Substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8h-purin-8-one compounds and their use in treating cancer

Abstract

The invention discloses a substituted 2-amino-9-(3, 3-difluoropiperidine-4-yl)-7, 9-dihydro-8H-purine-8-ketone compound with a structural formula as shown in formula (I): (I) The substituted 2-amino-9-(3, 3-difluoropiperidine-4-yl)-7, 9-dihydro-8H-purine-8-ketone compound disclosed by the invention as well as a derivative and pharmaceutically acceptable salt thereof, and a preparation method of the substituted 2-amino-9-(3, 3-difluoropiperidine-4-yl)-7, 9-dihydro-8H-purine-8-ketone compound. The compound can be used as a protein kinase inhibitor drug to play a role, especially can inhibit protein expression induced by DNA-PK, and can be used for treating or preventing diseases related to abnormal protein kinase activity. The compound can be used for treating cancer, such as cancer, cancer accompanied with brain metastasis, cancer accompanied with meningeal metastasis, glioma, glioblastoma, diffuse endogenous bridge glioma (DIPG) and the like, and can be independently applied or combined with other treatment modes (such as radiation therapy or chemotherapy).

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202380100684.X (22) Application Date 2023.07.21 (85) PCT International Application Entering National Phase Date 2026.01.22 (86) PCT International Application Application Data PCT / US2023 / 070713 2023.07.21 (87) PCT International Application Publication Data WO2025 / 023957 EN 2025.01.30 (71) Applicant Zhong Wei Address 957 Formdale Avenue, Corona, California, USA (72) Inventor Zhong Wei (74) Patent Agency Beijing Junhui Intellectual Property Agency (General Partnership) 11716 Patent Attorney Xing Wei (51) Int.Cl. C07D 487 / 06(2006.01) A61K 31 / 4188(2006.01) A61P 35 / 00(2006.01) (54) Invention Title Substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one Compounds and Their Use in Cancer Treatment (57) Abstract This invention discloses substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one compounds with the structural formula shown in Formula (I): (I) The substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one compounds of the present invention, their derivatives and pharmaceutically acceptable salts thereof, are capable of functioning as a class of protein kinase inhibitors, particularly inhibiting DNA-dependent protein kinases (DNA-PK). Induced protein expression, and can be used to treat or prevent diseases associated with abnormal protein kinase activity, such as cancer, cancer with brain metastases, cancer with meningeal metastases, glioma, glioblastoma, diffuse endophytic pontine glioma (DIPG), etc., can be administered alone or in combination with other treatments (such as radiotherapy or chemotherapy). Claims 2 pages, Description 48 pages, Drawings 10 pages CN 121794270 A 2026.04.03 CN 1 21 79 42 70 A 1. A compound comprising the structure shown in formula (I), wherein (I) R1 is independently selected from hydrogen, methyl, ethyl, isopropyl, deuterated methyl or oxetane; R2 is independently selected from methyl or deuterated methyl; R3 is independently selected from fluoride, methyl or OCH3; X is independently selected from CH or nitrogen. 2. A pharmaceutical composition comprising the compound according to claim 1, or a salt thereof, a solvate thereof, or a hydrate thereof.3. A DNA-PK inhibitor, characterized in that the active ingredient of the inhibitor is the compound according to claim 1; the inhibitor is capable of crossing the blood-brain barrier. 4. Use of the compound according to claim 1, or the pharmaceutical composition according to claim 2, or the inhibitor according to claim 3, in the preparation of a medicament for treating or preventing diseases related to DNA-PK activation induced by DNA-PK protein. 5. The use according to claim 4, characterized in that the protein is a DNA-dependent protein kinase. 6. The use according to claim 4, characterized in that the disease is a metastatic cancer of the central nervous system, brain cancer, proliferative disease, or cancer, wherein the compound of formula (I) is administered simultaneously, separately, or sequentially with radiotherapy. 7. The use according to claim 4, for the treatment of the cancer of claim 6, wherein the compound of formula (I) is administered simultaneously, separately, or sequentially with at least one other antitumor drug that may cause DNA double-strand breaks, said antitumor drug being selected from: cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amiroboracin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, rucapab, niraparib, taprazolepanib, pamipanib, pembrolizumab, nivolumab, cimipril, spartalizumab, sintilimab, tislelizumab, dostalimab, atezolizumab, avelumab, durvalumab, osimertinib, and WSD0922. 8. The use according to claim 6, characterized in that the disease is glioblastoma, diffuse endophytic pontine glioma, astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma, vestibular schwannoma, and medulloblastoma. 9. A method for treating cancer in a warm-blooded animal requiring such treatment, comprising administering to the warm-blooded animal a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, simultaneously, separately, or sequentially with other treatment modalities. Claims 2 / 2 Page 3 CN 121794270 A Substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one compounds and their use in cancer treatment Technical Field

[0001] This invention relates to novel 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one derivativesCompounds, their salts, hydrates, and polymorphs. In particular, the present invention relates to a substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one compound that selectively modulates DNA-dependent protein kinases (DNA-PK). This specification also relates to the use of such compounds and their salts in the treatment or prevention of DNA-PK kinase-mediated diseases, including cancer, particularly in the treatment of cancer, brain cancer, and metastatic cancers of the central nervous system via the non-homologous end joining (NHEJ) pathway, in combination with radiotherapy or an inducing DNA double-strand break agent. Background Art

[0002] DNA-dependent protein kinases (DNA-PK) consist of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and a Ku protein heterodimer (Ku70 / Ku80). DNA-PK is essential for the NHEJ pathway of DNA double-strand break (DSB) repair. NHEJ repairs damage by rejoining broken DNA ends. This mechanism is error-prone and active throughout the cell cycle, preferentially functioning in the early G1 / S phase. Simultaneously, DNA-PK is also essential for V(D)J recombination, which utilizes NHEJ to promote immune system diversity. DNA-PK also participates in other cellular processes, including telomere maintenance, transcriptional regulation, and replication stress response (Davis et al., 2014).

