CN114634522A - Purine ketone derivative, preparation method and medical application thereof - Google Patents

Purine ketone derivative, preparation method and medical application thereof Download PDF

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Publication number
CN114634522A
CN114634522A CN202111530105.4A CN202111530105A CN114634522A CN 114634522 A CN114634522 A CN 114634522A CN 202111530105 A CN202111530105 A CN 202111530105A CN 114634522 A CN114634522 A CN 114634522A
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cancer
group
membered
pharmaceutically acceptable
compound
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陆标
张蔡华
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The present disclosure relates to purinone derivatives, methods of their preparation, and their use in medicine. Specifically, the disclosure relates to a purinone derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a therapeutic agent, in particular an application of the derivative as a DNA-PK inhibitor and an application of the derivative in preparation of a medicament for treating and/or preventing cancer. Wherein each group in the general formula (I) is defined in the specification.

Description

Purine ketone derivative, preparation method and medical application thereof
Technical Field
The disclosure belongs to the field of medicines, and relates to a purinone derivative, a preparation method and application thereof in medicines. In particular, the disclosure relates to a purinone derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a DNA-PK inhibitor and use of the derivative in preparation of a medicament for treating and/or preventing cancer.
Background
DNA-dependent protein kinase (DNA-PK) is a serine/hydroxyl butyrate protein kinase complex consisting of heterodimers of catalytic subunits DNA-PKcs and Ku protein (Ku70/Ku80), and is an important protein in the process of DNA damage repair (Cancer Discovery,2014,4, 1126-1139); plays an important role in maintaining the stability of telomerase, participating in natural immunity and V (D) J recombination, regulating transcription and the like (Curr Opin Allergy Clin Immunol,2009,9, 503-509).
There are mainly 4 types of eukaryotic DNA repair: nucleotide Excision Repair (NER), Base Excision Repair (BER), mismatch repair (MMR) and Double Strand Break Repair (DSBR). NER can excise large fragments of DNA damage, BER can repair damage of individual bases, MMR is used to repair mismatches of bases, and DSBR includes two mechanisms: non-homologous end joining (NHEJ) and Homologous Recombination (HR). NHEJ directly links the truncation without the need for a template, and HR requires the use of intact sister chromatids as repair templates. NHEJ is the most major repair pathway and occurs in all phases of the cell cycle. HR, in turn, occurs primarily during the G2/M phase of the cell cycle (ChemMedChem,2017,12, 895-900). Playing a dominant role in DNA damage repair are kinases of the three PI 3K-related kinase (PIKK) families: DNA-dependent protein kinase (DNA-PK), ataxia-telangiectasia mutant kinase (ATM), and ATM and Rad3 related kinase (ATR). DNA-PK is primarily involved in the NHEJ pathway, ATM is primarily involved in the HR pathway, and ATR primarily repairs single-stranded DNA damage (Nat Rev Clin oncol, 2019, 81-104).
When the DNA double strand breaks, the circular Ku70/Ku80 heterodimer recognizes and binds to the broken DNA ends, recruiting DNA-PKcs. Recruitment of DNA-PKcs facilitates the movement of Ku heterodimers into DNA duplexes, allowing DNA-PKcs to act as tethers to break DNA ends and prevent degradation by exonucleases. Meanwhile, the combination with DNA promotes the activation of the catalytic activity of DNA-PKcs, and the main autophosphorylation sites are Ser2056 and Thr 2609. DNA-PKcs also causes phosphorylation of a range of downstream proteins, including Artemis, DNA ligase 4, histone H2A variants (H2AX), etc., that together accomplish DNA double strand repair (Nat Rev Clin oncol.,2019, 81-104).
DNA-PK is highly expressed in many types of tumor tissues and can cause tumor metastasis by stimulating angiogenesis and tumor cell migration (Clin Cancer Res,2019,25, 5623-. Moreover, the increase of the activity of DNA-PK is closely related to the drug resistance and the poor prognosis of chemotherapeutic drugs. Research shows that the DNA-PK inhibitor can obviously increase the sensitivity of tumor cells to X-ray Irradiation (IR) and chemotherapeutic drugs and increase the tumor inhibition effect of the PAPR inhibitor olaparib (Nat Commun, 2019,10, 5065-5079; Mol Cancer Res,2019, 17, 2457-2468).
