CN116685323A

CN116685323A - Purinone derivative, preparation method and medical application thereof

Info

Publication number: CN116685323A
Application number: CN202180085295.5A
Authority: CN
Inventors: 陆标; 王胜蓝; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-12-21
Filing date: 2021-12-21
Publication date: 2023-09-01
Also published as: TW202241901A; WO2022135360A1

Abstract

A purinone derivative represented by the general formula (IG), a process for preparing the same, a pharmaceutical composition containing the same, and use thereof as a therapeutic agent, in particular, use as a DNA-PK inhibitor and use in preparing a medicament for treating and/or preventing cancer. Wherein each group in the general formula (IG) is defined in the specification.

Description

Purinone derivative, preparation method and medical application thereof

Technical Field

The present disclosure relates to a purinone derivative, a preparation method thereof and application thereof in medicine, which belongs to the field of medicine. In particular, the present disclosure relates to purinone derivatives represented by general formula (IG), a method for preparing the same, pharmaceutical compositions containing the same, and use thereof as DNA-PK inhibitors in the preparation of medicaments for the treatment and/or prevention of cancer.

Background

DNA-dependent protein kinase (DNA-PK) is a serine/hydroxybutyrate kinase complex consisting of the catalytic subunits DNA-PKcs and heterodimers of the Ku proteins (Ku 70/Ku 80), an important protein in DNA damage repair (Cancer Discovery,2014,4,1126-1139); plays an important role in maintaining the stability of telomerase, participating in innate immunity and V (D) J recombination, transcriptional regulation and the like (Curr Opin Allergy Clin Immunol,2009,9,503-509).

DNA repair in eukaryotes is mainly of 4 types: nucleotide Excision Repair (NER), base Excision Repair (BER), mismatch repair (MMR), and Double Strand Break Repair (DSBR). NER can cleave large fragments of DNA lesions, BER can repair individual base lesions, MMR is used to repair base mismatches, and DSBR includes two mechanisms: non-homologous end joining (NHEJ) and Homologous Recombination (HR). NHEJ is directly linked to the stump without the need for a template, HR requires the use of the intact sister chromatid as a repair template. NHEJ is the predominant repair pathway, which occurs in all phases of the cell cycle. While HR occurs primarily in the G2/M phase of the cell cycle (ChemMedChem, 2017,12,895-900). Three kinases of the PI3K related kinase (PIKK) family play a leading role in DNA damage repair: DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated kinase (ATM), and ATM and Rad3 related kinase (ATR). DNA-PK is mainly involved in the NHEJ pathway, ATM is mainly involved in the HR pathway, and ATR is mainly responsible for repairing single-stranded DNA lesions (Nat Rev Clin Oncol.,2019,81-104).

When a DNA double strand breaks, the cyclic Ku70/Ku80 heterodimer recognizes and binds to the broken DNA end, recruiting DNA-PKcs. The recruitment of DNA-PKcs facilitates the movement of the Ku heterodimer into the DNA duplex, allowing the DNA-PKcs to act as a tether to break the DNA ends and prevent exonuclease degradation. At the same time, binding to DNA promotes activation of the catalytic activity of DNA-PKcs, the major autophosphorylation sites being Ser2056 and Thr2609.DNA-PKcs also result in the phosphorylation of a range of downstream proteins, including Artemis, DNA ligase 4, histone H2A variants (H2 AX), and the like, which together complete DNA double-strand repair (Nat Rev Clin Oncol.,2019,81-104).

DNA-PK is highly expressed in many types of tumor tissue and can cause tumor metastasis by stimulating angiogenesis and tumor cell migration (Clin Cancer Res,2019,25,5623-5637). Moreover, an increase in DNA-PK activity is closely related to drug resistance to chemotherapeutic agents and to a poor prognosis. Studies have shown that DNA-PK inhibitors significantly increase the sensitivity of tumor cells to x-ray radiation (IR) and chemotherapeutics, and increase the tumor-inhibiting effect of the PAPR inhibitor olaharib (Nat Commun.,2019,10,5065-5079;Mol Cancer Res,2019,17,2457-2468).

Several patents for DNA-PK inhibitors are currently issued by companies typified by AstraZeneca and Merck (WO 2019238929A1, WO2018114999A1, WO2014183850A1, etc.), and there is room for improvement in both in vitro activity and selectivity of these structural classes of compounds. Wherein the small molecule DNA-PK inhibitor of AstraZeneca entered clinical stage 10 in 2019. At present, no DNA-PK inhibitor drugs are approved for marketing, and thus there is a significant unmet medical need in the relevant patient population.

Disclosure of Invention

The present disclosure aims to provide a compound represented by the general formula (IG):

wherein:

G ¹ 、G ² and G ³ Identical or different and are each independently CR ² Or a nitrogen atom;

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring B is cycloalkyl or heterocyclyl;

R ¹ the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ² the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ³ selected from the group consisting ofHydrogen atom, alkyl group, haloalkyl group, cycloalkyl group and heterocyclic group, wherein each of said alkyl group, haloalkyl group, cycloalkyl group and heterocyclic group is independently optionally substituted with one or more substituents selected from halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, oxo group, cyano group, amino group, nitro group, hydroxyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

R ⁴ the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

p is 0, 1, 2, 3, 4 or 5; and is also provided with

q is 0, 1, 2, 3, 4 or 5.

In some preferred embodiments of the present disclosure, the compound of formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CR (CR) ² Or a nitrogen atom; g ² And G ³ Identical or different and are each independently CR ² ；R ² As defined in formula (IG).

In some preferred embodiments of the present disclosure, the compound of formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is a nitrogen atom; g ² And G ³ Identical or different and are each independently CR ² ；R ² As defined in formula (IG).

In some preferred embodiments of the present disclosure, there is provided a compound represented by the general formula (I):

wherein:

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring B is cycloalkyl or heterocyclyl;

R ³ Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and heterocyclyl groups, wherein each of said alkyl groups, haloalkyl groups, cycloalkyl groups, and heterocyclyl groups is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, oxo groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

n is 0, 1, 2 or 3;

p is 0, 1, 2, 3, 4 or 5; and is also provided with

q is 0, 1, 2, 3, 4 or 5.

