyclic heterocyclyl group with a cycloalkyl, aryl or heteroaryl group.
  • the fused heterocyclyl group is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl group), and more preferably a fused heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclyl group). fused heterocyclic group).
  • the fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (such as tricyclic fused heterocyclyl group, tetracyclic fused heterocyclyl group, etc.), preferably bicyclic fused heterocyclyl group or tricyclic fused heterocyclyl group, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/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-membered/6-membered bicyclic fused heterocyclyl
  • bridged heterocyclyl refers to a polycyclic heterocyclic system that shares two atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the bridged heterocyclyl group is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl group), and more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclyl group). Yuan-bridged heterocyclyl).
  • bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl such as tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.
  • bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl. base.
  • Non-limiting examples include:
  • Heterocyclyl may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ electron system, having 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e. 6 to 14 membered aryl group).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, 6 to 10 membered aryl group).
  • the monocyclic aryl group is, for example, phenyl.
  • Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the polycyclic aryl group also includes phenyl fused with one or more of heterocyclyl or cycloalkyl, or naphthyl fused with one or more of heterocyclyl or cycloalkyl, where the point of attachment on phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups. or Multiple.
  • heteroaryl refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) with a conjugated ⁇ electron system, which contains at least one (For example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo-substituted, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group).
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • Non-limiting examples of the polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene base, quinazolinyl, benzothiazolyl, carbazolyl, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent a polycyclic heteroaryl ring rings in the system Number of atoms.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclyl, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the ring
  • the number of atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • Non-limiting examples include:
  • Heteroaryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkyl groups.
  • amino protecting group refers to an easily removable group introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), watmethoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxyl protecting group refers to an easily removable group introduced on a hydroxyl group to block or protect the hydroxyl group for reactions on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Dimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, where aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, where heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • mercapto 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-, where alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers and their mixtures (e.g. racemates, mixtures of diastereomers) . Additional asymmetric atoms may be present for substituents in the compounds of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared through asymmetric synthesis or chiral auxiliaries, or when the molecule contains basic functional groups (such as amino) or acidic functional groups (such as carboxyl), and appropriate optical Reactive acids or bases form diastereomeric salts, and then the diastereoisomers are resolved by conventional methods known in the art to obtain pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond can be or both Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included.
  • tautomer or tautomeric form refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. it includes all possible The tautomers exist in the form of a single isomer or in the form of a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of a lactam-lactam equilibrium is shown below:
  • the compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom with the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as 2 H (deuterium, D), respectively.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of the drug. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete.
  • the replacement of partial deuterium means that at least one hydrogen is replaced by at least one deuterium.
  • a position when a position is specifically designated as “deuterium” or “D", that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. At least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, each is specified
  • the deuterium atom has an abundance of deuterium that is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporated). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • alkyl optionally substituted by halogen or cyano 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.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents.
  • a person skilled in the art will be able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically).
  • an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond, such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, as well as other ingredients such as pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • the unit dosage of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof.
  • the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present disclosure, which may be selected from inorganic salts or organic salts. This type of salt is safe and effective when used in mammals, and has due biological activity. They can be prepared individually during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • therapeutically effective amount refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of a therapeutically 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. The appropriate therapeutically effective amount in an individual case can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reaction or other problems or complications, has a reasonable benefit/risk ratio, and is effective for the intended use.
  • the present disclosure discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which method includes the following steps:
  • a nucleophilic substitution reaction occurs between a compound of general formula (Ia) or a salt thereof (preferably a hydrochloride) and a compound of general formula (Ib) under basic conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (I) Compounds or pharmaceutically acceptable salts thereof;
  • L is halogen, preferably Br
  • G 2 , G 3 , ring A, ring B, R 0 , R 1a , R 2 , R 3 , s, t, m and n are as defined in general formula (I).
  • the present disclosure discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which method includes the following steps:
  • L is halogen, preferably Br
  • X, Y, R 0 , R 1a , R 3 , R 6a , R 6b , t and n are as defined in general formula (II).
  • the present disclosure discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which method includes the following steps:
  • a nucleophilic substitution reaction occurs between a compound of general formula (IIIa) or a salt thereof (preferably a hydrochloride) and a compound of general formula (IIIb) under basic conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (III) Compounds or pharmaceutically acceptable salts thereof;
  • L is halogen, preferably Br
  • X, Y, R 0 , R 1a , R 7e , R 7f and n are as defined in general formula (III).
  • the bases that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine.
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, hydroxide Sodium, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.
  • the catalyst for the above nucleophilic substitution reaction is sodium iodide or potassium iodide, preferably sodium iodide.
  • the above reaction is preferably carried out in a solvent, and the solvents used include but are not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum Ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2- Dibromoethane and its mixtures.
  • the solvents used include but are not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum Ether, ethy
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M.
  • the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • MS was measured using Agilent 1200/1290 DAD-6110/6120Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS).
  • HPLC High performance liquid chromatography
  • High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm ⁇ 0.2mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200 ⁇ 300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC 50 value were measured using NovoStar microplate reader (BMG Company, Germany).
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemical companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenator and Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: dichloromethane/ethyl acetate system, the volume ratio of the solvent depends on the polarity of the compound. For adjustment, you can also add a small amount of alkaline or acidic reagents such as triethylamine and acetic acid for adjustment.
  • the crude compound 1d (140 mg, 407.7 ⁇ mol) was dissolved in dichloromethane (2 mL), 1 mL of 4M dioxane hydrochloride solution was added, and the reaction was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1e (110 mg, Yield: 96.5%), the product was directly used in the next reaction without purification.
  • Example 2 Using the synthetic route in Example 1, the first step raw material compound 1b was replaced with 5-bromo-3-fluoropyridine-2-carboxylic acid methyl ester (Nanjing Yaoshi) to obtain the title compound 3 (39 mg, yield: 17.3%).
  • the crude compound 4c (6.6g, 38.5mmol) was dissolved in methanol (50mL) and ethanol (50mL), potassium carbonate (6.4g, 46.3mmol) was added, and the reaction was carried out at 80°C for 16 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was dissolved in Ethyl acetate (100 mL), washed with water and saturated sodium chloride solution in sequence, collected the organic phase, dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure, the residue was purified by silica gel column chromatography using elution system C to obtain Title compound 4d (1.3 g, yield: 25.1%).
  • the residue is analyzed by high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: water phase (10mmol/L carbonic acid Ammonium hydrogen) and acetonitrile (gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) were purified to obtain the title compound 5 (racemate) (25 mg, yield: 31.9%).
  • Dichloromethane solution (2mL) continue stirring for 30 minutes, add triethylamine (584.8mg, 5.8mmol), return to room temperature and stir for 2 hours, add water to the reaction solution, extract with dichloromethane (10mL ⁇ 3), combine the organic phase, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6g (80mg, yield: 40.2 %).
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was analyzed by high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L (Ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL/min), the title compound 7b (50 mg, yield: 1.8%) was purified.