Several patents on DNA-PK inhibitors (WO2019238929A1, WO2018114999A1, WO2014183850A1, etc.) are published by companies represented by AstraZeneca and Merck, and these structural classes of compounds have room for improvement in both in vitro activity and selectivity. Wherein the small molecule DNA-PK inhibitor of AstraZeneca enters the first clinical stage 10 months in 2019. No DNA-PK inhibitor drugs are currently approved for marketing, and therefore there is a significant unmet medical need in the relevant patient population.
Disclosure of Invention
The object of the present disclosure is to provide a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:
Figure BDA0003410405860000021
wherein:
ring a is a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group;
R1the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitroHydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2is a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocyclyl, each of said 3 to 14 membered cycloalkyl and 3 to 14 membered heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R3selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, oxo groups, halogens, cyano groups, amino groups, nitro groups and hydroxyl groups;
R4the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, an oxo group, a halogen group, a cyano group, an amino group, a nitro group, and a hydroxyl group;
n is 0, 1 or 2; and is
m is 0, 1,2,3, 4 or 5.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring a is 3 to 8 membered cycloalkyl; preferably cyclopropyl.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1Are the same or different and are each independently a hydrogen atom or C1-6An alkyl group; preferably, R1Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4Are the same or different and are each independently a hydrogen atom or C1-6An alkyl group; preferably, R4Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 0.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 0.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof:
Figure BDA0003410405860000031
wherein:
R2and R3As defined in formula (I).
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R is2Is a 3-to 8-membered monocyclic heterocyclic group or a 6-to 14-membered polycyclic heterocyclic group, said 3-to 8-membered monocyclic heterocyclic group and 6-to 14-membered polycyclic heterocyclic group each independently being optionally selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, oxo, cyano, amino, nitro, hydroxy and C1-6Substituted with one or more substituents in the hydroxyalkyl group; preferably a 3 to 8 membered monocyclic heterocyclyl group; more preferably tetrahydropyranyl; most preferably
Figure BDA0003410405860000032
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R is2Is a 3 to 8 membered monocyclic heterocyclic group and a 6 to 14 membered fused heterocyclic group, a 6 to 14 membered spiroheterocyclic group and a 6 to 14 membered bridged heterocyclic group; the 3-to 8-membered monocyclic heterocyclic group and the 6-to 14-membered fused heterocyclic group, the 6-to 14-membered spiroheterocyclic group and the 6-to 14-membered bridged heterocyclic group are each independently optionally selected from the group consisting of halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, oxo, cyano, amino, nitro, hydroxy and C1-6Substituted with one or more substituents in hydroxyalkyl; preferably a 3 to 8 membered monocyclic heterocyclyl group;more preferably tetrahydropyranyl; most preferably
Figure BDA0003410405860000041
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R is3Is a hydrogen atom or C1-6An alkyl group; preferably, R3Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring a is 3 to 8 membered cycloalkyl; r1Are the same or different and are each independently a hydrogen atom or C1-6An alkyl group; r2Is a 3 to 8 membered monocyclic heterocyclyl; r3Is a hydrogen atom or C1-6An alkyl group; r4Are the same or different and are each independently a hydrogen atom or C1-6An alkyl group; n is 0, 1 or 2; and m is 0, 1,2,3, 4 or 5.
In some preferred embodiments of the present disclosure, the compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R2Is a 3 to 8 membered monocyclic heterocyclyl; r3Is a hydrogen atom or C1-6An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R2Is composed of
Figure BDA0003410405860000042
R3Is a hydrogen atom or C1-6An alkyl group. Table a typical compounds of the present disclosure include, but are not limited to:
Figure BDA0003410405860000043
another aspect of the present disclosure relates to a compound represented by general formula (IA), or a pharmaceutically acceptable salt thereof:
Figure BDA0003410405860000044
wherein:
x is halogen; preferably a chlorine atom;
ring A, R1、R2And m is as defined in formula (I).