In some preferred embodiments of the present disclosure, there is provided a compound represented by the general formula (II):

wherein:

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring B is cycloalkyl or heterocyclyl;

R ¹ identical or different and are each independently selected from hydrogen atoms, halogen, alkyl, alkenyl, alkyneAlkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy and hydroxyalkyl;

n is 0, 1 or 2;

p is 0, 1,2, 3, 4 or 5; and is also provided with

q is 0, 1,2, 3, 4 or 5.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5 to 6 membered heteroaryl or a 3 to 6 membered heterocyclyl; preferably a 5-membered heteroaryl or a 5-to 6-membered heterocyclyl; more preferably selected from imidazolyl, pyrazolyl, triazolyl, 1,2, 4-oxadiazol-5 (2H) -one, thiazolyl, pyrrolyl, thienyl and furanyl.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring a is a 5 membered heteroaryl, preferably selected from imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyrrolyl, thiophenyl and furanyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IG), the general formula (I) or the general formula (II)A compound or pharmaceutically acceptable salt thereof, wherein ring B is a 3 to 14 membered heterocyclyl; preferably 3 to 6 membered heterocyclyl; more preferably a 6 membered heterocyclyl; even more preferably tetrahydropyranyl; most preferably

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-membered heteroaryl or a 5-to 6-membered heterocyclyl; and ring B is a 3 to 6 membered heterocyclyl.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R ³ Is C _1-6 Alkyl or 3 to 6 membered cycloalkyl; preferably, R ³ Methyl or cyclopropyl; more preferably, R ³ Is methyl.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and oxo; preferably, R ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and oxo; further preferably, R ¹ The same or different and are each independently selected from the group consisting of hydrogen, methyl, and oxo; more preferably, R ¹ The same or different and are each independently a hydrogen atom or an oxo group.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and oxo; preferably, R ¹ Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; more preferably, R ¹ Is C _1-6 An alkyl group; most preferably, the first to fourthPreferably, R ¹ Is methyl.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ² Identical or different and are each independently selected from the group consisting of hydrogen, halogen, cyano and C _1-6 An alkyl group; preferably, R ² Identical or different and are each independently selected from the group consisting of hydrogen, cyano and C _1-6 An alkyl group; further preferably, R ² The same or different, and are each independently a hydrogen atom or a cyano group; more preferably, R ² Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ⁴ Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ⁴ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3, preferably 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (IG), formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CR (CR) ² Or a nitrogen atom; g ² And G ³ Identical or different and are each independently CR ² The method comprises the steps of carrying out a first treatment on the surface of the Ring a is a 5 membered heteroaryl or a 5 to 6 membered heterocyclyl; ring B isR ³ Methyl or cyclopropyl; r is R ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and oxo; r is R ² Identical or different and are each independently selected from the group consisting of hydrogen, cyano and C _1-6 An alkyl group; r is R ⁴ Is a hydrogen atom; p is 0, 1, 2 or 3; and q is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is a nitrogen atom; g ² And G ³ Identical or different and are each independently CR ² The method comprises the steps of carrying out a first treatment on the surface of the Ring a is a 5 membered heteroaryl; ring B isR ³ Is methyl; r is R ¹ Is C _1-6 An alkyl group; p is 0 or 1; r is R ² Is a hydrogen atom; r is R ⁴ Is a hydrogen atom; and q is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-membered heteroaryl or a 5-to 6-membered heterocyclyl; ring B isR ³ Methyl or cyclopropyl; r is R ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and oxo; r is R ² Identical or different and are each independently selected from the group consisting of hydrogen, cyano and C _1-6 An alkyl group; r is R ⁴ Is a hydrogen atom; n is 0 or 1; p is 0, 1, 2 or 3; and q is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-membered heteroaryl or a 5-to 6-membered heterocyclyl; ring B is R ³ Methyl or cyclopropyl; r is R ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and oxo; p is 0, 1, 2 or 3; r is R ² Identical or different and are each independently selected from the group consisting of hydrogen, cyano and C _1-6 An alkyl group; n is 0 or 1; r is R ⁴ Is a hydrogen atom; and q is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-membered heteroaryl; ring B isR ³ Is methyl; r is R ¹ Is C _1-6 An alkyl group; p is 0 or 1; r is R ² Is a hydrogen atom; n is 0 or 1; r is R ⁴ Is a hydrogen atom; and q is 0 or 1.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IG), or a pharmaceutically acceptable salt thereof, comprising:

the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IGB) or the salt thereof undergo a coupling reaction to obtain the compound shown in the general formula (IG) or the pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

ring a, ring B, G ¹ 、G ² 、G ³ 、R ¹ 、R ³ 、R ⁴ P and q are as defined in formula (IG).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, comprising:

The compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IB) or the salt thereof undergo a coupling reaction to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

ring a, ring B, R ¹ To R ⁴ N, p and q are as defined in 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, comprising:

the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IIB) or the salt thereof undergo a coupling reaction to obtain the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

ring a, ring B, R ¹ To R ⁴ N, p and q are as defined in formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (IG), general formula (I), general formula (II) and table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to the use of a compound of formula (IG), formula (I), formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting DNA-PK.

The present disclosure further relates to the use of a compound of general formula (IG), general formula (I), general formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer, preferably for the treatment and/or prevention of DNA-PK mediated cancer. Wherein the cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysplastic neuroepithelial tumor, glioblastoma multiforme, hybrid glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head 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 tumor (GIST), and pediatric cancer. Wherein the lymphoma is selected from the group consisting of hodgkin's disease and non-hodgkin's lymphoma (including mantle cell lymphoma); wherein the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, etc.) or Small Cell Lung Cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); the kidney cancer is preferably selected from the group consisting of renal cell carcinoma, clear cell and renal eosinophil tumor; wherein said sarcoma is preferably selected from the group consisting of chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma and kaposi's sarcoma.

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 (IG), formula (I), formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing cancer, preferably DNA-PK mediated cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (IG), formula (I), formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysplastic neuroepithelial tumor, glioblastoma multiforme, hybrid glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head 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 tumor (GIST), and pediatric cancer. Wherein the lymphoma is selected from the group consisting of hodgkin's disease and non-hodgkin's lymphoma (including mantle cell lymphoma); wherein the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, etc.) or Small Cell Lung Cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); the kidney cancer is preferably selected from the group consisting of renal cell carcinoma, clear cell and renal eosinophil tumor; wherein said sarcoma is preferably selected from the group consisting of chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma and kaposi's sarcoma.

The present disclosure further relates to a compound represented by general formula (IG), general formula (I), general formula (II) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound represented by general formula (IG), general formula (I), general formula (II) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting DNA-PK.