  • the following method evaluates the inhibitory effect of the disclosed compounds on the proliferation of DLD1 cells, DLD1 BRCA2-/- and MDA-MB-436 cells by detecting intracellular ATP content and based on the IC 50 size.
  • the experimental method is briefly described as follows:
  • DLD1 human colon cancer tumor cells (Nanjing Kebai, CBP60037)
  • DLD1 BRCA2-/- human BRCA2 gene knockout colon cancer tumor cells (Creative biogene, CSC-RT0015)
  • MDA-MB-436 human breast cancer cells (ATCC, HTB-130)
  • DLD1 cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2 to 3 times a week with a passage ratio of 1:6 or 1:8. During passage, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200 rpm for 3 minutes, discard the supernatant medium residue, and add fresh medium to resuspend the cells. Add 180 ⁇ L of cell suspension to the 96-well cell culture plate with a density of 2.78 ⁇ 10 3 cells/mL. Only 180 ⁇ L of complete culture medium is added to the periphery of the 96-well plate.
  • DLD1 BRCA2-/- cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2 to 3 times a week with a passage ratio of 1:6 or 1:8. During passage, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200 rpm for 3 minutes, discard the supernatant medium residue, and add fresh medium to resuspend the cells. Add 180 ⁇ L of cell suspension to the 96-well cell culture plate with a density of 8.34 ⁇ 10 3 cells/mL. Only 180 ⁇ L of complete culture medium is added to the periphery of the 96-well plate.
  • MDA-MB-436 cells were cultured in Leibovitz's L-15 medium containing 10% FBS, 10 ⁇ g/mL insulin, and 16 ⁇ g/mL glutathione, and were passaged 2 to 3 times a week, with a passage ratio of 1:3 or 1: 5. During passage, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200 rpm for 3 minutes, discard the supernatant medium residue, and add fresh medium to resuspend the cells. Add 180 ⁇ L of cell suspension to the 96-well cell culture plate with a density of 8.34 ⁇ 10 3 cells/mL. Only 180 ⁇ L of complete culture medium is added to the periphery of the 96-well plate.
  • the culture plates were incubated in an incubator for 24 hours (37°C, 5% CO2 ).
  • the disclosed compound has a good inhibitory effect on the proliferation of DLD1 BRCA2-/- and MDA-MB-436 cells.
  • PARP1 recombinant protein (Yiqiao Shenzhou, product number 11040-H08B);
  • Fluorescent probe self-made using compound with CAS number 1380359-84-1, Shanghai Hengrui;
  • Microplate reader PHERAstar FS (BMG Labtech)
  • the experiment described below uses the PARP1 Chemiluminescent Assay Kit (PARP1 Chemiluminescent Assay Kit, BPS, 80551, Lot#211124-K) to determine the effect of compounds on PARP1 Inhibition of enzyme activity.
  • the key to the PARP1 chemiluminescence detection kit is the use of biotinylated NAD+. By measuring the intensity of the chemiluminescence signal, the level of NAD + in the reaction system can be known, thereby calculating the degree of inhibition of PARP1 enzyme activity by the test compound.
  • the IC 50 value of a compound can be calculated from the inhibition rate at different concentrations.

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Abstract

本公开涉及稠合二环类化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的稠合二环类化合物、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，特别是作为PARP1抑制剂的用途和用于治疗和/或预防癌症的用途。

Description

稠合二环类化合物、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，涉及一种稠合二环类化合物、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)所示的稠合二环类化合物、其制备方法及含有该类化合物的药物组合物，以及其作为PARP1抑制剂的用途和用于治疗和/或预防癌症的用途。
背景技术
多聚ADP核糖聚合酶1(poly(ADP-ribose)polymerase 1，即PARP1)，首次被报道是在50多年前，之后逐渐被发现在DNA修复、维持基因组完整性以及调控多种代谢和信号转导过程等方面扮演着重要角色。PARP1能够催化ADP核糖残基从NAD+转移到目标底物上，构建一个多聚ADP核糖(poly(ADP-ribose)，PAR)链。PAR链的形成和清除发生在几乎所有的真核细胞中。
ADP-核糖化(ADP-ribosylation)是一种广泛存在于各种生理和病理过程的蛋白质翻译后修饰，指在酶的催化下将一个或多个ADP-核糖单元结合到蛋白质特定位点。PARP1是PARP超家族的第一个成员，该超家族由与PARP1具有同源性的蛋白质组成，现有17个成员，其中4个(PARP1、PARP2、PARP5A和PARP5B)能够合成PAR链。家族中的大多数其他酶只能构建单个ADP核糖(ADP-ribose)单元，因此被归类为单ADP核糖化酶(mono(ADP-ribosyl)ases(MARs))。
PARP1和PARP2因其在DNA损伤修复中的作用而被广泛研究。PARP1被DNA破坏激活，并起催化聚(ADP-核糖)(PAR)链向靶蛋白的作用。这种翻译后修饰称为聚二磷酸腺苷核糖基化(Poly-ADP-ribosylation，PARylation)，可介导将其他DNA修复因子募集到DNA损伤中。完成该募集任务后，PARP自动PARylation触发结合的PARP从DNA释放，从而允许访问其他DNA修复蛋白以完成修复。因此，PARP与受损位点的结合，其催化活性以及最终从DNA释放都是癌细胞对化学治疗剂和放射疗法引起的DNA损伤作出反应的重要步骤。
抑制PARP家族酶已被用作一种通过失活互补DNA修复途径选择性杀死癌细胞的策略。大量的临床前和临床研究表明，带有通过有害重组(HR)参与双链DNA断裂(DSB)修复的关键肿瘤抑制蛋白BRCA1或BRCA2有害改变的肿瘤细胞对小分子选择性敏感。DNA修复酶PARP家族的抑制剂。这类肿瘤的同源重组修复(HRR)途径不足，并且依赖于PARP酶的生存功能。尽管PARP抑制剂疗法主要针对BRCA突变的癌症，但PARP抑制剂已在非BRCA突变的肿瘤中进行了临床测试，这些肿瘤表现出同源重组缺陷(HRD)。
与其他PARP1/2抑制剂相比，对PARP1具有提高的选择性的PARP抑制剂可 以具有改善的功效和降低的毒性。我们相信对PARP1的选择性强抑制将导致PARP1在DNA上的捕获，通过在S期中复制叉的崩溃而导致DNA双链断裂(DSBs)。PARP1-DNA捕获是选择性杀死具有HRD的肿瘤细胞的有效机制。
因此，临床上急需有效和安全的PARP抑制剂，特别是对PARP1具有选择性的PARP抑制剂。
现已公开的PARP抑制剂的专利申请为WO2021013735A1、WO2009053373A1、WO2008107478A1、WO2021260092A1等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为杂芳基；
环B为芳基或杂芳基；
G2为CR6a或氮原子；
G3为CR6b或氮原子；
R0、R1a、R6a和R6b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR7aR7b、羟基、-C(O)R8a、-C(O)OR8a、-C(O)NR7aR7b、-S(O)pR8a、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR9aR9b、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R2相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR7cR7d、羟基和羟烷基；
各个R3相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR7eR7f、羟基、-C(O)R8b、-C(O)OR8b、-C(O)NR7eR7f、-S(O)qR8b、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR9cR9d、羟基、羟烷基、环烷基、杂环基、芳基和 杂芳基中的一个或多个取代基所取代；