[0003] DNA double-strand breaks are one of the most serious types of DNA damage. If DSBs are not repaired or are incorrectly repaired, they can lead to cell death, senescence, or chromosomal aberrations, potentially resulting in genomic instability and cell carcinogenesis. DSBs can be induced by endogenous factors, such as reactive oxygen species or replication errors generated during cellular metabolism, or by exogenous factors, including ionizing radiation and chemotherapeutic agents. Unlike homologous recombination (HR) repair (the second major repair pathway for DNA breaks, which repairs DNA damage using undamaged sister chromatids as templates; this mechanism is less efficient but ensures error-free repair), NHEJ, as the primary mechanism, repairs DNA damage without the need for a homologous template. The basic mechanisms of NHEJ include DNA end recognition, assembly and stabilization of the NHEJ complex at DNA double-strand break sites, bridging and promoting end stability, DNA end processing, break-end ligation, and dissociation of the NHEJ complex. Autophosphorylation of DNA-PKcs plays a crucial role in the NHEJ repair pathway, regulating DNA end processing, enzyme inactivation, and complex dissociation by inducing conformational changes. The two autophosphorylation sites of DNA-PK, Ser2056 and Thr2609, have been well characterized. DNA-PKcs can phosphorylate a variety of substrates. In the NHEJ pathway, substrates phosphorylated by DNA-PKcs include...Artemis, Ku70, Ku80, histone variant H2AX, and DNA ligase IV (Mohiuddin et al., 2019).

[0004] DNA-PK is considered an attractive therapeutic target for the treatment of various cancers, especially in the context of DNA-PK inhibitors combined with genotoxic chemotherapy or ionizing radiation (Medová et al., 2020). In addition, DNA-PK inhibitors may be effective as monotherapy against ATM-deficient lymphoma (Riabinska et al., 2013). Studies have reported that the DNA-PK inhibitor NU7026 can enhance the efficacy of topoisomerase II inhibitors in the treatment of leukemia by inhibiting NHEJ and G2 / M phase checkpoint blockade (Willmore et al., 2004). In addition, in preclinical studies, NU7441 showed significant chemosensitizing and radiosensitizing effects when used in combination with etoposide, doxorubicin, or ionizing radiation (Zhao et al., 2006). Studies have shown that AZD7648 can enhance the therapeutic effects of radiotherapy or doxorubicin in xenograft and patient-derived xenograft (PDX) models (Fok et al., 2019). M3814 significantly improved sensitivity to ionizing radiation (IR) and DSB inducers in various cancer cell lines by inhibiting the catalytic activity of DNA-PK (Zenke et al., 2020). However, current DNA-PK inhibitors are generally limited by poor pharmacokinetic characteristics; these compounds have poor solubility, are metabolically unstable in vivo, resulting in short serum half-lives and difficulty in maintaining adequate target coverage.

[0005] Glioblastoma or glioblastoma multiforme (GBM) is an advanced malignant WHO grade IV brain tumor. Due to the presence of the blood-brain barrier (BBB), there are currently no approved targeted therapies capable of achieving effective doses in the brain for the treatment of GBM or DIPG patients. Radiation therapy and surgery combined with temozolomide remain the primary treatment options, but with limited efficacy. Especially for patients with DIPG, radiation therapy is the only treatment option, and relapse occurs within 5.5 months (Hamer et al., 2010). GBM is a global brain disease; all GBMs have clinically significant tumor regions and a complete blood-brain barrier (BBB). Failure to provide effective treatment to all tumor regions of GBM leads to treatment failure and inevitable relapse (Sarkaria et al., 2018). The role of DNA-PK in radiosensitivity, and the potential use of DNA-PK inhibitors that can cross the blood-brain barrier as radiosensitizers, may be very useful for treating brain cancer or metastatic cancers of the central nervous system, especially for indications where radiation therapy is the only treatment option, such as DIPG.

[0006] Therefore, there is an urgent need for DNA-PK inhibitors that are highly efficient, selective, and have good pharmacokinetic characteristics. Furthermore, blood-brain barrier-penetrating therapy is the preferred treatment for cancer and metastatic cancers of the central nervous system. Summary of the Invention

[0007] In view of the importance of radiation resistance in the aforementioned cancers, particularly brain cancers, especially glioblastoma, DIPG, and metastatic cancers of the central nervous system, DNA-PK inhibitors capable of reaching effective doses for the treatment or prevention of cancer are particularly important. The object of this invention is to provide substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one compounds having the pharmaceutical properties required for DNA-PK protein kinase inhibitors, and their uses.

[0008] This invention also provides compounds with favorable physical and chemical properties (e.g., high permeability and low efflux rate), and / or favorable toxicity characteristics (e.g., reduced hERG activity and lower risk of drug interactions), and / or other more favorable metabolic profiles (non-aldehyde oxidase substrates). Therefore, when such compounds are administered in combination with radiotherapy or other DNA double-strand breakers, effective doses can be achieved for the treatment and / or prevention of cancer, metastatic cancer of the central nervous system, and cancer.

[0009] The object of the present invention is achieved by the following technical solution: The present invention relates to a compound comprising the structures of formulas (I), (II), and (III), said compound being: Specification 2 / 48 pages 5 CN 121794270 A

[0010] (I)

[0011] (II) Specification 3 / 48 pages 6 CN 121794270 A

[0012] (III) wherein R1 is independently selected from hydrogen, methyl, ethyl, isopropyl, deuterated methyl, or oxetane; R2 is independently selected from methyl or deuterated methyl; R3 is independently selected from fluoride, methyl, or OCH3; X is independently selected from CH or nitrogen.

[0013] The present invention also relates to a pharmaceutical composition comprising the aforementioned compound, or a salt thereof, a solvate thereof, a hydrate thereof, or a polymorph thereof, and a pharmaceutically acceptable excipient or adjuvant thereof.

[0014] The present invention also relates to a DNA-PK inhibitor, wherein the inhibitor is an active ingredient of the aforementioned compound; the inhibitor is capable of crossing the blood-brain barrier.

[0015] The present invention also relates to the use of the aforementioned compound, the aforementioned pharmaceutical composition, or the aforementioned inhibitor in the preparation of a medicament for treating or preventing diseases mediated by DNA-PK kinases.

[0016] Preferably, the protein is an activated DNA-PK kinase.

[0017] Preferably, the disease is a metastatic cancer of the central nervous system, a proliferative disease, brain cancer, a central nervous system disease, or cancer.