The present disclosure further relates to a compound represented by general formula (IG), general formula (I), general formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of cancer, preferably for the treatment and/or prevention of DNA-PK mediated cancer. Wherein the cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysplastic neuroepithelial tumor, glioblastoma multiforme, hybrid glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head 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 tumor (GIST), and pediatric cancer. Wherein the lymphoma is selected from the group consisting of hodgkin's disease and non-hodgkin's lymphoma (including mantle cell lymphoma); wherein the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, etc.) or Small Cell Lung Cancer (SCLC), preferably non-small cell lung cancer (NSCLC); the kidney cancer is preferably selected from the group consisting of renal cell carcinoma, clear cell and renal eosinophil tumor; wherein said sarcoma is preferably selected from the group consisting of chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma and kaposi's sarcoma.

The tumors that appear in the above definition of cancer are malignant tumors.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, 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) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be from 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the 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 to 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 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. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The 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. The above-described sweeteners 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 an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical 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. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

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 suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare 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 will therefore melt in the rectum to release the drug.

The compounds 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, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific 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, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the 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 from 1 to 20 carbon atoms, preferably an alkyl group (i.e., C) containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl), more preferably alkyl having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and 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, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any useful point of attachment, preferably selected from one or more of D atom, 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 group which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane which is a straight or branched chain group containing from 1 to 20 carbon atoms (i.e., C _1-20 Alkylene groups), 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) _1-12 Alkylene groups), more preferably alkylene groups having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C _2-6 Alkenyl). Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkynyl groups), more preferably alkynyl groups containing 2 to 6 carbon atoms (i.e. C _2-6 Alkynyl). 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 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, the cycloalkyl ring comprising 3 to 20 carbon atoms (i.e., 3 to 20 membered cycloalkyl), preferably comprising 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), preferably comprising 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably comprising 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). 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 cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered spirocycloalkyl) polycyclic group, which may contain one or more double bonds, sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings. 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). The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a 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 monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused ring alkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered fused ring alkyl) ring in the system, each ring in the system sharing an adjacent pair of carbon atom(s) of an all-carbon polycyclic group wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered (i.e., 6 to 14 membered fused ring alkyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered fused ring alkyl). The number of constituent rings may be divided into a double ring, a triple ring, a tetra ring and a polycyclic condensed ring alkyl group, preferably a double ring or a triple ring, more preferably a 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 double ring condensed ring alkyl group. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered bridged cycloalkyl) ring, any two rings sharing two all carbon polycyclic groups of carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered (i.e., 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered bridged cycloalkyl). Cycloalkyl groups which may be classified into bicyclic, tricyclic, tetracyclic and polycyclic bridged groups according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples includePreferably is

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they 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 "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atom, halogen, 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) in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably containing from 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 to 4 (e.g., 1,2,3, and 4) are heteroatoms; further preferred contain 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; even more preferably, 3 to 6 ring atoms (i.e., 3 to 6 membered heterocyclyl) of which 1-3 (e.g., 1,2, and 3) are heteroatoms; most preferably containing 5 or 6 ring atoms (i.e., 5 to 6 membered heterocyclyl) of which 1-3 are heteroatoms; most preferably, it contains 6 ring atoms (i.e., 6 membered heterocyclyl groups), 1-3 of which are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, 1,2, 4-oxadiazol-5 (2H) -one, 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 (i.e., 5 to 20 membered spiroheterocyclyl) polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered spiroheterocyclyl). The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl 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 single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

the term "fused heterocyclyl" refers to a 5-to 20-membered (i.e., 5-to 20-membered fused heterocyclyl) ring in the system sharing an adjacent pair of atoms with the other rings in the system, one or more of which rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Preferably 6 to 14 membered (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 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered fused heterocyclyl). The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic and polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 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 bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

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 which are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered bridged heterocyclyl). Heterocyclic groups which may be classified into a bicyclic, tricyclic, tetracyclic and polycyclic bridged ring base according to the number of constituent rings, are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

the heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from 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 being a ring sharing adjacent pairs of carbon atoms) group (i.e., a 6 to 14 membered aryl group), preferably a 6 to 10 membered (i.e., a 6 to 10 membered aryl group), having a conjugated pi electron system, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, 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., a 5 to 14 membered heteroaryl) containing 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 to 6 membered heteroaryl), and most preferably 5 membered (i.e., 5 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, with substituents selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxy protecting group" refers to a hydroxy derivative that is typically used to block or protect a hydroxy group while the reaction proceeds on other functional groups of the compound. As an example, preferably, the hydroxyl protecting group may be (C _1-10 Alkyl or aryl radicals ₃ Silyl groups, for example: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, and the like; may be C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy substituted C _1-4 Alkyl groups such as: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; may be (C) _1-10 Alkyl or aryl) acyl groups, for example: formyl, acetyl and benzoylP-nitrobenzoyl and the like; may be (C) _1-6 Alkyl or 6 to 10 membered aryl) sulfonyl; may also be (C) _1-6 Alkoxy or 6 to 10 membered aryloxy) carbonyl.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an 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-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl, cycloalkyl are as defined above.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr (b)Or at the same time containAndtwo configurations.

In the chemical structure of the compounds of the present disclosure, the bondThe configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are included.

Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, with the structures of the present disclosure, replacement of hydrogen with "deuterium" or "tritium", or with ¹⁸ F-fluorine labeling [ ] ¹⁸ F isotope) substitutionSubstituted for fluorine, or by ¹¹ C-， ¹³ C-, or ¹⁴ C-enriched carbon ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein each available hydrogen atom of the deuterated form of the compound attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus achieving certain therapeutic advantages.

"optionally" or "optionally" is intended to mean 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 cyano _1-6 Alkyl "means that halogen or cyano may be, but is not necessarily, present, and the description includes cases where alkyl is substituted with halogen or cyano and cases where alkyl is not substituted with halogen or cyano.

"substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. May be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate groups 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 and 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 intended effect. 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, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

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 are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A process for preparing a compound represented by the general formula (IG) of the present disclosure, or a pharmaceutically acceptable salt thereof, which comprises:

the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IGB) or the salt thereof are subjected to coupling reaction under alkaline condition in the presence of a catalyst to obtain the compound shown in the general formula (IG) or the pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

Scheme II

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

The compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IB) or the salt thereof are subjected to coupling reaction under alkaline conditions in the presence of a catalyst to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

ring a, ring B, R ¹ To R ⁴ N, p and q are as defined in formula (I).