R7a、R7b、R7c、R7d、R7e、R7f、R9a、R9b、R9c和R9d相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；或者
R7a和R7b与相连的氮原子一起形成杂环基，或者R7c和R7d与相连的氮原子一起形成杂环基，或者R7e和R7f与相连的氮原子一起形成杂环基，或者R9a和R9b与相连的氮原子一起形成杂环基，或者R9c和R9d与相连的氮原子一起形成杂环基，所述形成的杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R8a和R8b相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
p为0、1或2；
q为0、1或2；
m为0、1或2；
n为0、1或2；
s为0、1、2、3或4；且
t为0、1、2或3。
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为至少含有一个氮原子的5元或6元的杂芳基；在一些实施方案中，，环A选自吡唑基、噻吩基和咪唑基；在一些实施方案中，环A为吡唑基。
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，其中选自 优选地，为 更优选地，为其中，R2a选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR7cR7d、羟基和羟烷基，R7c、R7d、m和n如通式(I)中所定义。
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m为1或2；优选地，m为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B为6至10元芳基或5至10元杂芳基；优选地，环B为苯基或6元杂芳基；更优选地，环B为吡啶基。
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G2为CR6a，R6a如通式(I)中所定义。
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G3为CR6b，R6b如通式(I)中所定义。
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G2为CR6a，R6a如通式(I)中所定义；和/或G3为CR6b，R6b如通式(I)中所定义。
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s为0或1；优选地，s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，其为通式(II)所示的化合物或其可药用的盐：
其中：
X和Y相同或不同，且各自独立地为氮原子或CR2a；
R2a选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR7cR7d、羟基和羟烷基；
R0、R1a、R6a、R6b、R7c、R7d、R3、n和t如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中各个R3相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6羟烷基、氰基、-NR7eR7f、羟基、-C(O)R8b、 -C(O)OR8b和-C(O)NR7eR7f，R8b、R7e和R7f如通式(I)中所定义；优选地，R3为-C(O)NR7eR7f，R7e和R7f如通式(I)中所定义；更优选地，R3为-C(O)NHCH3。
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中R6a选自氢原子、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基和C1-6羟烷基；优选地，R6a选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，R6a为氢原子。
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中R6b选自氢原子、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基和C1-6羟烷基；优选地，R6b选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，R6b为氢原子。
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中R6a为氢原子；和/或R6b为氢原子。
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中t为1或2；优选为1。
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
其中：
X和Y相同或不同，且各自独立地为氮原子或CR2a；
R2a选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR7cR7d、羟基和羟烷基；
R0、R1a、R7c、R7d、R7e、R7f和n如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中n为1或2；优选地，n为1。
在本公开一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中X为氮原子。
在本公开一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中Y为CR2a，R2a如通式(II)中所定义；优选地，Y为CH。
在本公开一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中X为氮原子；和/或Y为CH。
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R2相同或不同，且各自独立地选自C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基和C1-6羟烷基；优选地，各个R2相同或不同，且各自独立地选自C1-6烷基和C1-6羟烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中R2a选自氢原子、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基和C1-6羟烷基；优选地，R2a选自氢原子、C1-6烷基和C1-6羟烷基；优选地，R2a为氢原子。
在本公开一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中R0选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；优选地，R0为氢原子或卤素；更优选地，R0为卤素；最优选地，R0为F。
在本公开一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中R1a选自氢原子、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基和C1-6羟烷基；优选地，R1a为C1-6烷基；更优选地，R1a为甲基。
在本公开一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中R7e和R7f相同或不同，且各自独立地选自氢原子、C1-6烷基、C1-6羟烷基、3至8元环烷基和3至8元杂环基；优选地，R7e和R7f相同或不同，且各自独立地为氢原子或C1-6烷基；更优选地，R7e和R7f相同或不同，且各自独立地为氢原子或甲基。
在本公开一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中为优选地，为其中，R2a和n如通式(II)中所定义。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，R0为氢原子或卤素；R1a为C1-6烷基；R6a选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；R6b选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；n为1；X为氮原子；Y为CR2a，R2a选自氢原子、C1-6烷基和C1-6羟烷基；t为1；R3为-C(O)NR7eR7f，且R7e和R7f相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，R0为卤素；R1a为C1-6烷基；n为1；X为氮原子；Y为CH；且R7e和R7f相同或不同，且各自独立地为氢原子或C1-6烷基。
表A本公开的典型化合物包括但不限于：
本公开的另一方面涉及通式(IIa)所示的化合物或其盐：
其中：
R3为-C(O)NR7eR7f；
t为1、2或3；
X、Y、R7e、R7f和n如通式(II)中所定义。
本公开的另一方面涉及通式(IIIa)所示的化合物或其盐：
其中：
X、Y、R7e、R7f和n如通式(III)中所定义。
表B本公开的典型中间体化合物包括但不限于：

本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
通式(Ia)的化合物或其盐(优选盐酸盐)与通式(Ib)的化合物发生亲核取代反应，得到通式(I)的化合物或其可药用的盐；
其中：
L为卤素，优选为Br；
G2、G3、环A、环B、R0、R1a、R2、R3、s、t、m和n如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIa)的化合物或其盐(优选盐酸盐)与通式(IIb)的化合物发生亲核取代反应，得到通式(II)的化合物或其可药用的盐；
其中：
L为卤素，优选为Br；
X、Y、R0、R1a、R3、R6a、R6b、t和n如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIa)的化合物或其盐(优选盐酸盐)与通式(IIIb)的化合物发生亲核取代反应，得到通式(III)的化合物或其可药用的盐；
其中：
L为卤素，优选为Br；
X、Y、R0、R1a、R7e、R7f和n如通式(III)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)或通式(III)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)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物在制备PARP1抑制剂中的用途。
本公开进一步涉及通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物在制备治疗和/或预防由PARP1介导的疾病或病症 的药物中的用途。
本公开进一步涉及通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐或包括其的药物组合物在制备用于治疗和/或预防癌症、原发性血小板增多症或真性红细胞增多症的药物中的用途。
本公开进一步涉及一种抑制PARP1的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种治疗和/或预防由PARP1介导的疾病或病症的方法，其包括给予所需患者抑制有效量的通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种治疗和/或预防癌症、原发性血小板增多症或真性红细胞增多症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作PARP1抑制剂。
本公开进一步涉及一种通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防由PARP1介导的疾病或病症。
本公开进一步涉及一种通式(I)、通式(II)或通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防癌症、原发性血小板增多症或真性红细胞增多症的药物。