Another aspect of the disclosure relates to a compound of formula (IIA), or a pharmaceutically acceptable salt thereof:
Figure BDA0003410405860000051
wherein:
x is halogen; preferably a chlorine atom;
R2as defined in formula (II).
Table B typical intermediate compounds of the present disclosure include, but are not limited to:
Figure BDA0003410405860000052
another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0003410405860000053
the compound of the general formula (IA) or the pharmaceutically acceptable salt thereof and the compound of the general formula (IB) or the pharmaceutically acceptable salt thereof are subjected to coupling reaction to obtain the compound of the general formula (I) or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably a chlorine atom;
ring A, R1To R4N and m are as defined in formula (I).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (II), or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0003410405860000061
the compound of the general formula (IIA) or the pharmaceutically acceptable salt thereof and the compound of the general formula (IIB) or the pharmaceutically acceptable salt thereof are subjected to coupling reaction to obtain the compound of the general formula (II) or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably a chlorine atom;
R2and R3As defined in formula (II).
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by general formula (I), general formula (II), or table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The disclosure further relates to the use of a compound of formula (I), formula (II) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the inhibition of DNA-PK.
The disclosure further relates to the use of a compound of formula (I), formula (II) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer. Wherein said cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastoma, neuroblastoma, germ cell tumors, teratomas, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, sarcoma gastrointestinal stromal tumors (GIST), and pediatric cancer; wherein said sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, and kaposi's sarcoma; wherein said lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein said lung cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC) and lung squamous cell carcinoma, preferably non-small cell lung cancer (NSCLC); wherein said renal cancer is selected from the group consisting of renal cell carcinoma, clear cell carcinoma, and eosinophilic renal carcinoma.
The present disclosure further relates to a method of inhibiting DNA-PK comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure further relates to the use in a medicament for the treatment and/or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein said cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastoma, neuroblastoma, germ cell tumors, teratomas, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumors (GIST), and pediatric cancer; wherein said sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, and kaposi's sarcoma; wherein said lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein said lung cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC) and lung squamous cell carcinoma, preferably non-small cell lung cancer (NSCLC); wherein said renal cancer is selected from the group consisting of renal cell carcinoma, clear cell carcinoma, and eosinophilic renal carcinoma.
The present disclosure further relates to a compound of formula (I), formula (II) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
The present disclosure further relates to a compound of formula (I), formula (II) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting DNA-PK.
The disclosure further relates to a compound of formula (I), formula (II) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of cancer. Wherein said cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastoma, neuroblastoma, germ cell tumors, teratomas, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumors (GIST), and pediatric cancer; wherein said sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, and kaposi's sarcoma; wherein said lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein said lung cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC) and lung squamous cell carcinoma, preferably non-small cell lung cancer (NSCLC); wherein said renal cancer is selected from the group consisting of renal cell carcinoma, clear cell carcinoma, and eosinophilic renal carcinoma.
The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.
The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. 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 may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Description of the terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group containing 1 to 12 (e.g., 1,2,3, 4, 5, 6, 7, 8, 9,10, 11, and 12) carbon atoms1-12Alkyl), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C)1-6Alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and each thereofBranched chain isomers, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon radical having 2 residues derived from a parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, which is a straight or branched chain radical containing from 1 to 20 carbon atoms (i.e., C)1-20Alkylene) preferably containing 1 to 12 (e.g. 1,2,3, 4, 5, 6, 7, 8, 9,10, 11 and 12) carbon atoms (i.e. C)1-12Alkylene) groups, more preferably alkylene groups having 1 to 6 carbon atoms (i.e., C)1-6Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)2-), 1-ethylene (-CH (CH)3) -), 1, 2-ethylene (-CH)2CH2) -, 1-propylene (-CH (CH)2CH3) -), 1, 2-propylene (-CH)2CH(CH3) -), 1, 3-propylene (-CH)2CH2CH2-) 1, 4-butylene (-CH2CH2CH2CH2-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituent preferably being selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxyOne or more of heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, and oxo.