Scheme III

A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IIB) or the salt thereof are subjected to coupling reaction under alkaline condition in the presence of a catalyst to obtain the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

ring a, ring B, R ¹ To R ⁴ N, p and q are as defined in formula (II).

Reagents providing basic conditions in the above synthetic schemes include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1, 8-diazabicycloundec-7-ene, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; cesium carbonate is preferred.

Catalysts used in the above synthetic schemes include, but are not limited to, tetrakis (triphenylphosphine) palladium, palladium dichloride, palladium acetate, methane sulfonic 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) iron-dichloro-palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, and the like, with methane sulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) being preferred.

The reaction of the above steps is preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, 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 in conjunction with the examples, which are not intended to 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 ^-6 Units of (ppm) are given. NMR was performed using a Bruker AVANCE NEO 500.500M magnetonucleo-magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q actual (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

The high performance liquid phase was prepared by using a Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the 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 a fumigant yellow sea silica gel of 200 to 300 mesh as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

4-methyl-5- ((7-methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-2-yl) amino) -2- (1H-pyrazol-1-yl) benzonitrile 1

First step

4-methyl-5-nitro-2- (1H-pyrazol-1-yl) benzonitrile 1b

2-fluoro-4-methyl-5-nitrobenzonitrile 1a (1.00 g,5.55mmol, prepared as described in patent application WO2017125530A1, P256), pyrazole (328 mg,13.34mmol, obtained), and potassium carbonate (921 mg,6.66mmol, hu test) were mixed and suspended in 25mL of N, N-dimethylformamide, and stirred for 2 hours. To the reaction solution was added 50mL of water, extracted with ethyl acetate (30 ml×3), the resulting organic phase was concentrated under reduced pressure, and the residue was purified with CombiFlash rapid preparation instrument using eluent system a to give the title product 1b (522 mg), yield: 41.2%.

MS m/z(ESI):228.9[M+1]。

Second step

5-amino-4-methyl-2- (1H-pyrazol-1-yl) benzonitrile 1c

Compound 1b (522 mg,2.29 mmol) and palladium on charcoal (wet) (49 mg,0.46mmol, enokia) were mixed and suspended in 50mL of ethanol, and the reaction was stirred for 17 hours with hydrogen substitution 6 times. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 1c (450 mg), yield: 99.2%.

MS m/z(ESI):198.9[M+1]。

Third step

Compound 1c (74 mg,0.37 mmol), 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one 1d (100 mg,0.37mmol, prepared as disclosed in patent application "CN110177791a, P43"), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (34 mg,0.037mmol, iconazole) and cesium carbonate (243 mg,0.75mmol, sha-far) were dissolved in 20ml of 1, 4-dioxane under argon atmosphere, heated to 100 ℃ and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified using a CombiFlash rapid prep machine with eluent system a to give the title product 1 (70 mg), yield: 43.7%.

MS m/z(ESI):431.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.81(s,1H),8.35-8.29(m,2H),8.18(s,1H),7.85-7.80(m,1H),7.66(s,1H),6.65-6.55(m,1H),4.45-4.40(m,1H),4.00-3.97(m,2H),3.50-3.40(m,5H),2.56-2.53(m,2H),2.43(s,3H),1.71-1.69(m,2H)。

Example 2

7-methyl-2- ((2-methyl-4- (1H-1, 2, 3-triazol-1-yl) phenyl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one 2

First step

1- (3-methyl-4-nitrophenyl) -1H-1,2, 3-triazole 2c

4-fluoro-2-methyl-1-nitrobenzene 2a (3.0 g,19.34mmol, prepared as disclosed in patent application "U.S. Pat. No. 3,262A 1, P26") was dissolved in 20mL of N, N-dimethylformamide, 1,2, 3-triazole (1.74 g,25.2 mmol) and potassium carbonate (4.01 g,29.05 mmol) were added in sequence and stirred at 80℃for 3 hours. Water was added, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified using a CombiFlash flash rapid prep machine with eluent system A to give compound 2b (1.5 g, yield: 38.0%) and compound 2c (1.8 g, yield: 45.4%).

MS m/z(ESI):205.1[M+1]。

Second step

2-methyl-4- (1H-1, 2, 3-triazol-1-yl) aniline 2d

Compound 2C (100 mg,0.49 mmol) was dissolved in 15mL of methanol under hydrogen atmosphere, 10% Pd/C (80 mg) was added, and the mixture was stirred at room temperature for 1 hour. Diatomaceous earth was filtered, washed once with methanol, and the filtrate was dried by spin to give compound 2d (80 mg), yield: 93.8%.

MS m/z(ESI):175.0[M+1]。

Third step

Compound 2d (80 mg,0.46 mmol) and compound 1d (120 mg,0.45 mmol) were suspended in 1, 4-dioxane (10 mL), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (30 mg,0.033 mmol) and cesium carbonate (292 mg,0.90 mmol) were added sequentially, and the mixture was heated to 100℃and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified using a CombiFlash rapid prep machine with eluent system a to give the title product 2 (108 mg), yield: 59.5%.

MS m/z(ESI):407.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.75(s,1H),8.60(s,1H),8.10(s,1H),7.96(s,1H),7.86(d,1H),7.75(s,1H),7.67(d,1H),4.45(brs,1H),4.02(d,2H),3.43(t,2H),3.25(s,3H),2.56(brs,2H),2.36(s,3H),1.64(d,2H)。

Example 3

7-methyl-2- ((2-methyl-4- (2H-1, 2, 3-triazol-2-yl) phenyl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one 3

First step

2-methyl-4- (2H-1, 2, 3-triazol-2-yl) aniline 3a

Compound 2b (120 mg,0.60 mmol) was dissolved in 15mL of methanol, 10% Pd/C (80 mg) was added, the hydrogen was replaced three times, and the mixture was stirred at room temperature for 1 hour. Diatomaceous earth was filtered, washed once with methanol, and the filtrate was dried by spin to give compound 3a (100 mg), yield: 94.8%.

MS m/z(ESI):175.0[M+1]。

Second step

Compound 3a (100 mg,0.57 mmol) and compound 1d (139 mg,0.52 mmol) were suspended in 1, 4-dioxane (10 mL), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (30 mg,0.033 mmol) and cesium carbonate (375 mg,1.15 mmol) were added sequentially, and the mixture was heated to 100℃and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified using CombiFlash rapid prep machine with eluent system a to give the title product 3 (110 mg), yield: 48.5%.