[0018] Preferred metastatic cancers of the central nervous system include cancers with brain metastases, cancers with meningeal metastases,Gliomas, diffuse pontine gliomas (DIPG), and glioblastomas.

[0019] Preferred diseases include brain cancer, lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, membranous adenocarcinoma, kidney cancer, lymphoma, ovarian cancer, gastric cancer, skin cancer, bone cancer, gliomas, neuroblastomas, hepatocellular carcinoma, papillary renal cell carcinoma, or head and neck squamous cell carcinoma.

[0020] Preferably, the disease is non-small cell lung cancer (NSCLC).

[0021] Preferably, the disease is non-small cell lung cancer (NSCLC) with brain metastases.

[0022] Preferably, the disease is non-small cell lung cancer (NSCLC) with meningeal metastases.

[0023] Preferably, the disease is a glioma. Specification 4 / 48 pages 7 CN 121794270 A

[0024] Preferably, the disease is a glioblastoma.

[0025] Preferably, the disease is diffuse endophytic pontine glioma (DIPG).

[0026] Preferably, the disease is lymphoma.

[0027] On the other hand, the present invention relates to a method for treating a disease or disease symptom in a subject in need, the method comprising administering to the subject an effective amount of any of the general formula compounds of the present invention, or a pharmaceutically acceptable salt, solvate, or hydrate thereof (or a combination thereof). The disease or disease symptom may be any disease regulated by DNA-PK protein kinase in a DNA damage response pathway, particularly including diseases associated with abnormal DNA double-strand break repair caused by radiation or other factors. These diseases or disease symptom may be, for example, cancer or proliferative diseases or conditions (e.g., including the related diseases described in the present invention).

[0028] Compared with the prior art, the present invention has the following beneficial effects: 1) The 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one derivative and its pharmaceutically acceptable salt of the present invention can penetrate the blood-brain barrier and have the pharmaceutical properties of protein kinase inhibitors. They are particularly suitable for acting on proteins expressed via DNA-PK and can be used to treat or prevent diseases related to abnormal protein kinase activity, such as cancer, cancer with brain metastases, cancer with meningeal metastases, glioma, glioblastoma, and diffuse endophytic pontine glioma (DIPG).

[0029] 2) The 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one derivative and its pharmaceutically acceptable salt of the present invention have a low efflux rate, which can reduce efflux enzyme-mediated drug resistance.

[0030] 3) The 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one derivatives and their pharmaceutically acceptable salts of the present invention have good pharmacokinetic characteristics (non-aldehyde oxidase substrates) and, relative to other PIKK, such asATR and ATM have high biological activity and selectivity, which can minimize potential targeting toxicity, reduce the burden of medication for patients, and improve patient medication compliance.

[0031] 4) The 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purine-8-one derivatives and their pharmaceutically acceptable salts of the present invention have a low risk of inhibiting hERG and other ion channels and have high safety; in addition, they have good compatibility when used in combination with other drugs, and the potential drug interaction risk and time-dependent inhibition risk are both low.

[0032] The accompanying drawings show the chemical structures of the following compounds: (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (1); (R / S)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (2); (R / S)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (2); (3)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one; (R / S)-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one; (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro- 8H-purine-8-one (5); (R / S)-9-(3,3-difluoro-1-(oxacyclobutane-3-yl)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (6); (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (7); (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-methoxy) 121794270 A-based-[1,2,4]triazolo[1][5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (8); (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidozop[1,2-a]pyridin-6-yl)amino)-7-methyl- 7,9-Dihydro-8H-purine-8-one (9); (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (10); (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (11); (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (12) (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one; (13) (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one; (14)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one; (15) Triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one; (R)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one; (R)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one; (R)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one; (methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (18); (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (19); (R)-9-(3,3-difluoro-1-(oxecyclobutane-3-yl)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (20); (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (21); (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (22); (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (23); (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9- Dihydro-8H-purine-8-one (24); (R)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (25); (R)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2,4]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (26); (R)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo ... (27) (R)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazolo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one; (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one; 8-Ketone (29); (S)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,[5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (30); (S)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine- 8-one (31); (S)-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (32); (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (33); (S)-9-(3,3-difluoro-1-(oxecyclobutane-3-yl)piperidin-4-yl)-7-methyl-2-((7- Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (34); (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (35); (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one 2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (36); (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (37); (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,4-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (37); (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,4-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one 2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (38); (S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (39); (S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one(40); (S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (41); (S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazolo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (42) Figure 2 shows the chemical synthesis reaction formula for 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine A. Figure 3 shows the chemical synthesis reaction formula for 7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-6-amine B. Figure 4 shows the chemical synthesis reaction formula for 7-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-amine C. Figure 5 shows the chemical synthesis reaction formula for 7-fluoroimidazo[1,2-a]pyridine-6-amine D. Figure 6 shows the chemical synthesis reaction formula for 7-methylimidazo[1,2-a]pyridine-6-amine E. Figure 7 shows the compound: tert-butyl4-(2-chloro-7-(methyl-d3)-8-oxo-7,8-dihydro-9H-purine-9-yl)- 3,3-Difluoropiperidine-1-carboxylic acid ester F4', tert-butyl-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)- The chemical synthesis reaction formulas of 3,3-difluoropiperidin-1-carboxylic acid ester F4, 2-chloro-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one F6' and 2-chloro-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one F6 are shown in Figure 8, which is a general method for the chiral resolution of racemic products 1-14. Figure 9 shows a typical example of chiral resolution of racemic mixtures using a general method. Figure 10 shows (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (1). Figure 11 shows the chemical synthesis reaction formula for (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (11). Figure 12 shows the chemical synthesis reaction formula for (R / S)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (2).Figure 13 shows the chemical synthesis reaction formula for (R / S)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (3). Figure 14 shows the chemical synthesis reaction formula for (R / S)-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (4). The chemical synthesis reaction diagram in Figure 15 is (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (5). The chemical synthesis reaction diagram in Figure 16 is (R / S)-9-(3,3-difluoro-1-(oxecyclobutane-3-yl)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (6). The chemical synthesis reaction formulas for (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (7) are shown in Figure 17 and 18 respectively. Figure 19 shows the chemical synthesis reaction formula for (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (9). Figure 20 shows the chemical synthesis reaction formula for (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (10). Figure 21 shows the chemical synthesis reaction formula for (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (10). Chemical synthesis reaction formula of 6-yl)amino)-7,9-dihydro-8H-purine-8-one (12)Figure 22 shows the chemical synthesis reaction formula of (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (13). Figure 23 shows the chemical synthesis reaction formula of (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazolo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (14). Specific embodiments of the present invention are explained as follows: The terms “improvement” and “treatment” are used interchangeably, and are used to indicate, in addition to (but not limited to) therapeutic benefits and / or preventive benefits, also to indicate the reduction, inhibition, prevention or stabilization of a disease (e.g., the disease or condition described herein).