The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups (i.e., C) containing 2 to 12 (e.g., 2,3, 4, 5, 6, 7, 8, 9,10, 11, and 12) carbon atoms are preferred2-12Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C)2-6Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl (i.e., C) groups containing 2 to 12 (e.g., 2,3, 4, 5, 6, 7, 8, 9,10, 11, and 12) carbon atoms are preferred2-12Alkynyl), more preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C)2-6Alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms (i.e., 3 to 20-membered cycloalkyl groups), preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14-membered cycloalkyl groups), further preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl groups), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged ring alkyl groups.
The term "spirocycloalkyl" refers to a polycyclic group (i.e., a 5 to 20 membered spirocycloalkyl group) having a single 5 to 20 membered ring with one carbon atom (referred to as the spiro atom) in common between the rings, which may contain one or more double bonds. Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group and a multi spirocycloalkyl group, according to the number of spiro atoms shared between rings, and preferably the single spirocycloalkyl group and the double spirocycloalkyl group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0003410405860000111
the term "fused cycloalkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered fused cycloalkyl) all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 (i.e. 6 to 14 fused cycloalkyl) members, more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 fused cycloalkyl) members. They can be classified into bicyclic, tricyclic, tetracyclic and polycyclic fused cycloalkyl groups according to the number of constituent rings, and are preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0003410405860000112
the term "bridged cycloalkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered bridged cycloalkyl), all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14 (i.e. 6 to 14 bridged cycloalkyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 bridged cycloalkyl). They may be classified into bicyclic, tricyclic, tetracyclic and polycyclic bridged cycloalkyl groups according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0003410405860000121
the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the ring(s) attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl
Figure BDA0003410405860000122
Tetrahydronaphthyl radical
Figure BDA0003410405860000123
Benzocycloheptalkyl radical
Figure BDA0003410405860000124
Etc.; indanyl is preferred
Figure BDA0003410405860000125
Tetrahydronaphthyl
Figure BDA0003410405860000126
Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms (i.e., a 3 to 20 membered heterocyclyl), wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which sulfur may optionally be oxo (i.e., to form s (o) or s (o)2) But not including the cyclic moiety of-O-, -O-S-or-S-with the remaining ring atoms being carbon. Preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 and 14) ring atoms (i.e., 3 to 14 membered heterocyclyl), of which 1-4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 6 to 14 ring atoms (e.g., 6, 7, 8, 9,10, 11, 12, 13 and 14) (i.e., 6 to 14 membered heterocyclyl), wherein 1-3 are heteroatoms (e.g., 1,2 and 3); more preferably 3 to 8 ring atoms (i.e. 3 to 8 membered heterocyclyl), of which 1-3 (e.g. 1,2 and 3) are heteroatoms; most preferably 5 or 6 ring atoms (i.e. 5 or 6 membered heterocyclyl) are included, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group (i.e., a 5 to 20 membered spiroheterocyclyl) in which one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form S (O) or S (O))2) And the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 (e.g. 6, 7) members8, 9,10, 11, 12, 13 and 14 membered) (i.e. 6 to 14 membered spiroheterocyclyl group), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spiroheterocyclyl group). The spiro heterocyclic groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group and a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0003410405860000131
the term "fused heterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered fused heterocyclyl) polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., to form S (O) or S (O))2) And the remaining ring atoms are carbon. Preferably 6 to 14 (e.g., 6, 7, 8, 9,10, 11, 12, 13 and 14) membered (i.e., 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 (e.g., 7, 8, 9 or 10) membered (i.e., 7 to 10 membered fused heterocyclyl). They can be classified into bicyclic, tricyclic, tetracyclic and polycyclic fused heterocyclic groups according to the number of constituting rings, and are preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0003410405860000132
the term "bridged heterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered bridged heterocyclyl) polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may be sulfurOptionally oxo (i.e. to form S (O) or S (O))2) And the remaining ring atoms are carbon. Preferably 6 to 14 (e.g. 6, 7, 8, 9,10, 11, 12, 13 and 14) membered (i.e. 6 to 14 bridged heterocyclyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) membered (i.e. 7 to 10 bridged heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic and polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0003410405860000141
the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:
Figure BDA0003410405860000142
and the like.