MS m/z(ESI):407.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.56(s,1H),8.10(s,1H),8.09(s,1H),7.90(s,1H),7.82(d,1H),7.80(s,1H),7.78(d,1H),4.39-4.45(m,1H),3.4.00(d,2H),3.42(t,2H),3.31(s,3H),2.54-2.57(m,2H),2.36(s,3H),1.67(d,2H)。

Example 4

7-methyl-2- ((2-methyl-4- (1H-pyrazol-1-yl) phenyl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one 4

Compound 1d (100 mg,0.37 mmol), 2-methyl-4- (1H-pyrazol-1-yl) aniline 4a (65 mg,0.37mmol, prepared as disclosed in patent application "WO2004062665A1, P39"), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (34 mg,0.037mmol, iconazole) and cesium carbonate (243 mg,0.75mmol, shao) were dissolved in 10ml 1, 4-dioxane under argon atmosphere, heated to 100 ℃, and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified using a CombiFlash rapid prep machine with eluent system a to give the title product 4 (64.2 mg), yield: 42.5%.

MS m/z(ESI):406.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.49(s,1H),8.42-8.41(m,1H),8.05(s,1H), 7.71-7.68(m,3H),7.60-7.58(m,1H),6.52-6.51(m,1H),4.44-4.37(m,1H),3.99-3.95(m,2H),3.44-3.39(m,2H),3.30(s,3H),2.57-2.52(m,2H),2.32(s,3H),1.68-1.64(m,2H)。

Example 5

3- (3-methyl-4- ((7-methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-2-yl) amino) phenyl) -1,2, 4-oxadiazol-5 (2H) -one 5

First step

3-methyl-4- ((7-methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl-8, 9-dihydro-7H-purin-2-yl) amino) benzonitrile 5b

Compound 1d (280 mg,1.04 mmol), 4-amino 3-methylbenzonitrile 5a (160 mg,1.21mmol, prepared as disclosed in patent application "WO2011086377A1, P26-27"), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (60 mg,0.066 mmol) and cesium carbonate (780 mg,2.42 mmol) were dissolved in 20ml of 1, 4-dioxane under argon atmosphere, heated to 100 ℃ and stirred for 17 hours. The reaction was concentrated under reduced pressure, and the residue was purified with a CombiFlash rapid prep machine using eluent system a to give compound 5b (320 mg), yield: 72.5%.

MS m/z(ESI):365.1[M+1]。

Second step

N' -hydroxy-3-methyl-4- ((7-methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-2-yl) amino) benzamidine 5c

Compound 5b (320 mg,0.88 mmol) was dissolved in 15mL of ethanol, sodium bicarbonate (222 mg,2.64 mmol) and hydroxylamine chloride (184 mg,2.64 mmol) were added sequentially and stirred at 70℃for 17 hours. Concentration, addition of water, filtration, washing with water gave compound 5c (220 mg), yield: 63.0%.

MS m/z(ESI):398.1[M+1]。

Third step

Compound 5c (220 mg,0.55 mmol) was suspended in 10mL of 1, 4-dioxane, 1, 8-diazabicyclo [5.4.0] undec-7-ene (93 mg,0.61 mmol) and diimidazole ketone (99 mg,0.61 mmol) were added sequentially and stirred at 90℃for 3 hours. Concentration, neutralization with water, dilute hydrochloric acid, filtration, water washing, methanol recrystallization, filtration gave the title product 5 (95 mg), yield: 40.5%.

MS m/z(ESI):424.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ12.7(s,1H),8.62(s,1H),8.15(s,1H),8.03(d,1H),7.65(s,1H),7.60(d,1H),4.40-4.45(m,1H),3.99(d,2H),3.43(t,2H),3.30(s,3H),2.54-2.57(m,2H),2.35(s,3H),1.69(d,2H)。

Example 6

4-methyl-2- (1-methyl-1H-pyrazol-4-yl) -5- ((7-methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-2-yl) amino) benzonitrile 6

Compound 1d (100 mg,0.37 mmol), 5-amino-4-methyl-2- (1-methyl-1H-pyrazol-4-yl) benzonitrile 6a (90 mg,0.42mmol, prepared using the method disclosed in patent application "WO2017125530A1, P317-318"), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (34 mg,0.037mmol, iconazole) and cesium carbonate (364 mg,1.12mmol, shao) were dissolved in 15ml 1, 4-dioxane under argon atmosphere, heated to 100 ℃ and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified with a CombiFlash rapid prep machine using eluent system a to give the title product 6 (57.2 mg), yield: 34.6%.

MS m/z(ESI):445.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.65(s,1H),8.19(s,1H),8.16(s,1H),8.13(s,1H),7.91(s,1H),7.56(s,1H),4.44-4.38(m,1H),4.00-3.96(m,2H),3.92(s,3H),3.47-3.44 (m,2H),3.31(s,3H),2.52-2.49(m,2H),2.36(s,3H),1.70-1.67(m,2H)。

Example 7

4-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- ((7-methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-2-yl) amino) benzonitrile 7

First step

4-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5-nitrobenzonitrile 7b

2-bromo-4-methyl-5-nitrobenzonitrile 7a (300 mg,1.24mmol, prepared as described in patent application "WO2017125530A1, P311") was suspended in a mixture of (1-methyl-1H-pyrazol-5-yl) boronic acid (220 mg,1.75mmol, shao), [1, 1-bis (diphenylphosphorus) ferrocene ] palladium dichloride (92 mg,0.13mmol, icorn) and potassium carbonate (517 mg,3.74mmol, shanghai) under argon atmosphere, and stirred for 7 hours at a temperature of 100 ℃ C. In 18mL of a mixed solvent of 1, 4-dioxane and water (V/V=5:1). The reaction was concentrated under reduced pressure and the residue was purified with a CombiFlash rapid prep machine using eluent system a to give the title product 7b (94 mg), yield: 31.2%.

MS m/z(ESI):242.9[M+1]。

Second step

5-amino-4-methyl-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile 7c

Compound 7b (94 mg,0.39 mmol) and palladium on charcoal (wet) (42 mg,0.39mmol, enoki) were mixed and suspended in 20mL of ethanol, and the reaction was stirred for 17 hours with hydrogen substitution 6 times. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 7c (75 mg), yield: 91.1%.