[0033] “Disease” means any condition or symptom that impairs / interferes with the normal function of cells, organs, or tissues.

[0034] “Marker” means any alteration associated with a disease or symptom. For example, any disease or symptom that causes an alteration in the expression level or activity of a protein / polynucleotide.

[0035] Terms such as “comprising,” “containing,” and “having” as used herein have the meanings conferred by patent law; “substantially comprising” or “substantially” have the same meanings conferred by patent law, and the term is open to the presence of things other than those referenced, provided that the essential or novel features of the referenced thing are not altered by the presence of things other than those referenced, but does not include implementations of the prior art.

[0036] As used herein, the terms “antagonist” and “inhibitor” are used interchangeably to refer to a compound or drug that can inhibit the biological function of a target protein or peptide by means of, for example, inhibiting the activity or expression of a protein or peptide. Although some of the antagonists described herein interact with specific target proteins or peptides (e.g., by binding to DNA-PK), these compounds also inhibit the biological activity of target proteins or peptides by interacting with other members of the signal transduction pathways of the target proteins or peptides, including members that inhibit tumor development, growth, or spread within the defined scope, or members associated with unwanted immune responses exhibited in autoimmune diseases.

[0037] As used herein, the terms “anticancer agent,” “antitumor agent,” or “chemotherapy agent” mean any medicine that can be used to treat a cancerous disease. One class of anticancer agents includes chemotherapy agents. “Chemotherapy” means one or more chemotherapy agents and / or other agents administered in various ways, including intravenously, orally, subcutaneously, intramuscularly, intraperitoneally, intravesically, percutaneously, buccally, or by inhalation.

[0038] As used herein, the term “cell proliferation” refers to an increase in the number of cells (e.g., an increase in size) due to cell division, which is consistent with proliferative signals in cell morphology.

[0039] As used herein, the term “co-administration” means the simultaneous administration of two or more drugs, and the simultaneous administration of a combination of two or more pharmaceutical agents, and the administration at different times or alone of two or more drugs and / or their metabolites.

[0040] As used herein, the term “effective amount” or “effective therapeutic amount” means an amount of a compound or pharmaceutical composition described herein sufficient to achieve its intended use (including, but not limited to, the treatment of a disease). In one embodiment, the assay found that the amount was effective in killing or inhibiting the growth or spread of cancer cells, the size or number of tumors, or the severity, stage, and progression of cancer. The effective therapeutic amount may vary depending on the intended application, such as in vitro or in vivo, the symptoms and severity of the disease, the age of the subject, weight, or route of administration. The term also applies to doses that induce target cells to reduce cell migration through, for example, a specific response. The specific dose depends on, for example, the specific compound selected, the species of the subject and their age / existing health condition or health status, the route of administration, the severity of the disease, combination with other pharmaceutical agents, the time of administration, the tissue of administration, and the device of administration.

[0041] As used herein, the term “therapeutic effect” includes therapeutic benefit and / or preventive benefit. Preventive effect includes delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping, or reversing a disease or symptom, or any combination thereof.

[0042] As used herein, the term “signal transduction” is the process of sending stimulatory or inhibitory signals to cells to initiate an intracellular response. A “regulator” of a signal transduction pathway refers to a compound that modulates one or more activities of cellular proteins mediated by a specific signal transduction pathway. A “regulator” can increase (agonist) or inhibit (antagonist) the activity of signal transduction molecules.

[0043] As used herein, the term “selective inhibition” refers to the ability of the compound to selectively reduce the activity of a target signal relative to off-target target activity, through direct or indirect interaction. For example, a compound selectively inhibits DNA-PK activity by at least about 2, about 3, about 5, about 10, about 20, about 50, about 100, or more times the activity of ATM kinase.

[0044] As used herein, the term “radiotherapy” means exposure of a subject to a radiation emitter, including but not limited to alpha particles emitting radioactive nuclides (e.g., actinium and thorium radioactive nuclides) (e.g., beta emitters), converted electron emitters (e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation, including but not limited to X-rays, gamma rays, and neutrons.

[0045] As used herein, the term “subject” includes, but is not limited to, humans (e.g., any age group, or any sex (e.g., infants, children, or adolescents), or adult subjects (e.g., young adults, middle-aged, or elderly)) and / or other primates (e.g., children, children, or adolescents)).Examples include cynomolgus monkeys and rhesus monkeys; mammals, including commercially relevant mammals such as cattle, sheep, goats, pigs, horses, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, geese, quails, ducks, and / or turkeys.

[0046] As used herein, the term “in vivo” refers to an activity that occurs in the body of a subject. Events in rodents, such as rats, mice, guinea pigs, etc., are also included in vivo.

[0047] As used herein, the term “in vitro” refers to an event that occurs outside the body. For example, in vitro detection includes any detection that occurs outside the body. In vitro detection includes cell detection based on live or dead cells, as well as cell-free detection for incomplete cells.

[0048] As used herein, the term “compound” is also intended to include salts of the general formula herein. The term also includes any solvates, hydrates, and polymorphs of any of the foregoing substances. In certain aspects of the invention described in this application, specific references to “solvate,” “hydrate,” or “polymorph” should not be made. In other aspects of the invention, the use of the term "compound" without reference to these other forms does not imply that such forms are excluded.

[0049] Salts of the compounds of the present invention are formed between acidic and basic groups (e.g., amino functional groups) of the compounds. According to another preferred embodiment, the compounds are pharmaceutically acceptable acid addition salts.