The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares an adjacent pair of carbon atoms) group (i.e., a 6 to 14 membered aryl group) having a conjugated pi-electron system, preferably a 6 to 10 membered (i.e., a 6 to 10 membered aryl group), such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0003410405860000143
aryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system (i.e., 5-to 14-membered heteroaryl) comprising 1 to 4 heteroatoms (e.g., 1,2,3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0003410405860000151
heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the parent ring atom by removal of one hydrogen atom, or2 residues derived from the parent ring atom by removal of two hydrogen atoms from the same ring atom or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".
The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.
The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to-OH.
The term "mercapto" refers to-SH.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "oxo" refers to "═ O".
The term "carbonyl" refers to C ═ O.
The term "carboxy" refers to-C (O) OH.
In the chemical structure of the compounds described in the present disclosure, a bond
Figure BDA0003410405860000161
Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure
Figure BDA0003410405860000162
Can be that
Figure BDA0003410405860000163
Or at the same time comprise
Figure BDA0003410405860000164
Figure BDA0003410405860000165
Two configurations.
The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure, replacing hydrogen with "deuterium" or "tritium", or18F-fluorine labeling: (18Isotope of F) instead of fluorine, or with11C-，13C-, or14C-enriched carbon (C11C-，13C-, or14C-carbon labeling;11C-，13c-, or14C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein each available hydrogen atom of the compound in deuterated form attached to a carbon atom is independently replaceable with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, tri-deuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.
"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano1-6Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen or cyano.
"substituted" means that one or more, preferably 1 to 6, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.
Synthesis of the Compounds of the disclosure
In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
scheme one
A process for the preparation of a compound of the general formula (I), or a pharmaceutically acceptable salt thereof, which comprises:
Figure BDA0003410405860000181
the compound of the general formula (IA) or the pharmaceutically acceptable salt thereof and the compound of the general formula (IB) or the pharmaceutically acceptable salt thereof are subjected to coupling reaction under alkaline conditions and in the presence of a catalyst to obtain the compound of the general formula (I) or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably a chlorine atom;
ring A, R1To R4N and m are as defined in formula (I).
Scheme two
Another aspect of the present disclosure relates to a method of preparing a compound of formula (II), or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0003410405860000182
the compound of the general formula (IIA) or the pharmaceutically acceptable salt thereof and the compound of the general formula (IIB) or the pharmaceutically acceptable salt thereof are subjected to coupling reaction under alkaline conditions and in the presence of a catalyst to obtain the compound of the general formula (II) or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably a chlorine atom;
R2and R3As defined in formula (II).
The reagents that provide basic conditions in the above synthetic schemes include organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1, 8-diazabicycloundecen-7-ene; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably cesium carbonate.
The catalyst used in the above synthesis scheme includes, but is not limited to tetrakis (triphenylphosphine) palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2, 4',6' -triisopropyl-1, 1 '-biphenyl) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), 1' -bis (dibenzylphosphine) dichlorodiamondral palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, tris (dibenzylideneacetone) dipalladium and the like, preferably methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2, 4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II).
The reaction of the above step is preferably carried out in a solvent including, but not limited to: 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-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE NEO 500M NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultratate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.
Chiral HPLC assay using Agilent 1260DAD HPLC.
High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.
Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Average inhibition rate of kinase and IC50NovoSt for value measurementar microplate reader (BMG, Germany).
Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate: the volume ratio of methanol and solvent is adjusted according to the polarity of the compound, or small amount of alkaline or acidic reagent such as triethylamine and acetic acid can be added for adjustment.
Example 1
7-cyclopropyl-2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7H-purin-8 (9H) -one 1
Figure BDA0003410405860000201
First step of
2-chloro-7-cyclopropyl-9- (tetrahydro-2H-pyran-4-yl) -7H-purin-8 (9H) -one 1b
2-chloro-9- (tetrahydro-2H-pyran-4-yl) -7H-purin-8 (9H) -one, 1a (300mg, 1.18mmol, prepared as disclosed in the patent "WO 2018114999A 1", intermediate 19, page 62) and cyclopropylboronic acid (202mg, 2.36mmol, Jiangsu Aikang), sodium carbonate (250mg, 2.36mmol, guyao), copper acetate (319.8mg, 1.76mmol, guyao), bipyridine (275.6mg, 1.76mmol, adalimus) were dissolved in 1, 2-dichloroethane/N, N-dimethylformamide (12mL/6mL) and stirred at 70 ℃ for 16 hours. 50mL of water was added, dichloromethane (60 mL. times.2) was extracted, the organic phases were combined, washed successively with water (60mL) and saturated sodium chloride solution (60mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using a Combiflash flash Rapid prep with eluent System B to give the title product 1B (300mg, yield: 86.4%). MS M/z (ESI) 295.0[ M +1 ].