优选地，本公开所述的由PARP1介导的疾病或病症为癌症。
优选地，本公开所述的癌症选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、结直肠癌(如结肠癌和直肠癌)、肺癌、肾癌、肝癌(如肝细胞癌)、宫颈癌、子宫内膜癌、骨髓瘤(如多发性骨髓瘤)、白血病(如急性白血病、慢性白血病、骨髓性白血病、骨髓纤维化、红白血病)、淋巴瘤(如弥漫大B-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T-细胞或B-细胞源的淋巴样恶性肿瘤、滤泡性淋巴瘤)、听神经瘤、基底细胞癌、胆管癌、膀胱癌、脑癌、支气管癌、肉瘤(如软骨肉瘤、纤维肉瘤、平滑肌肉瘤、脂肪肉瘤、淋巴管肉瘤、粘液肉瘤、成骨原性肉瘤、横纹肌肉瘤、尤文氏瘤)、脊索瘤、绒毛膜癌、颅咽管瘤、囊腺癌、胚胎癌、血管内皮细胞瘤、室管膜瘤、上皮癌、食管癌(又叫食道癌)、睾丸癌、胶质瘤、重链病、成血管细胞瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、成神经细胞瘤、NUT中线癌、神经胶质瘤、骨癌、鼻咽癌、口腔癌、甲状 腺癌、松果体瘤、成视网膜细胞瘤、皮脂腺癌、精原细胞瘤、皮肤癌、鳞状细胞癌、滑膜瘤、汗腺癌、瓦尔登斯特伦巨球蛋白血症和维尔姆斯瘤；所述的肉瘤优选为尤文氏瘤；优选地，所述的癌症选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、结直肠癌和肺癌。
优选地，本公开所述的癌症的癌细胞为BRCA1或BRCA2缺陷型，优选BRCA2缺陷型。
优选地，本公开所述的癌症的癌细胞的BRCA1或BRCA2有缺陷，优选BRCA2有缺陷。
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达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
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悬浮液的赋形剂。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，或矿物油或其混合物。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，用上述那些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、排泄的速率、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。
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”指饱和的直链或带有支链的脂肪族烃基，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C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C1-12烷基)，更优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：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。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被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
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C1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C1-6亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-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被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
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或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6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，其可以在任何可使用的连接点被取代，取代基优选选自D原子、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或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔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D原子、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D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环系统(即多环环烷基)，其具有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)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)，最优选具有3至6个环原子的环烷基(即3至6元环烷基)。
所述的单环环烷基，非限制性的实例包括：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、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环系统，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；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-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选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元单螺环烷基。非限制性的实例包括：
其连接点可在任意位置；
等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环系统，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选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元双环稠环烷基。非限制性的实例包括：，其连接点可在任意位置； 等。
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环系统，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：
其连接点可在任意位置。
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被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、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的单环杂环(即单环杂环基)或多环杂环系统(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；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-)，且具有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)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)；最优选具有5或6个环原子的杂环基(即5或6元杂环基)。
所述的单环杂环基，非限制性的实例包括：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。
所述的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”指环之间共用一个原子(称螺原子)的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；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-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选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元单螺杂环基。非限制性的实例包括：
等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；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-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、 10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选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元双环稠杂环基。非限制性的实例包括：
等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环系统，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；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-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：
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被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、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电子体系的单环全碳芳环(即单环芳基)或多环芳环系统(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环系统中的环原子个数，非限制性的实例包括：
等。
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被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、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”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环系统(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；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-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的杂芳基(即5或6元杂芳基)。
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、三唑基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基等。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环 原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。非限制性的实例包括：