MS m/z(ESI):213.0[M+1]。

Third step

Compound 7c (75 mg,0.35 mmol), compound 1d (100 mg,0.37 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (33 mg,0.036mmol, iconazole) and cesium carbonate (348 mg,1.06mmol, shao-chong) were dissolved in 15ml of 1, 4-dioxane under argon atmosphere, heated to 100 ℃ and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified using a CombiFlash rapid prep machine with eluent system a to give the title product 7 (75.4 mg), yield: 48.0%.

MS m/z(ESI):445.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.82(s,1H),8.39(s,1H),8.19(s,1H),7.55-7.54(m,1H),7.51(s,1H),6.48-6.47(m,1H),4.47-4.40(m,1H),4.00-3.96(m,2H),3.79(s,3H),3.45-3.40(m,2H),3.33(s,3H),2.56-2.47(m,2H),2.42(s,3H),1.72-1.68(m,2H)。

Example 8

4-methyl-2- (1-methyl-1H-pyrazol-3-yl) -5- ((7-methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-2-yl) amino) benzonitrile 8

First step

4-methyl-2- (1-methyl-1H-pyrazol-3-yl) -5-nitrobenzonitrile 8a

Compound 7a (300 mg,1.24 mmol), (1-methyl-1H-pyrazol-3-yl) boronic acid (187 mg,1.49mmol, prepared by the method disclosed in patent application "US20190106427A1, P446-447"), [1, 1-bis (diphenylphosphorus) ferrocene ] palladium dichloride (92 mg,0.13mmol, iconazole) and potassium carbonate (517mg, 3.74mmol, sha) were mixed and suspended in 25ml of a mixed solvent of 1, 4-dioxane and water (V/v=5:1) under argon atmosphere, and the mixture was heated to 100 ℃ and stirred for 7 hours. The reaction was concentrated under reduced pressure and the residue was purified using a CombiFlash rapid prep machine with eluent system a to give the title product 8a (96 mg), yield: 31.8%.

MS m/z(ESI):242.9[M+1]。

Second step

5-amino-4-methyl-2- (1-methyl-1H-pyrazol-3-yl) benzonitrile 8b

Compound 8a (96 mg,0.40 mmol) and palladium on charcoal (wet) (43 mg,0.40mmol, enoki) were suspended in 20mL of ethanol, replaced with hydrogen 6 times, and the reaction was stirred for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 8b (71 mg), yield: 84.4%.

MS m/z(ESI):213.0[M+1]。

Third step

Compound 8b (71 mg, 0.336 mmol), compound 1d (100 mg,0.37 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (31 mg,0.034mmol, iconazole) and cesium carbonate (327 mg,1.00mmol, shao-chong) were dissolved in 15ml of 1, 4-dioxane under argon, heated to 100 ℃ and stirred for 17 hours. The reaction was concentrated under reduced pressure, and the residue was purified with a CombiFlash rapid prep machine using eluent system a to give the title compound 8 (81.1 mg), yield: 54.5%.

MS m/z(ESI):445.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.69(s,1H),8.24(s,1H),8.16(s,1H),7.83-7.82(m,1H),7.76(s,1H),6.80-6.79(m,1H),4.46-4.39(m,1H),4.00-3.97(m,2H),3.93(s,3H),3.45-3.40(m,2H),3.32(s,3H),2.56-2.47(m,2H),2.40(s,3H),1.71-1.68(m,2H)。

Example 9

7-methyl-2- ((4-methyl-6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one 9

First step

4-methyl-2- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridine 9b

2-bromo-4-methyl-5-nitropyridine 9a (300 mg,1.38mmol, bi-medicine), (1-methyl-1H-pyrazol-4-yl) boronic acid (192 mg,1.52mmol, shao), [1, 1-bis (diphenylphosphorus) ferrocene ] palladium dichloride (102 mg,0.139mmol, aikang) and potassium carbonate (514 mg,4.15mmol, shang-test) were mixed and suspended in 18mL of a mixed solvent of 1, 4-dioxane and water (V/V=5:1) under argon atmosphere, and the mixture was heated to 100℃and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified with CombiFlash flash rapid prep. using eluent system a to give the title product 9b (200 mg), yield: 66.3%.

MS m/z(ESI):218.9[M+1]。

Second step

4-methyl-6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-amine 9c

Compound 9b (200 mg,0.916 mmol) and palladium on charcoal (wet) (98 mg,0.39mmol, enoki) were suspended in 25mL of ethanol, replaced with hydrogen 6 times, and the reaction was stirred for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 9c (172 mg), yield: 99.7%.

MS m/z(ESI):188.9[M+1]。

Third step

Compound 9c (183mg, 0.972 mmol), compound 1d (200 mg,0.744 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (68 mg,0.075mmol, iconazole) and cesium carbonate (178 mg,2.23mmol, shao) were added to 30ml of 1, 4-dioxane under argon, heated to 100 ℃ and stirred for 17 hours. The reaction was concentrated under reduced pressure and the residue was purified using a CombiFlash flash rapid prep machine with eluent system a to give the title product 9 (145.7 mg), yield: 46.5%.

MS m/z(ESI):421.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.64(s,1H),8.54(s,1H),8.19(s,1H),8.02(s,1H),7.93(s,1H),7.51(s,1H),4.43-4.37(m,1H),3.98-3.95(m,2H),3.89(s,3H),3.44-3.39(m,2H),3.34(s,3H),2.56-2.48(m,2H),2.25(s,3H),1.68-1.65(m,2H)。

Biological evaluation

The present disclosure is explained in further detail below in connection with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1

DNA-PK enzymology experiment method

1. Purpose of experiment

Detection of the level of phosphorylated P53 by HTRF method, inhibition of DNA-PK enzyme Activity by reactive Compounds, IC based on the inhibition effect ₅₀ The compounds were evaluated for in vitro activity.

2. Experimental method

Substrate P53 (Eurofins, cat# 14-952-M) was diluted with reaction buffer [25mM HEPES (Gibco, cat# 15630-080), pH8.0,0.01% Brij-35 (Thermo, cat# 20150), 1% glycerol (Bio, cat# A100854-0100) ] to 500nM; the DNA-PK enzyme (Eurofins, cat# 14-950M) was diluted to 0.16nM with dilution buffer [25mM HEPES pH8.0,0.01%Brij-35,1% glycerol, 5mM DTT (Bio, cat# B645939), 1mg/mL BSA (Biyun Tian, cat# ST 023) ]; magnesium acetate (Sigma, cat# 63052) was diluted with dilution buffer to 40mM and ATP (Thermo, cat# PV 3227) was diluted to 29.2. Mu.M. The formulated compound 10. Mu. L, DNA-PKase 2.5. Mu.L, 500nM P53 substrate 2.5. Mu. L, ATP 5. Mu.L was added sequentially to 384 well plates (Thermo, cat. No. 267462) using a liquid workstation (PV 3227, cat. No. SP 2-096-0125-03). Incubation was carried out for 1 hour at 25℃after mixing.