Second step of
7-cyclopropyl-2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7H-purin-8 (9H) -one 1
Compound 1b (300mg, 1.01mmol) and 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine 1c (151mg, 1.01mmol, prepared using the method disclosed in the patent "WO 2018114999a1, page 53, intermediate 4), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2, 4',6' -triisopropyl-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-2-yl) palladium (II) (138.5mg, 152.67 μmol, shaoyuan), cesium carbonate (661.6mg, 2.03mmol, the national drug) were dissolved in 1, 4-dioxane (30mL) and stirred under nitrogen at 100 ℃ for 16 hours. 50mL of water was added, extraction was performed with ethyl acetate (60 mL. times.2), the organic phases were combined, washed successively with water (60mL) and saturated sodium chloride solution (60mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified with a Combiflash flash Rapid prep using an eluent system A to give the title product 1(175mg, yield: 42.3%). MS M/z (ESI) 407.0[ M +1 ].
1H NMR(500MHz,DMSO-d6):δ9.09(s,1H),8.68(s,1H),8.37(s,1H),8.06(s,1H),7.70(s,1H),4.41-4.34(m,1H),3.96-3.93(m,2H),3.42-3.39(m,2H),2.93-2.89(m,1H),2.37(s,3H),1.67-1.63(m,2H),0.99-0.89(m,4H)。
Biological evaluation
The present disclosure is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.
DNA-PK enzymology experimental method
1. Purpose of experiment
HTRF method for detecting phosphorylation P53 level, reaction compound inhibiting DNA-PK enzyme activity, and IC based on inhibition effect50The compounds were evaluated for in vitro activity.
2. Experimental methods
Substrate P53(Eurofins, #14-952-M) was diluted to 500nM with reaction buffer [25mM HEPES (Gibco, #15630-080), pH8.0, 0.01% Brij-35(Thermo, #20150), 1% glycerol (raw, # A100854-0100) ]; DNA-PK enzyme (Eurofins, #14-950M) was diluted to 0.16nM with dilution buffer [25mM HEPES pH8.0, 0.01% Brij-35, 1% glycerol, 5mM DTT (Bio Inc, # B645939), 1mg/mL BSA (Biyunyan, # ST023) ]; magnesium acetate (Sigma, #63052) was diluted to 40mM with dilution buffer before ATP (Thermo, # PV3227) was diluted to 29.2. mu.M. The prepared compound 10. mu. L, DNA-PK enzyme 2.5. mu.L and 500nM P53 substrate 2.5. mu. L, ATP 5. mu.L were added sequentially to 384-well plates (Thermo, #267462) using a liquid workstation (PV3227, # SP 2-096-0125-03). After mixing, incubation was carried out at 25 ℃ for 1 hour.
Stop buffer [12.5mM HEPES pH8.0, 0.005% Brij-35, 0.5% glycerol, 250mM EDTA (Thermo, # AM9260G) ] and assay mix [50mM HEPES pH7.0, 150mM NaCl (Bio, # B548121), 267mM KF (national drug, 7789-23-3), 0.1% sodium cholate (Sigma, # C6445), 0.01% Tween 20(Sigma, # P7949), 0.0125% sodium azide (Sigma, # S8032), anti-phospho-P53 Eu (Cisbbio, #61P08KAE)0.42 ng/well, and anti-GST-d 2(Cisbio, 61 GSTTDLF) 25 ng/well ] were added in sequence to 384 well plates using a liquid workstation, each 5. mu.L, overnight at 25 ℃. The absorbance at 665nm and 620nm was read using a microplate reader (BMG, PHERAstar FS). The data were analyzed using Graphpad Prism6, see table 1.