等。
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被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
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。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、对甲氧苄基等。
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，用于阻断或保护羟基而在化合物的其它官能团上进行反应。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)、叔丁基二甲基硅基(TBS)、叔丁基二甲基硅基(TBDMS)、叔丁基二苯基硅基(TBDPS)、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“甲叉基”指＝CH2。
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-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”或“氧代基”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。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。
本公开的化合物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在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能 的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺的平衡实例如下所示：
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。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，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
本公开的化合物，当其一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即至少67.5％的氘掺入)。在一些实施方案中，每个被指定 的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即至少99.5％的氘掺入)。
“任选地”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选地(任选)被卤素或者氰基取代的烷基”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”或“取代的”指基团中的一个或多个氢原子，优选1～6个，更优选1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(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键的碳原子(如烯)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可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。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。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。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。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”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗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，个案中合适的治疗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：
通式(Ia)的化合物或其盐(优选盐酸盐)与通式(Ib)的化合物在碱性条件下，任选在催化剂的存在下发生亲核取代反应，得到通式(I)的化合物或其可药用的盐；
其中：
L为卤素，优选为Br；
G2、G3、环A、环B、R0、R1a、R2、R3、s、t、m和n如通式(I)中所定义。
方案二
本公开通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
通式(IIa)的化合物或其盐(优选盐酸盐)与通式(IIb)的化合物在碱性条件下，任选在催化剂的存在下发生亲核取代反应，得到通式(II)的化合物或其可药用的盐；
其中：
L为卤素，优选为Br；
X、Y、R0、R1a、R3、R6a、R6b、t和n如通式(II)中所定义。
方案三
本公开通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
通式(IIIa)的化合物或其盐(优选盐酸盐)与通式(IIIb)的化合物在碱性条件下，任选在催化剂的存在下发生亲核取代反应，得到通式(III)的化合物或其可药用的盐；
其中：
L为卤素，优选为Br；
X、Y、R0、R1a、R7e、R7f和n如通式(III)中所定义。
所述提供碱性条件的碱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、乙酸钠、乙酸钾、乙醇钠、叔丁醇钠和叔丁醇钾，；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、氢氧化锂一水合物、氢氧化锂和氢氧化钾；优选为N,N-二异丙基乙胺。
上述亲核取代反应的催化剂为碘化钠或碘化钾，优选碘化钠。
上述反应优选在溶剂中进行，所用的溶剂包括但不限于：N-甲基吡咯烷酮、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
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120Quadrupole 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 HPLC1200VWD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。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明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，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，D:二氯甲烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基-2-吡啶甲酰胺1
第一步
2-(6-(甲氧基羰基)吡啶-3-基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1c
将5-溴吡啶-2-羧酸甲酯1b(200mg，925.78μmol，上海韶远)，2,6-二氢-1H-吡咯并[3,4-c]吡唑-5(4H)-甲酸叔丁酯1a(290mg，1.38mmol，上海毕得)溶于1,4-二氧六环(5mL)，加入碘化亚铜(35mg，183.77μmol)，(1S,2S)-(+)-1,2-环己二胺(21mg，183.90μmol)，碳酸铯(301mg，923.82μmol)，氮气保护下，升温至120℃搅拌反应14小时。反应液冷却至室温，硅藻土过滤后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1c(205mg，产率：64.3％)。
MS m/z(ESI):345.2[M+1]。
第二步
2-(6-(甲基氨基羰基)吡啶-3-基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1d
将化合物1c(200mg，580.8μmol)溶于15mL 1M甲胺的乙醇溶液，搅拌反应48小时，反应液减压浓缩得到粗品标题化合物1d(190mg，产率：95.2％)，产品不经纯化直接进行下一步反应。
MS m/z(ESI):344.2[M+1]。
第三步
5-(5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基-2-吡啶甲酰胺盐酸盐1e
将粗品化合物1d(140mg，407.7μmol)溶于二氯甲烷(2mL)中，加入4M的盐酸二氧六环溶液1mL，搅拌反应0.5小时，反应液减压浓缩后得到粗品标题化合物1e(110mg，产率：96.5％)，产品不经纯化直接用于下步反应。
MS m/z(ESI):244.2[M+1]。
第四步
5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基-2-吡啶甲酰胺1
将粗品化合物1e(51mg，182μmol)，7-(溴甲基)-8-氟-3-甲基喹喔啉-2(1H)-酮1f(50mg，184μmol，采用专利申请“US20220009901A1”中说明书第14页的Intermediate 29公开的方法制备而得)，N,N-二异丙基乙胺(119mg，920μmol)，碘化钠(5.5mg，36μmol)溶于乙腈(5mL)，80℃反应5小时，反应液减压浓缩后，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物1(15mg，产率：18.7％)。
MS m/z(ESI):434.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ9.06(s,1H),8.74(s,1H),8.38(d,1H),8.31(d,1H),8.09(d,1H),7.53(d,1H),4.11(d,2H),3.84(s,2H),3.79(s,2H),2.82(t,3H),2.42(d,3H)。
实施例2
6-氟-5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基吡啶-2-甲酰胺2
第一步
6-氨基-5-(5-(叔丁氧基羰基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)吡啶-2-甲酸2b
将化合物1a(271.7mg，1.3mmol，上海韶远)，5-溴-6-氨基吡啶-2-羧酸甲酯 2a(200mg，865.6μmol，上海毕得)溶于二甲亚砜(6mL)，加入碘化亚铜(33mg，173.1μmol)，L-脯氨酸(20mg，173.1μmol)，碳酸铯(564mg，1.73mmol)，氮气置换，微波120℃搅拌反应2小时，反应液降至室温后，硅藻土过滤，滤液用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-40％，流速：30mL/min)纯化得到标题化合物2b(50mg，产率：16.7％)。
MS m/z(ESI):344.4[M-1]。
第二步
2-(2-氨基-6-(甲基氨基甲酰基)吡啶-3-基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔
丁酯2c
将化合物2b(20mg，57.9μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(37.4mg，289.5μmol)，O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(33mg，86.9μmol)，甲胺盐酸盐(5.9mg，86.8μmol)，恢复室温搅拌反应16小时，反应液中加入水稀释，用乙酸乙酯萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物2c(20mg)。