A stop solution [12.5mM HEPES pH8.0, 0.005% Brij-35, 0.5% glycerol, 250mM EDTA (Thermo, cat# AM 9260G) ] and a detection mixture [50mM HEPES pH7.0,150mM NaCl (Bio# B548121), 267mM KF (Guozhi., 7789-23-3), 0.1% sodium cholate (Sigma, cat# C6445), 0.01% Tween 20 (Sigma, cat# P7949), 0.0125% sodium azide (Sigma, cat# S8032), anti-phosphorylate-P53 Eu (Cisbio, cat# 61P08 KAE) 0.42 ng/well and anti-GST-d 2 (Cisbio, 61 GSTDLF) 25/well ] were sequentially added to 384 well plates using a liquid station and incubated overnight at 25 ℃. Values of absorption at 665nm and 620nm were read using a microplate reader (BMG, PHERAstar FS). Analytical processing of the data using Graphpad Prism 6 is shown in table 1.

TABLE 1 IC of the inhibitory Activity of the compounds of the present disclosure against DNA-PK enzymes ₅₀ Value of

Examples numbering	IC ₅₀ (nM)
1	0.13
2	1.85

3	0.46
4	0.36
5	0.36
6	0.26
8	0.17
9	0.37

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on DNA-PK enzymes.

Test example 2

DNA-PK cell proliferation inhibition assay

1. Purpose of experiment

By detecting intracellular ATP level responsive cell activity, the killing effect of the compound on non-small cell lung cancer cell line A549 is studied, and IC based on the killing effect ₅₀ Size the compounds were evaluated for in vitro activity.

2. Experimental method

A549 cells (ATCC, CCL-185) were digested with pancreatin (Gibico, 25200-072) at 37℃for 3 minutes, with complete medium [ F-12K medium (Gibico, 21127030), 10% FBS (ThermoFisher Scientific, 10099-141)]Resuspension counting, adding 1000 cells per well into 96 well plate (Corning, 3903), adding CO ₂ Constant temperature incubator (Therm)o Fisher, HERAcell 240 i) cultured overnight at 37 ℃.

The compound was formulated using a Bravo liquid station (Agilent Technologies, SGS120TH 34702) and diluted with complete medium for use. The cell culture plate was removed, 10. Mu.L of the culture solution was aspirated, 5. Mu.L of the diluted compound was added, and CO was returned ₂ Culturing in a constant temperature incubator for 1 hour; bleomycin (selectk, S1214) was diluted to 20 μm using complete medium and 5 μl (500 nM final concentration) was added to each well in the plate. Put the culture plate back to CO ₂ The incubator continues to cultivate. After 6 days, the plates were removed, 50. Mu.L CellTiter-Glo (Promega, G7573) was added to each well and incubated at 25℃for 5 minutes in the absence of light. The luminescence values were measured using a microplate reader (PerkinElmer, vector 3), and the data were analyzed using Graphpad Prism 6, with the results shown in table 2.

TABLE 2 IC of the inhibitory Activity of the compounds of the present disclosure on DNA-PK cell proliferation ₅₀ Value of

Examples numbering	IC ₅₀ (nM)
1	105
3	143
4	122
6	51
8	70
9	37

Conclusion: the compound has good inhibition effect on DNA-PK cell proliferation.

Test example 3

TTK enzymatic experiment

1. Purpose of experiment

Detecting ATP level change by Lantha Screen method, and inhibiting TTK enzyme activity by reaction compound according to IC of inhibiting effect ₅₀ The selectivity of the compounds was evaluated.

2. Experimental method

With reaction buffer [50mM HEPES (Gibco, # 11344-041) pH7.5, 10mM MgCl ₂ (Sigma，#M2670)、2mM DTT(Sigma，#D0632)、0.01％Triton X-100(Sigma，#T9284)]TTK enzyme (Invitrogen, #PR 7264B), substrate fluorescein-Poly GAT (Invitrogen, #PV3611) and ATP (ADP-Glo Kinase Assay Kit, promega, #V 9102) were diluted separately. 100nL of the prepared compound, and 5. Mu.L of TTK enzyme, substrate and ATP were sequentially added to a 96-well plate (Corning, # 3365). Incubation was carried out for 30 minutes at 28℃after mixing. Adding 10 mu L detection buffer solution into each wellTb-PY20 antibody kit, invitrogen, #PV3552), was incubated for 1 hour at 28℃after homogenization. The value of luminescence was read using Envision (PE). The data were analyzed using Graphpad Prism and the results are shown in table 3.

TABLE 3 IC of inhibitory Activity of the compounds of the present disclosure against TTK enzymes ₅₀ Value of

Examples numbering	IC ₅₀ (nM)
1	7584
6	2776
9	1852

Conclusion: the compound disclosed by the disclosure has weak inhibition effect on TTK enzyme and good selective inhibition effect on DNA-PK enzyme.

Test example 4

Pharmacokinetic evaluation

1. C57 mouse test

1. Summary

The drug concentration in plasma at various times after administration of the compound of example 9 and positive control 1 was determined by LC/MS method using C57 mice as the test animals, C57 mice were perfused (i.g.) i.v.). Pharmacokinetic behavior of the compounds of the present disclosure in C57 mice was studied and their pharmacokinetic profile was assessed.

2. Test protocol

2.1 test drug

Compound of example 9 and positive control example 1. Positive control 1 (see compound of example 3 of WO2018114999 A1) has the following structure:

2.2 test animals

C57 mice, 36 females, were equally divided into 4 groups and purchased from velariwa laboratory animal ltd.

2.3 pharmaceutical formulation

A certain amount of the compound of example 9 and positive control 1 was weighed, and 5% by volume of DMSO+5% by volume of Tween 80+90% by volume of physiological saline was added to dissolve the compound and the positive control 1, thereby preparing a clear solution of 0.1 mg/mL.

2.4 administration of drugs

Gastric lavage administration group: the dosage is 2.0mg/kg, and the dosage volume is 0.2mL/10g.