[0050] As used herein (unless otherwise stated), the term "prodrug" refers to a class of compounds that can undergo hydrolysis, oxidation, or other types of reactions under biological conditions (in vitro or in vivo) to generate the compounds of the present invention. Prodrugs may be active only after the above-described reactions have occurred under biological conditions, or they may be active in their unreacted form. Examples of prodrugs of the present invention include, but are not limited to, analogs or derivatives of compounds of the general formula disclosed herein, and biohydrolyzable groups, such as amide and ester analogs.

[0051] A prodrug salt is a compound formed by an acidic group of an acid and a prodrug (e.g., an amino functional group) or a basic group of a base and a prodrug (e.g., a carboxyl functional group). In one embodiment, the prodrug salt is a pharmaceutically acceptable salt.

[0052] Particularly preferred prodrugs and prodrug salts are those capable of improving the bioavailability of the compounds of the present invention in mammals or humans (e.g., easier absorption by oral administration) or, relative to the parent compound, facilitating the delivery of the compounds of the present invention to specific biological compartments (e.g., the brain or central nervous system). Preferred prodrugs include derivatives obtained by attaching groups capable of improving water solubility or enhancing active transintestinal transport to the general formula structure described herein.

[0053] As used herein, the term "pharmaceutically acceptable" means suitable for contact with human and other mammalian tissues.A pharmaceutical composition that is safe for use without reasonable toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio compared to its components. "Pharmaceutically acceptable salt" means any non-toxic salt that, when administered to a subject, can directly or indirectly provide the compound or prodrug of the present invention.

[0054] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydroiodic acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, citric acid, maleic acid, oxalic acid, picric acid, acetic acid, adipic acid, alginic acid, aspartic acid, sulfuric acid, boric acid, butyric acid, valeric acid, camphoric acid, camphor thiocyanate, digluconic acid, dodecyl sulfate, tervastatinic acid, formic acid, fumaric acid, hydroiodic acid, benzoic acid, 2-hydroxyethanesulfonic acid, fumaric acid, stearic acid, lactobionic acid, propionic acid, lauric acid, oleic acid, nicotinic acid, lactic acid, cinnamic acid, succinic acid, mandelic acid, malic acid, tartaric acid, lactic acid, pyruvic acid, Pectic acid, methanesulfonic acid, dihydroxynaphthyl acid, benzenesulfonic acid, persulfate, palmitic acid, malonic acid, glycerophosphate, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, salicylic acid, ascorbic acid, 3-phenylpropionic acid, gluconic acid, glucuronic acid, phosphoric acid, glutamic acid, ethanesulfonic acid, p-bromobenzenesulfonic acid, and carbonic acid, as well as related inorganic and organic acids.

[0055] As used herein, the term "hydrate" means a compound containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein, the term "solvent" means a compound containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces, such as water, dichloromethane, 2-propanol, acetone, methanol, ethanol, etc. Pharmaceutically acceptable solvates and hydrates may include, for example, complexes of 1 to about 100, 1 to about 10, 1 to about 4, about 3, or about 2 solvent or water molecules. It should be understood that the term "compound" as used herein includes the compound and its solvates, hydrates, and mixtures thereof.

[0056] As used herein, the term "polymorph" refers to the solid crystalline form of a compound or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., thermal, optical, or water content), density, hygroscopicity, solubility, compressibility, and dissolution rate.

[0057] As used herein, the term "isomer" refers to different compounds having the same molecular formula. "Stereoisomer" refers to isomers that differ only in the arrangement of atoms. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include geometric double bond cis and trans isomers, also known as E-isomers and Z-isomers; R-enantiomers and S-enantiomers; diastereomers, (D) isomers and (L) isomers, their racemic mixtures, and other mixtures, all of which are described herein.

[0058] The double bond around the carbon-carbon substituent is designated as “Z” or “E” configuration, wherein the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise stated, the structure describes both the “E” and “Z” isomers.

[0059] Substituents around the carbon-carbon double bond may be referred to as “cis” or “trans”, where “cis” means that the substituent is on the same side of the double bond, and “trans” means that the substituent is on both sides of the double bond. The arrangement of the carbon rings around the substituent may also be designated as “cis” or “trans”. The term “cis” refers to a substituent on the same side of the ring plane, and the term “trans” refers to a substituent on both sides of the ring plane. A mixture of substituents on the same side and opposite sides of the two ring planes is referred to as “cis / trans”.

[0060] As used herein, the term “enantiomer” refers to a pair of non-overlapping, mutually mirror-overlapping stereoisomers. Any mixture of enantiomers in any proportion may be referred to as a “racemic” mixture. The term “(±)” refers to a racemic mixture (where applicable). A “diastereomer” is a mirror image having at least two asymmetric atoms but whose stereoisomers are distinct. Absolute stereochemistry is specified according to the Cahn-Lingold-Prelog R-S system. If the compound is an enantiomer, the stereochemistry of each chiral carbon may be specified as R or S. If the absolute configuration of the compound is unknown, it may be specified as (+) or (-) according to the direction of rotation of its polarized light at the (right or left) wavelength of the sodium D line. Some of the substances described herein contain one or more asymmetric centers, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined in absolute stereochemistry as (R) or (S) for each asymmetric atom. Pharmaceutical compositions and methods include all of these possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optical activity (R) and (S) can also be prepared using chiral synthetic methods or chiral reagents, or using conventional techniques.

[0061] The term "enantiomer excess" as used herein can be calculated using the formula shown below. In the example shown below, the composition contains 90% of one enantiomer, such as the S enantiomer, and 10% of another enantiomer, such as the R enantiomer.

[0062] ee value = (90-10) / 100 = 80%.