MS m/z(ESI):359.2[M+1]。
第三步
5-(5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-6-氟-N-甲基吡啶-2-甲酰胺2d
将粗品化合物2c(20mg，55.8μmol)溶于氟化氢吡啶络合物(1mL)，加入亚硝酸钠(46.2mg，669.6μmol)，反应1小时后加水淬灭，用二氯甲烷酯萃取除去杂质(5mL)，水相过滤后用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈20％-35％，流速：30mL/min)纯化得到标题化合物2d(14.5mg，产率：99％)。
MS m/z(ESI):262.2[M+1]。
第四步
6-氟-5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基吡啶-2-甲酰胺2
将化合物2d(14.5mg，55.5μmol)，化合物1f(15mg，55.5μmol)，N,N-二异丙基乙胺(36mg，277.5μmol)，碘化钠(2.1mg，13.8μmol)溶于乙腈(2mL)，80℃反应0.5小时，反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物2(2mg，产率：8％)。
MS m/z(ESI):452.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ12.42(s,1H),8.70(d,1H),8.45(d,1H),8.09–8.04(m,2H),7.53(d,1H),7.36(s,1H),4.11(s,2H),3.85(s,2H),3.81(s,2H),2.82(d,3H),2.42(s,3H)。
实施例3
3-氟-5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基吡啶-2-甲酰胺3
采用实施例1中的合成路线，将第一步原料化合物1b替换为5-溴-3-氟吡啶-2-甲酸甲酯(南京药石)得到标题化合物3(39mg，产率：17.3％)。
MS m/z(ESI):452.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ12.48(s,1H),8.94(d,1H),8.62(d,1H),8.40(s,1H),8.23(dd,1H),7.54(d,1H),7.37(t,1H),4.11(s,2H),3.85(s,2H),3.81(s,2H),2.79(d,3H),2.43(s,3H)。
实施例4
5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢-4H-噻吩并[2,3-c]吡咯-2-基)-N-甲基吡啶-2-甲酰胺4
第一步
3-(溴甲基)噻吩-2-羧酸甲酯4b
将3-甲基噻吩-2-甲酸甲酯4a(9.5g，60.8mmol，上海毕得)，N-溴代丁二酰亚胺(11.9g，66.9mmol)溶于四氯化碳(80mL)，氮气置换，70℃下加入偶氮二异丁腈(2g，12.1mmol)，搅拌反应3小时，反应液冷却至室温，加入饱和碳酸钠溶液，用二氯甲烷萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物4b(10.2g，产率：71.3％)。
第二步
3-(氨基甲基)噻吩-2-羧酸甲酯4c
将化合物4b(11.5g，48.9mmol)溶于7M氨甲醇溶液(70mL)，搅拌反应2小时后减压浓缩，残余物中加入乙醚(50mL)打浆，过滤，滤饼用乙醚洗涤，干燥后即得到粗品标题化合物4c(6.6g，产率：78.8％)。
第三步
4,5-二氢-6H-噻吩并[2,3-c]吡咯-6-酮4d
将粗品化合物4c(6.6g，38.5mmol)溶于甲醇(50mL)和乙醇(50mL)，加入碳酸钾(6.4g，46.3mmol)，80℃反应16小时，反应液减压浓缩，残余物溶于乙酸乙酯(100mL)，依次用水，饱和氯化钠溶液洗涤，收集有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物4d(1.3g，产率：25.1％)。
MS m/z(ESI):140.2[M+1]。
第四步
2-溴-4,5-二氢-6H-噻吩并[2,3-c]吡咯-6-酮4e
将化合物4d(0.5g，3.6mmol)溶水(7mL)和乙酸(9mL)，冰浴下滴加溴(632.3mg，4mmol)，保持温度搅拌反应3小时，反应液中加入水，用饱和碳酸氢钠溶液中和，二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物4e(800mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):217.9[M+1]。
第五步
2-溴-6-氧代-4,6-二氢-5H-噻吩并[2,3-c]吡咯-5-羧酸叔丁酯4f
将粗品化合物4e(1g，4.6mmol)，4-二甲氨基吡啶(282.4mg，2.3mmol)，三乙胺(1.4g，13.8mmol)混于二氯甲烷(30mL)，加入二碳酸二叔丁酯(2g，9.2mmol)，搅拌反应16小时，反应液用饱和碳酸氢钠溶液洗涤，收集有机相，减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物4f(1.2g，产率：82.2％)。MS m/z(ESI):262.1[M-55]。
第六步
2-溴-4,6-二氢-5H-噻吩并[2,3-c]吡咯-5-羧酸叔丁酯4g
将化合物4f(500mg，1.57mmol)溶于四氢呋喃(10mL)中，氮气氛围冰浴下缓慢滴加1M硼烷四氢呋喃络合物(7.9mL)，滴完后升至40℃反应16小时，反应液冷却至室温，加入少量甲醇和水，70℃搅拌1小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物4g(300mg，产率：62.7％)。
第七步
2-(6-(甲基氨基甲酰基)吡啶-3-基)-4,6-二氢-5H-噻吩并[2,3-c]吡咯-5-羧酸叔丁酯4i
将化合物4g(250mg，821.8μmol)，(6-(甲基氨基甲酰基)吡啶-3-基)硼酸4h(177.5mg，986.2μmol，上海毕得)，碳酸钾(226.8mg，1.6mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(120.3mg，164.4μmol)混于1,4-二氧六环(30mL)和水(6mL)中，氮气置换，90℃反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物4i(220mg，产率：74.4％)。
MS m/z(ESI):360.2[M+1]。
第八步
5-(5,6-二氢-4H-噻吩并[2,3-c]吡咯-2-基)-N-甲基吡啶-2-甲酰胺盐酸盐4j
将化合物4i(50mg，139.1μmol)溶于二氯甲烷(3mL)中，加入4M氯化氢的1,4-二氧六环溶液(3mL)，搅拌反应1小时，反应液减压浓缩得到粗品标题化合物4j(40mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):260.3[M+1]。
第九步
5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢-4H-噻吩并[2,3-c]吡咯-2-基)-N-甲基吡啶-2-甲酰胺4
将粗品化合物4j(40mg，139μmol)，化合物1f(43.9mg，162μmol)，N,N-二异丙基乙胺(174.4mg，1.3mmol)，碘化钠(20.2mg，135μmol)溶于乙腈(5mL)，90℃反应3小时，反应液减压浓缩后，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物4(20mg，产率：33％)。
MS m/z(ESI):450.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.86(d,1H),8.73-8.70(m,1H),8.14-8.12(m,1H),8.01(d,1H),7.57(s,1H),7.53(d,1H),7.39-7.36(m,2H),4.03(s,2H),4.01(s,2H),3.88(s,2H),2.82(s,3H),2.42(m,3H)。
实施例5
(±)-5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-6-甲基-5,6-二氢吡咯并 [3,4-c]吡唑-2(4H)-基)-N-甲基吡啶-2-甲酰胺5
第一步
(±)-2-(6-(甲氧基羰基)吡啶-3-基)-6-甲基-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸苄酯5b
将化合物1b(100mg，462.9μmol)、(±)-6-甲基-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸苄酯5a(111mg，431.4μmol，采用文献“Bioorganic and Medicinal Chemistry,2018,vol.26,#8,p.2107-2150”公开的方法制备而得)、碘化亚铜(18mg，94.5μmol)、磷酸钾(197mg，928.1μmol)、反式-N,N'-二甲基-1,2-环己烷二胺(27mg，189.8μmol，上海泰坦)混于1,4-二氧六环(4mL)，氮气置换，升温至120℃搅拌反应16小时，反应液冷却至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系D纯化得到标题化合物5b(外消旋体)(176mg，产率：96.8％)。
MS m/z(ESI):393.2[M+1]。
第二步
(±)-6-甲基-2-(6-(甲基氨基甲酰基)吡啶-3-基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸苄酯5c
将化合物5b(176mg，448.5μmol)溶于30％甲胺乙醇溶液(1.5mL)，搅拌16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系D纯化得到标题化合物5c(外消旋体)(188mg，产率：107％)。
MS m/z(ESI):392.2[M+1]。
第三步
(±)-N-甲基-5-(6-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)吡啶-2-甲酰胺5d
将化合物5c(188mg，480.3μmol)溶于二氯甲烷(2mL)溶解，氮气氛围0℃下 加入33％溴化氢的乙酸溶液(3.5g，14.3mmol)，保持温度搅拌30分钟，反应液减压浓缩，残余物中加入氯仿溶解，并加入少量N,N-二异丙基乙胺，减压浓缩后残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5d(外消旋体)(127mg，产率：102％)。
MS m/z(ESI):258.2[M+1]。
第四步
(±)-5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-6-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基吡啶-2-甲酰胺5
将化合物5d(45mg，174.9μmol)，化合物1f(48mg，177μmol)，N,N-二异丙基乙胺(45mg，348.1μmol)，碘化钠(5mg，22μmol)溶于乙腈(2mL)，80℃反应3小时，反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物5(外消旋体)(25mg，产率：31.9％)。
MS m/z(ESI):448.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ9.06(d,1H),8.73(q,1H),8.35(s,1H),8.32(dd,1H),8.10(d,1H),7.54(d,1H),7.36(t,1H),4.22(d,1H),4.04–3.96(m,2H),3.88(d,1H),3.58(d,1H),3.38(d,1H),2.83(d,3H),2.42(s,3H),1.43(d,3H).