Intravenous administration group: the administration dosage is 1.0mg/kg, and the administration volume is 0.1mL/10g.

3. Operation of

Gastric lavage administration group: blood is collected for 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours to 0.1mL after administration, and the blood is placed in an EDTA-K2 anticoagulation test tube and centrifuged at 10000rpm for 5 minutes (4 ℃) to separate plasma within 1 hour, and the blood is preserved at-80 ℃. The blood collection to centrifugation process was operated under ice bath conditions.

Intravenous administration group: the same gastric lavage group was treated by taking 0.1mL blood at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, 24 hours after administration.

Determination of the content of test compounds in the plasma of mice following administration of different concentrations of drug: 25. Mu.L of mouse plasma samples at each time after administration was taken, 200. Mu.L of acetonitrile and 50. Mu.L of camptothecin (100 ng/mL) as an internal standard solution were added, vortexed and mixed for 5 minutes, centrifuged for 10 minutes (4000 rpm), and 0.1. Mu.L of the supernatant of the plasma samples was taken for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 4 pharmacokinetic parameters for the compounds of the present disclosure are as follows:

conclusion: the compound disclosed by the disclosure has good drug absorption activity in a C57 mouse body, high oral bioavailability and pharmacokinetic advantage.

2. Beagle (Beagle) dog test

1. Summary

The drug concentration in plasma was determined using LC/MS method in beagle dogs as the test animals at different times after the administration of the compound of example 9 and positive control 1 by gastric lavage (i.g.) i.v.). Pharmacokinetic behavior of the compounds of the present disclosure in beagle dogs was studied and their pharmacokinetic profile was assessed.

2. Test protocol

2.1 test drug

Compound of example 9 and positive control example 1.

2.2 test animals

The number of beagle dogs is 16, the male and female dogs are divided into 4 groups on average, and the beagle dogs are respectively injected into the stomach and are administrated by intravenous injection after fasted for one night.

2.3 pharmaceutical formulation

An amount of the compound of example 9 and positive control 1 was weighed, and 5% by volume DMSO+20% by volume PG+20% by volume PEG400+55% by volume physiological saline was added to prepare a clear solution of 0.4mg/mL (gavage administration group) and a clear solution of 0.25mg/mL (intravenous administration group).

2.4 administration of drugs

Gastric lavage administration group: the administration dose was 2.0mg/kg, and the administration volume was 5.0mL/kg.

Intravenous administration group: the administration dosage is 0.5mg/kg, and the administration volume is 2.0mL/kg.

3. Operation of

Gastric lavage administration group: blood is collected from the jugular vein or the forelimb vein for 1.0mL at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24.0 hours before and after the administration, and the blood is placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000rpm for 5 minutes (4 ℃), and plasma is separated in 1 hour, and the blood is stored at-80 ℃ for testing. The blood collection to centrifugation process was operated under ice bath conditions. The animals were fed 3 hours after administration.

Intravenous administration group: blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0 and 24 hours before and 5 minutes after administration, and the same-gavage administration group was treated.

Determination of the content of test compounds in beagle plasma after drug administration at different concentrations: after administration, 20. Mu.L of beagle plasma samples at each time were taken, 400. Mu.L of methanol (containing 100ng/mL of an internal standard solution) was added to precipitate proteins, the mixture was vortexed for 1 minute, and the mixture was centrifuged at 18000g for 7 minutes, and 1. Mu.L of the supernatant was obtained from the plasma samples for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 5 pharmacokinetic parameters for the compounds of the present disclosure are as follows:

conclusion: the compound disclosed by the disclosure has good drug absorption activity in beagle dogs, high oral bioavailability and pharmacokinetic advantage.

Claims

A compound of the general formula (IG) or a pharmaceutically acceptable salt thereof:

wherein:

G ¹ 、G ² and G ³ Identical or different and are each independently CR ² Or a nitrogen atom;

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring B is cycloalkyl or heterocyclyl;

R ¹ the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ² the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ³ selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and heterocyclyl groups, wherein each of said alkyl groups, haloalkyl groups, cycloalkyl groups, and heterocyclyl groups is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, oxo groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ⁴ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

p is 0, 1, 2, 3, 4 or 5; and is also provided with

q is 0, 1, 2, 3, 4 or 5.
The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof according to claim 1, wherein G ¹ Is CR (CR) ² Or a nitrogen atom; g ² And G ³ Identical or different and are each independently CR ² ；R ² As defined in claim 1.
The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (I):

wherein:

n is 0, 1, 2 or 3;

ring a, ring B, R ¹ To R ⁴ P and q are as defined in claim 1.
A compound of the general formula (IG) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-to 6-membered heteroaryl or a 3-to 6-membered heterocyclyl; preferably a 5 membered heteroaryl or a 5 to 6 membered heterocyclyl.
A compound of the general formula (IG) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3 to 14 membered heterocyclyl; preferably 3 to 6 membered heterocyclyl; more preferably a 6 membered heterocyclyl; even more preferably tetrahydropyranyl.
The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ³ Is C _1-6 Alkyl or 3 to 6 membered cycloalkyl; preferably, R ³ Is methyl or cyclopropyl.
The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and oxo.
The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ² Identical or different and are each independently selected from the group consisting of hydrogen, halogen, cyano and C _1-6 An alkyl group; preferably, R ² Is a hydrogen atom.
The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ⁴ Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group.
A compound of general formula (IG) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.
The compound represented by the general formula (IG) according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:
a process for producing a compound represented by the general formula (IG) according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises:

Coupling the compound of formula (IA) or a salt thereof with the compound of formula (IGB) or a salt thereof to obtain the compound of formula (IG) or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

ring a, ring B, G ¹ 、G ² 、G ³ 、R ¹ 、R ³ 、R ⁴ P and q are as defined in claim 1.
A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, which comprises:

coupling the compound of formula (IA) or a salt thereof with the compound of formula (IB) or a salt thereof to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably a chlorine atom;

ring a, ring B, R ¹ To R ⁴ N, p and q are as defined in claim 3.
A pharmaceutical composition comprising a compound of general formula (IG) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of a compound of general formula (IG) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for inhibiting DNA-PK.
Use of a compound of general formula (IG) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysplastic neuroepithelial tumor, glioblastoma multiforme, hybrid glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulval cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumor (GIST), and pediatric cancer; wherein said sarcoma is preferably selected from the group consisting of chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma and kaposi's sarcoma; wherein the lung cancer is preferably non-small cell lung cancer.