TABLE 1 IC of inhibitory Activity of the presently disclosed Compounds on DNA-PK enzymes50The value is obtained.
Example numbering IC50(nM)
1 0.35
And (4) conclusion: the compound disclosed by the invention has a good inhibition effect on DNA-PK enzyme.

Claims (14)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
Figure FDA0003410405850000011
wherein:
ring a is a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group;
R1the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R2is 3-14 membered cycloalkyl or 3-14 membered heterocyclyl, each of said 3-14 membered cycloalkyl and 3-14 membered heterocyclyl is independently optionally substituted with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroarylSubstituted by substituent groups;
R3selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, oxo groups, halogens, cyano groups, amino groups, nitro groups and hydroxyl groups;
R4the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, an oxo group, a halogen group, a cyano group, an amino group, a nitro group, and a hydroxyl group;
n is 0, 1 or 2; and is provided with
m is 0, 1,2,3, 4 or 5.
2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein ring a is 3 to 8 membered cycloalkyl; preferably cyclopropyl.
3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or2, wherein R1Are the same or different and are each independently a hydrogen atom or C1-6An alkyl group.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein R4Are the same or different and are each independently a hydrogen atom or C1-6An alkyl group.
5. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, which is a compound of formula (II), or a pharmaceutically acceptable salt thereof:
Figure FDA0003410405850000021
wherein:
R2and R3As defined in claim 1.
6. According to claim1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is2Is a 3-to 8-membered monocyclic heterocyclic group or a 6-to 14-membered polycyclic heterocyclic group, said 3-to 8-membered monocyclic heterocyclic group and 6-to 14-membered polycyclic heterocyclic group each independently being optionally selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, oxo, cyano, amino, nitro, hydroxy and C1-6Substituted with one or more substituents in hydroxyalkyl; preferably a 3 to 8 membered monocyclic heterocyclyl group; more preferably tetrahydropyranyl.
7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein R3Is a hydrogen atom or C1-6An alkyl group.
8. The compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, selected from the following compounds:
Figure FDA0003410405850000022
9. a compound of formula (IA), or a pharmaceutically acceptable salt thereof:
Figure FDA0003410405850000023
wherein:
x is halogen; preferably a chlorine atom;
ring A, R1、R2And m is as defined in claim 1.
10. A compound of formula (IA), or a pharmaceutically acceptable salt thereof, according to claim 9, which is a compound of:
Figure FDA0003410405850000031
11. a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which comprises:
Figure FDA0003410405850000032
the compound of the general formula (IA) or the pharmaceutically acceptable salt thereof and the compound of the general formula (IB) or the pharmaceutically acceptable salt thereof are subjected to coupling reaction to obtain the compound of the general formula (I) or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably a chlorine atom;
ring A, R1To R4N and m are as defined in claim 1.
12. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
13. Use of a compound of general formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 12 for the manufacture of a medicament for the inhibition of DNA-PK.
14. Use of a compound of general formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 12 for the preparation of a medicament for the treatment and/or prevention of cancer; wherein said cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastoma, neuroblastoma, germ cell tumors, teratomas, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumors (GIST), and pediatric cancer; wherein said sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, and kaposi's sarcoma; wherein said lung cancer is preferably non-small cell lung cancer (NSCLC).
CN202111530105.4A 2020-12-15 2021-12-14 Purine ketone derivative, preparation method and medical application thereof Pending CN114634522A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110177791A (en) * 2016-12-20 2019-08-27 阿斯利康(瑞典)有限公司 Amino-triazolopyridine compound and its purposes in treating cancer
CN114195805A (en) * 2020-09-18 2022-03-18 首药控股(北京)股份有限公司 DNA-PK selective inhibitor and preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110177791A (en) * 2016-12-20 2019-08-27 阿斯利康(瑞典)有限公司 Amino-triazolopyridine compound and its purposes in treating cancer
CN114195805A (en) * 2020-09-18 2022-03-18 首药控股(北京)股份有限公司 DNA-PK selective inhibitor and preparation method and application thereof

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