实施例6
5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-N-甲基吡啶-2-甲酰胺6

第一步
6-(甲基氨基甲酰基)烟酸甲酯6b
将2,5-吡啶二甲酸二甲酯6a(4g，20.5mmol，上海泰坦)，无水氯化镁(973.5mg，10.2mmol)溶于四氢呋喃(50mL)中，搅拌反应30分钟后缓慢滴加30％甲胺乙醇溶液(3.2g，30.74mmol)，加完后继续反应16小时，反应液减压浓缩后即得粗品标题化合物6b(3.8g)，产品不经纯化直接用于下步反应。
MS m/z(ESI):195.2[M+1]。
第二步
5-(羟甲基)-N-甲基吡啶-2-甲酰胺6c
将粗品化合物6b(4g，20.6mmol)溶于甲醇(30mL)中，加入硼氢化钠(3.9g，103mmol)，搅拌反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物6c(1.6g，产率：48.4％)。
MS m/z(ESI):167.2[M+1]。
第三步
5-甲酰基-N-甲基吡啶-2-甲酰胺6d
将化合物6c(50mg，300.8μmol)溶于二氯甲烷(3mL)中，加入二氧化锰(523mg，6mmol)，搅拌反应5小时，反应液过滤，滤液减压浓缩即得到粗品标题化合物6d(50mg)，产品不经纯化，直接用于下步反应。
MS m/z(ESI):165.2[M+1]。
第四步
2-(6-(甲基氨基甲酰基)吡啶-3-基)-3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯6f
将粗品化合物6d(50mg，304.6μmol)，(3R,4S)-rel-3,4-二氨基吡咯烷-1-羧酸叔 丁酯6e(79.7mg，396μmol，上海毕得)，碘(116mg，456.9μmol)，碳酸钾(126.1mg，913.7μmol)溶于叔丁醇(12mL)中，氮气置换，70℃反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物6f(80mg，产率：76％)。
MS m/z(ESI):346.4[M+1]。
第五步
2-(6-(甲基氨基甲酰基)吡啶-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯6g
将草酰氯(165.4mg，1.3mmol)溶于无水二氯甲烷(5mL)中，-78℃加入二甲亚砜(190mg，2.4mmol)，搅拌30分钟后加入化合物6f(200mg，579μmol)的二氯甲烷溶液(2mL)，继续搅拌30分钟加入三乙胺(584.8mg，5.8mmol)，恢复室温搅拌反应2小时，反应液中加入水，用二氯甲烷萃取(10mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物6g(80mg，产率：40.2％)。
MS m/z(ESI):344.2[M+1]。
第六步
N-甲基-5-(1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)吡啶-2-甲酰胺盐酸盐6h
将化合物6g(80mg，233μmol)溶于二氯甲烷(4mL)，加入4M氯化氢的1,4-二氧六环溶液(4mL)，搅拌反应2小时，反应液减压浓缩得到粗品标题化合物6h(65mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):244.3[M+1]。
第七步
5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-N-甲基吡啶-2-甲酰胺6
将粗品化合物6h(65mg，233μmol)，化合物1f(86.9mg，320μmol)，N,N-二异丙基乙胺(318.7mg，2.4mmol)，碘化钠(37mg，246.6μmol)溶于乙腈(5mL)，90℃反应3小时，反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物6(5mg，产率：4.6％)。
MS m/z(ESI):434.2[M+1]。
1H NMR(500MHz,CDCl3):δ12.89(s,2H),9.11(s,1H),8.80-8.77(m,1H),8.35-8.33(m,1H),8.05(d,1H),7.53(d,1H),7.39-7.36(m,1H),4.12(s,2H),3.93(s,2H),3.79(s,2H),2.82(s,3H),2.42(m,3H)。
实施例7
4-氟-5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢吡咯并[3,4-c]吡
唑-2(4H)-基)-N-甲基吡啶-2-甲酰胺7
第一步
2-(4-氟-6-(甲氧羰基)吡啶-3-基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯
将5-溴-4-氟吡啶-2-甲酸甲酯7a(1.75g，7.5mmol，采用专利申请“WO2023051716”中说明书第53页实施例12公开的方法制备而得)，化合物1a(1.56g，7.5mmol，上海毕得)溶于1,4-二氧六环(40mL)，甲烷磺酸(2-二叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(593.7mg，747.7μmol)，磷酸钾(3.2g，15mmol)，氮气保护下，升温至120℃搅拌反应14小时。反应液冷却至室温，过滤，滤液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-40％，流速：30mL/min)纯化得到标题化合物7b(50mg，产率：1.8％)。
MS m/z(ESI):363.4[M+1]。
第二步
4-氟-5-(5-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)-N-甲基吡啶-2-甲酰胺7
采用实施例1中的合成路线，将第二步原料化合物1c替换为化合物7b得到标题化合物7(2mg，产率：12.4％)。
MS m/z(ESI):452.4[M+1]。
1H NMR(500MHz,DMSO-d6):δ12.48(s,1H),9.04(d,1H),8.89(d,1H),8.03(d,2H),7.54(d,1H),7.39(d,1H),4.11(s,2H),3.87(s,2H),3.82(s,2H),2.83(d,3H),2.43(s,3H)。
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1、细胞增殖实验
以下方法通过检测细胞内ATP含量，根据IC50大小评价本公开化合物对DLD1细胞、DLD1BRCA2-/-和MDA-MB-436细胞增殖的抑制效果。实验方法简述如下：
一、实验材料及仪器
1、DLD1，人结肠癌肿瘤细胞(南京科佰，CBP60037)
2、DLD1BRCA2-/-，人BRCA2基因敲除结肠癌肿瘤细胞(Creative biogene，CSC-RT0015)
3、MDA-MB-436，人乳腺癌细胞(ATCC，HTB-130)
4、胎牛血清(GIBCO，10091-148)
5、CellTite-Glo试剂(Promega，G7573)
6、96孔细胞培养板(corning，3903)
7、胰酶(invitrogen，25200-072)
8、酶标仪(BMG，PHERAsta)
9、细胞计数仪(上海睿钰生物科技有限公司，IC1000)
二、实验步骤
DLD1细胞培养在含10％FBS的RPMI-1640培养基中，一周传代2～3次，传代比列1:6或1:8。传代时，用胰酶消化细胞后转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，加入新鲜培养基重悬细胞。在96孔细胞培养板中加入180μL的细胞悬液，密度为2.78×103细胞/mL，96孔板外围只加入180μL的完全培养基。
DLD1BRCA2-/-细胞培养在含10％FBS的RPMI-1640培养基中，一周传代2～3次，传代比列1:6或1:8。传代时，用胰酶消化细胞后转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，加入新鲜培养基重悬细胞。在96孔细胞培养板中加入180μL的细胞悬液，密度为8.34×103细胞/mL，96孔板外围只加入180μL的完全培养基。
MDA-MB-436细胞培养在含10％FBS、10μg/mL胰岛素、16μg/mL谷胱甘肽的Leibovitz's L-15培养基中，一周传代2～3次，传代比列1:3或1:5。传代时，用胰酶消化细胞后转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，加入新鲜培养基重悬细胞。在96孔细胞培养板中加入180μL的细胞悬液，密度为8.34×103细胞/mL，96孔板外围只加入180μL的完全培养基。
将培养板在培养箱培养24小时(37℃，5％CO2)。
将待测样品用DMSO稀释成2mM，并以3倍依次稀释成10个浓度，并设置空白和对照孔。取配制成梯度浓度的待测化合物溶液5μL加入到95μL新鲜培养基中。再向培养板中加入20μL上述含药物的培养基溶液。将培养板在培养箱孵育6天(37℃，5％CO2)。在96孔细胞培养板中，每孔加入90μL CellTiter-Glo试剂，室温避光放置5-10min，在PHERAstar中读取化学发光信号值，数据使用GraphPad 软件处理，结果见表1。
表1本公开化合物对DLD1、DLD1BRCA2-/-和MDA-MB-436细胞增殖的抑制作用
结论：本公开化合物对DLD1BRCA2-/-和MDA-MB-436细胞增殖具有较好的抑制作用。
测试例2、本公开化合物对PARP1、PARP2结合活性的测定
体外PARP1、PARP2结合活性通过以下的方法进行测试。
一、实验材料及仪器
1、PARP1重组蛋白(义翘神州，货号11040-H08B)；
2、PARP2重组蛋白(BPS，货号80502)
3、荧光探针(采用CAS号为1380359-84-1的化合物自制，上海恒瑞)；
4、384孔板(Corning，3575)
5、酶标仪PHERAstar FS(BMG Labtech)
二、实验步骤