[0063] Therefore, a composition containing 90% of one enantiomer and 10% of the other enantiomer is considered to have an 80% enantiomer excess. Some compositions described herein contain at least about 50% of the R enantiomer excess, i.e., about 75%, about 90%, about 95%, or about 99% of the S enantiomer. In other words, the composition contains the S enantiomer relative to the R enantiomer.An enantiomer excess of the enantiomer. In other embodiments, some compositions described herein contain at least about 50% of the R enantiomer in excess, i.e., about 75%, about 90%, about 95%, or about 99% of the R enantiomer. In other words, the composition has an R enantiomer excess relative to the S enantiomer. For example, in some embodiments, the isomer / enantiomer ratio can provide the ee value for the respective enantiomer and may also be referred to as “optical enrichment,” “enantiomer enrichment,” “enantiomer purity,” and “non-racemic,” which are used interchangeably herein. These terms refer to a weight percentage of one enantiomer greater than the amount of the other enantiomer in a control mixture of racemic compositions (e.g., greater than 1:1 by weight). For example, the enantiomer of the S enantiomer accounts for about 75% of the weight of the enantiomer (e.g., greater than about 50% of the compound weight, or at least about 80%). In some embodiments, enrichment greater than about 80% (by weight) provides a substance that is “substantially enantiomer-enriched,” “substantially enantiomer-pure,” or “substantially non-racemic,” meaning that relative to another enantiomer, this enantiomer constitutes at least 85% by weight of the composition, for example, at least about 90% (by weight) of the formulation, or even, for example, about 95% (by weight). In some embodiments, one enantiomer constitutes at least about 90% (by weight) of the compounds provided herein. In other embodiments, one enantiomer constitutes at least about 95%, about 98%, or about 100% (by weight) of the compounds provided herein. In some embodiments, the compound is a racemic mixture of (S) and (R). In other embodiments, a method is provided in which the mixture is present primarily as a single compound (S) or a single compound (R) in the mixture of compounds. For example, the compound mixture has an enantiomer excess of more than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or higher. In other embodiments, the compound mixture has an excess of more than about 55% to about 99.5%, more than about 60% to about 99.5%, more than about 65% to about 99.5%, more than about 70% to about 99.5%, more than about 75% to about 99.5%, more than about 80% to about 99.5%, more than about 85% to about 99.5%, more than about 96% to about 99.5%, more than about 97% to page 11 / 48 of the specification, CN 121794270 A, more than about 98% to more than about 99.5%, more than about 99% to about 99.5% or higher of (S)-enantiomer.In other embodiments, the compound mixture has a purity of (R)-enantiomers greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In other embodiments, the compound mixture has an excess of more than about 55% to about 99.5%, more than about 60% to about 99.5%, more than about 65% to about 99.5%, more than about 70% to about 99.5%, more than about 75% to about 99.5%, more than about 95% to about 99.5%, more than about 85% to about 99.5%, more than about 96% to about 99.5%, more than about 97% to about 99.5%, more than about 98% to more than about 99.5%, more than about 99% to about 99.5%, or more.

[0064] In other embodiments, the compound mixture contains the same chemical entity except for its stereochemical orientation (i.e., (S) or (R)). For example, if a -CH(R)- unit is present in the compound and R is not hydrogen, then -CH(R)- is the same chemical entity regardless of the (S) or (R) stereochemical orientation. In some embodiments, the (S)-isomer is present in excess as the (S)-enantiomer in a mixture of the same chemical entity, in an amount greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 90% to about 99.5%, greater than about 90% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or higher.

[0065] In another embodiment, the amount of (R)-isomer in the same chemical entity (other than its stereochemical orientation) relative to the (S)-isomer is about 55%, about 60%, about 65%, about 90%, about 95%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In some embodiments, the excess of (R)-enantiomers in a mixture of identical chemical entities (except for their stereochemical orientation) is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 75% to about 99.5%, greater than about 75% to about 99.5%, greater than about 75% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or higher.

[0066] Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), formation of chiral salts and crystallization, or non-synthetic synthesis.

[0067] Optical isomers can also be obtained by conventionally resolving racemic mixtures with optically active acids or bases (e.g., by forming diastereomer salts). Examples of suitable acids include, but are not limited to, tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, dimethoxy tartaric acid, and camphor sulfonic acid. Isomers can be isolated from mixtures of optically active bases of these salts by diastereomer crystallization. Alternatively, the disclosed compounds are reacted with an activated form of an optically pure acid or an optically pure isocyanate to synthesize covalent diastereomer molecules. The synthesized enantiomers can be separated by conventional methods (such as chromatography, distillation, crystallization, or sublimation) and then hydrolyzed to obtain enantiomer-enriched compounds. Optically active compounds can also be obtained by using active materials. In some embodiments, these isomers may be in the form of free acids, free bases, esters, or salts.

[0068] In some embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that includes two or more interconvertible compounds resulting from the migration and conversion of at least one form of hydrogen atom and covalent bond (e.g., single bond to double bond, triple bond to single bond, or vice versa). "Tautomerism" includes proton or proton migration tautomerism, which is considered a subset of acid-base chemical formulas. "Proton transfer tautomerism" involves proton migration accompanied by bond changes. The exact proportion of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerism is possible (e.g., in solution) and chemical equilibrium of tautomers can be reached. Tautomerism (i.e., the reaction that provides tautomer pairs) may be catalyzed by acid or base, or may occur with or without external reagents. Such tautomerizations include, but are not limited to, ketones with enols, amides with imides, enamines with imides, and one form of enamine with different forms of enamine. Specific examples of ketone-enol tautomers are pentane-2,4-dione and 4-hydroxypentane-3-en-2-one tautomers. Another example of tautomerism is the tautomerism of phenols and ketones. Specific examples of phenol-ketone tautomers are pyridine-4-phenol and pyridine-4-(1H)-one tautomers.

[0069] Unless otherwise stated, it is intended that the structures described herein include compounds in which only one or more isotopically enriched atoms are present. For example, the compound has a structure in which one of the hydrogen atoms is substituted with deuterium or tritium, or has a structure in which carbon 13 or carbon 14 within the scope of the disclosure is enriched.

[0070] This invention also includes those “isotopically labeled derivatives,” which are pharmaceutically acceptable forms of the compounds described herein, in addition to one or more atoms of different atomic masses commonly found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, and 36Cl. Some isotopically labeled disclosed compounds (e.g., compounds labeled with 3H and 14C) are used to determine the tissue distribution of the compound and / or substrate. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are readily prepared and detected. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H or D) may provide certain therapeutic advantages due to their greater metabolic stability (e.g., increased half-life or reduced dose requirements in vivo). Isotopically labeled disclosed compounds can generally be prepared by replacing the isotopically labeled reagents with non-isotopically labeled reagents. Some embodiments provided herein may also contain one or more non-natural atomic isotopes to form such compounds. All isotopic variants of the disclosed compounds, whether radioactive or not, are used herein within the scope of this disclosure. In some embodiments, radiolabeled compounds may be used to study the metabolism and tissue distribution of compounds to alter metabolic pathways or rates or other biological functions.