384孔板每孔加入8μL结合缓冲液；将荧光探针溶解于二甲亚砜中，稀释至相应的浓度，再将用二甲亚砜配制的荧光探针20倍稀释于结合缓冲液(50mM Tris-HCl pH 8.0，50mM NaCl，1mM MgCl2，0.1mM EDTA，0.01％IGEPAL)中，每孔加入2μL；将测试化合物溶解于二甲亚砜中，并根据实验需要稀释至各浓度梯度，再将用二甲亚砜配制各浓度化合物20倍稀释于结合缓冲液中，每孔加入2μL；用结合缓冲液将PARP1或PARP2蛋白稀释至相应的浓度，8μL/孔加入黑色384孔板中，混合均匀后在25℃孵育40分钟。用酶标仪PHERAstar FS中FP程序读取信号值。数据使用GraphPad软件处理。
本公开化合物的PARP1、PARP2结合抑制活性通过以上的试验进行测定，测得的IC50值见表2。
表2本公开化合物对PARP1、PARP2结合抑制活性
结论：本公开化合物对PARP1具有选择性的抑制作用。
测试例3PARP1酶活性测定实验
下面的体外筛选试验是用来测定本公开化合物对于PARP1酶活性的抑制作用。
以下所述的实验通过使用PARP1化学发光检测试剂盒(PARP1Chemiluminescent Assay Kit,BPS,80551,Lot#211124-K)，来测定化合物对PARP1 酶活性的抑制作用。PARP1化学发光检测试剂盒的关键是使用了生物素化的NAD+，通过测定化学发光信号的强度，可得知反应体系中NAD+的水平，从而计算测试化合物对PARP1酶活性的抑制程度。
实验的详细操作以及所用的试剂的配制，如组蛋白混合液(Histone mixture)、混合液(Master mixture)、实验缓冲液(Assay buffer)及化学发光底物(ELISA ECL Substrate)等，可参照PARP1化学发光测试试剂盒说明书。
实验步骤简述如下：用组蛋白混合液(Histone mixture)包被96孔平底板，4度过夜。封闭液(Blocking buffer 3)室温封闭90分钟。向孔板中每孔加入2ng/μl PARP1酶20μl，每孔加入Master mixture 25μl。测试化合物溶解于二甲基亚砜，随后用缓冲液稀释到实验所需浓度，向孔板中每孔加入5μl。混合后室温孵育1小时，然后加入链霉亲和素标记辣根过氧化物酶，室温孵育30分钟。最后加入1:1混合的ECL Substrate A和ECL Substrate B，使用PHERAstar检测化学发光信号，数据用GraphPad软件处理，计算出化合物对PARP1酶活性的抑制率。
化合物的IC50值可通过不同浓度下的抑制率计算得出。
结论：本公开化合物对PARP1激酶的增殖具有明显的抑制活性。

Claims (19)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    其中：
    环A为杂芳基；
    环B为芳基或杂芳基；
    G2为CR6a或氮原子；
    G3为CR6b或氮原子；
    R0、R1a、R6a和R6b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR7aR7b、羟基、-C(O)R8a、-C(O)OR8a、-C(O)NR7aR7b、-S(O)pR8a、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR9aR9b、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    各个R2相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR7cR7d、羟基和羟烷基；
    各个R3相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR7eR7f、羟基、-C(O)R8b、-C(O)OR8b、-C(O)NR7eR7f、-S(O)qR8b、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR9cR9d、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R7a、R7b、R7c、R7d、R7e、R7f、R9a、R9b、R9c和R9d相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；或者
    R7a和R7b与相连的氮原子一起形成杂环基，或者R7c和R7d与相连的氮原子一起形成杂环基，或者R7e和R7f与相连的氮原子一起形成杂环基，或者R9a和R9b与相连的氮原子一起形成杂环基，或者R9c和R9d与相连的氮原子一起形成杂环基，所述形成的杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷 氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R8a和R8b相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
    p为0、1或2；
    q为0、1或2；
    m为0、1或2；
    n为0、1或2；
    s为0、1、2、3或4；且
    t为0、1、2或3。
  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选自吡唑基、噻吩基和咪唑基；优选地，环A为吡唑基。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其中m为1。
  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，其中环B为吡啶基。
  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G2为CR6a，R6a如权利要求1中所定义；和/或G3为CR6b，R6b如权利要求1中所定义。
  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，其为通式(II)所示的化合物或其可药用的盐：
    其中：
    X和Y相同或不同，且各自独立地为氮原子或CR2a；
    R2a选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR7cR7d、羟基和羟烷基；
    R0、R1a、R6a、R6b、R7c、R7d、R3、n和t如权利要求1中所定义。
  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，其中n为1。
  8. 根据权利要求6或7中所述的通式(I)所示的化合物或其可药用的盐，其中X为氮原子；和/或Y为CH。
  9. 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，其中R3为-C(O)NR7eR7f；其中R7e和R7f如权利要求1中所定义。
  10. 根据权利要求1至9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R6a为氢原子；和/或R6b为氢原子。
  11. 根据权利要求1至10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R0为氢原子或卤素。
  12. 根据权利要求1至11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R1a为C1-6烷基。
  13. 化合物或其可药用的盐，其选自以下任一化合物：

  14. 一种通式(IIa)所示的化合物或其盐：
    其中：
    R3为-C(O)NR7eR7f；
    t为1、2或3；
    X、Y、R7e、R7f和n如权利要求6中所定义。
  15. 化合物或其盐，其选自以下任一化合物：
  16. 一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
    通式(Ia)的化合物或其盐(优选盐酸盐)与通式(Ib)的化合物发生亲核取代反应，得到通式(I)的化合物或其可药用的盐；
    其中：
    L为卤素，优选为Br；
    G2、G3、环A、环B、R0、R1a、R2、R3、s、t、m和n如权利要求1中所定义。
  17. 一种药物组合物，所述药物组合物含有根据权利要求1至13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。
  18. 根据权利要求1至13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17所述的药物组合物在制备PARP1抑制剂中的用途。
  19. 根据权利要求1至13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17所述的药物组合物在制备用于治疗和/或预防癌症、原发性血小板增多症或真性红细胞增多症的药物中的用途；所述的癌症优选选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、结直肠癌、肺癌、肾癌、肝癌、宫颈癌、子宫内膜癌、骨髓瘤、白血病、淋巴瘤、听神经瘤、基底细胞癌、胆管癌、膀胱癌、脑癌、支气管癌、肉瘤、脊索瘤、绒毛膜癌、颅咽管瘤、囊腺癌、胚胎癌、血管内皮细胞瘤、室管膜瘤、上皮癌、食管癌、睾丸癌、胶质瘤、重链病、成血管细胞瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、成神经细胞瘤、NUT中线癌、骨癌、鼻咽癌、口腔癌、甲状腺癌、松果体瘤、成视网膜细胞瘤、皮脂腺癌、精原细胞瘤、皮肤癌、鳞状细胞癌、滑膜瘤、汗腺癌、瓦尔登斯特伦巨球蛋白血症和维尔姆斯瘤；所述的肉瘤优选为尤文氏瘤；优选地，所述的癌症选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、结直肠癌和肺癌。
PCT/CN2023/116099 2022-08-31 2023-08-31 稠合二环类化合物、其制备方法及其在医药上的应用 WO2024046420A1 (zh)

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