[0071] As used herein, the term “stereoisomer” refers to an enantiomer and a diastereomer.

[0072] As used herein, the term “halogen” refers to any group of fluorine, chlorine, bromine, or iodine.

[0073] As used herein, the term “alkyl” refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 10 carbon atoms, preferably containing 1 to 8 carbon atoms. The expression “lower alkyl” refers to an alkyl group containing 1 to 4 (including 1 and 4) carbon atoms.

[0074] The term “arylalkyl” refers to the portion of an alkyl group in which an alkyl hydrogen atom is replaced by an aryl group.

[0075] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 10, preferably 2 to 4, carbon atoms, with at least one carbon-carbon double bond. When an alkenyl group is attached to a nitrogen atom, it is preferred that the group is not directly attached to a carbon atom with a double bond.

[0076] The term "alkoxy" refers to an -O-alkyl group containing 1 to 10 carbon atoms, having a straight-chain, branched, saturated cyclic structure, or a combination thereof, which is attached to the parent molecule structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopropoxy, cyclobutoxy, and cyclohexyloxy. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms.

[0077] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 10 (i.e., C2-10 alkynyl) carbon atoms, preferably 2 to 4, with at least one carbon-carbon triple bond. When an alkynyl group is attached to a nitrogen atom, it is preferred that the group is not directly attached to a carbon atom with a triple bond.

[0078] The term "alkylene" refers to a divalent straight-chain bridge (e.g., -(CH2)X-, where X is 1 to 5) with 1 to 3 lower alkyl groups connected by single bonds, which may be substituted with 1 to 3 lower alkyl groups.

[0079] The term "alkynylene" refers to a straight-chain bridge containing carbon-carbon triple bonds with 2 to 5 carbon atoms connected by single bonds, and which may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylenes include -C≡C-, -CH2-C≡C-, -CH(CH3)C≡C-, and -C≡C-CH(C2H5)CH2-.

[0080] As used herein, the terms "cycloalkyl" and "cycloalkenyl" include cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons, which are respectively saturated and partially unsaturated. Specification 13 / 48 pages 16 CN 121794270 A

[0081] The term “Ar” or “aryl” refers to an aromatic cyclic group (e.g., a 6-membered monocyclic or 10-membered bicyclic ring system) containing 6 to 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, and biphenyl.

[0082] The terms “heterocyclic,” “heterocyclic,” or “heterocyclic group” refer to a fully saturated or partially unsaturated cyclic group, for example, a 3- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 15-membered tricyclic ring system containing at least one heteroatom in at least one ring, wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Each ring of a heterocyclic group containing a heteroatom may contain 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur, wherein nitrogen and sulfur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. Heterocyclic groups can be attached to any heteroatom or carbon atom of a ring or cyclic system.

[0083] The term “substituent” refers to a group that “substitutes” on any functional group described herein, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl groups. Suitable substituents include, but are not limited to, halogens, CN, NO2, OR, SR, S(O)2OR, NRR', C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, (NR)NRR', N(NR)NRR', C(O)(O)R, S(O)2R, R', C(O)R', C(O)R, N(R)(CH2)nOH, (CH2)nOR, (CH2)nC(O)NRR', NRS(O)2R', where n is independently 0 to 6 (inclusive). Each R is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. Each R' is independently hydrogen, alkenyl, alkynyl, C3-C6 cycloalkyl, aryl, heterocyclic, heteroaryl, C1-C4 alkyl, or a C1-C4 alkyl substituted with C3-C5 cycloalkyl, aryl, heterocyclic, or heteroaryl. Each R'' is independently C3-C6 cycloalkyl, aryl, heterocyclic, heteroaryl, C1-C4 alkyl, orC1-C4 alkyl groups substituted with C3-C6 cycloalkyl, aryl, heterocyclic, or heteroaryl groups. Each of the C3-C5 cycloalkyl, aryl, heterocyclic, heteroaryl, and C1-C4 alkyl groups in each of R, R', and R'' may optionally be substituted with halogen, CN, C1-C4 alkyl, OH, C1-C4 alkoxy, NH2, C1-C4 aminoalkyl, C1-C4 dialkylamino, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, or 1,2-methylenedioxy.

[0084] The term "oxo" refers to an oxygen atom that, when attached to carbon, forms a carbonyl group, when attached to nitrogen, forms an N-oxide, and when attached to sulfur, forms a sulfoxide or sulfone.

[0085] The term "acyl" refers to an alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclic carbonyl, or heteroaryl carbonyl substituent, all of which may be further substituted by other substituents.

[0086] The term "CDCl3" refers to deuterated chloroform.

[0087] The term “CD3OD” refers to deuterated methanol.

[0088] The term “DMSO-d6” refers to deuterated dimethyl sulfoxide.

[0089] The term “LC-MS: (ESI)” refers to electrospray ionization liquid chromatography-mass spectrometry. The term “alteration” as used herein is defined as a change in relative physiological state. Exemplary alterations include mutation, deletion, fusion with other proteins, overexpression, or underexpression.

[0090] In any definition of a variable herein, the enumeration of chemical groups includes defining the variable as any single group or a combination of enumerated groups. The description of embodiments of a variable herein includes taking this embodiment as any single embodiment, or in combination with any other embodiment or any part thereof. The description of embodiments of this embodiment includes taking this embodiment as any single embodiment, or in combination with any other embodiment or any part thereof.

[0091] The compounds of the present invention may contain one or more asymmetric centers, and therefore exist in various forms such as racemic mixtures and racemic mixtures, single enantiomers, single diastereomers, and diastereomer mixtures. The present invention explicitly includes all isomer forms of such compounds. The compounds of the present invention may exist in various tautomer forms, in which case the present invention explicitly includes all tautomers of the compounds described herein. The present invention includes all isomer forms of such compounds. The present invention explicitly includes all crystal forms of the compounds.

[0092] Compounds of the present invention: Specification 14 / 48 pages 17 CN 121794270 A In one aspect, the present invention provides compounds of formula (I):

[0093] or salts thereof; or hydrates, solvates or polymorphs thereof; wherein: R1 is independently selected from hydrogen, methyl, ethyl, isopropyl, deuterated methyl or oxetane; R2 is independently selected from methyl or deuterated methyl; R3 is independently selected from fluoride, methyl or OCH3; X is independently selected from CH or nitrogen.

[0094] In another embodiment, the present invention provides a compound of formula (II):

[0095]

[0096] or a salt thereof; or a hydrate, solvate or polymorph thereof; wherein: R1 is independently selected from hydrogen, methyl, ethyl, isopropyl, deuterated methyl or oxetane; R2 is independently selected from methyl or deuterated methyl; R3 is independently selected from fluoride, methyl or OCH3; X is independently selected from CH or nitrogen.

[0097] In another embodiment, the present invention provides a compound of formula (III): Specification 15 / 48 pages 18 CN 121794270 A

[0098]

[0099] or a salt thereof; or a hydrate, solvate or polymorph thereof; wherein: R1 is independently selected from hydrogen, methyl, ethyl, isopropyl, deuterated methyl or oxetane; R2 is independently selected from methyl or deuterated methyl; R3 is independently selected from fluoride, methyl or OCH3; X is independently selected from CH or nitrogen.

[0100] Representative compounds of the present invention are compounds 1-42 shown in Figures 1A-C. Unless otherwise explicitly stated, the stereoconfiguration of each chiral carbon atom in this embodiment is independently R / S, R, or S configuration. The structures described herein include those of compounds 1-42 shown in Figures 1A-C, which may contain certain CH, CH2, CH3, NH, NH2 (amino), and OH (hydroxyl) groups, the corresponding hydrogen atoms of which are not explicitly labeled; but will be read as CH, CH2, CH3, NH, NH2, or OH as appropriate. In some structural formulas, a hyphen indicates a methyl group.

[0101] Representative compounds of the present invention are shown below: (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (1) (R / S)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (2) (R / S)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (3) (R / S)-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (4) (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one(5) (R / S)-9-(3,3-difluoro-1-(oxetane-3-yl)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (6) (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (7) Specification 16 / 48 pages 19 CN 121794270 A (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (8) (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (9) (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (10) (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (11) (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (12) (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (13) (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (14) (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (15)(R)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (16) (R)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (17) (R)-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (18) (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (19) (R)-9-(3,3-difluoro-1-(oxecyclobutane-3-yl)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one 4] Triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (20) (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (21) (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (22) (R)-9-(3 ,3-Difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (23) (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (24) (R)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (25) (R)- 9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (26)(R)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (27) (R)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (28) (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (29) (S)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (30) (S)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (31) (S)-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (32) (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (33) (S)-9-(3,3-difluoro-1-(oxecyclobutane-3-yl)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one 4] Triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (34) (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (35) (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (36) (S)-9-(3 ,3-Difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidazolo[1,2-a]pyridin-6-yl)amino(37) (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (38) (S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (39) (S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (40) (S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (41) (S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (42) The synthesis of the general formula compounds described herein can be easily performed by those skilled in synthetic chemistry, for example, using the relevant methods and intermediates disclosed herein.

[0102] Other synthetic methods for the general formula compounds described herein can be easily modified based on the references cited herein. Various improvements and optimizations to the above methods can be performed by those skilled in the art.

[0103] The specific models and compounds described above are not limiting. The chemical structural formulas in this technical solution are labeled with multiple variables. Regardless of whether these variables are represented by the same variable symbols (e.g., R1, R2, R, R', R'', X, etc.), they can be interpreted based on the chemical groups (including some groups, atoms, etc.) defined at the corresponding sites of the general formula compounds. The applicability of the chemical groups in the compound structure to the synthesis of another compound can be determined by those skilled in the art. Other synthetic methods for synthesizing the general formula compounds described herein and their synthetic precursors, including methods not explicitly described in this disclosure, are all conventional chemical methods that can be performed by those skilled in the art. Methods for optimizing reaction conditions to reduce the formation of competing byproducts are well known in the art. The methods described herein may also include additional steps before or after the steps described herein to introduce or remove suitable protecting groups, thereby ultimately enabling the synthesis of the compounds described herein. Furthermore, the various synthetic steps may be performed in different orders or sequences to obtain the desired compounds. Synthetic Chemistry of CompoundsMethods related to transformation and protecting groups (protection and deprotection) are well known in the art.

[0104] The processes described herein are intended to transform a compound of one formula into a compound of another formula. A transformation process refers to one or more chemical transformations that can be carried out in situ or after separation from an intermediate compound. The transformation may include reacting a starting compound or intermediate with additional reagents (including reagents described in the references cited herein) using techniques and methods known in the art. The intermediate may be purified (e.g., filtration, distillation, sublimation, crystallization, grinding, solid-phase extraction and chromatographic separation) or may be used directly without purification.

[0105] The combinations of substituents and variables described in this invention are limited to combinations capable of forming stable compounds.

[0106] This invention also provides a composition comprising an effective amount of any of the general formulas described herein, or (where applicable) a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or prodrug of the compound, and an acceptable carrier. Preferably, the compositions of this invention are prepared for pharmaceutical use (pharmaceutical compositions), wherein the carrier is a pharmaceutically acceptable carrier. Given compatibility with other components of the formulation, and in the case of a pharmaceutically acceptable carrier, the carrier must be "acceptable" and not impair its receptor in amounts normally used in pharmaceuticals.

[0107] "Pharmaceutically acceptable carrier"; or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents, etc. A pharmaceutically acceptable carrier or excipient does not impair the pharmacological activity of the disclosed compound and is non-toxic when administered in doses sufficient to deliver the compound. The use of such media and reagents for pharmaceutically active substances is well known in the art. Unless any conventional media or reagent is incompatible with the active ingredient, the use of therapeutic compositions as disclosed herein is considered. Examples of pharmaceutically acceptable carriers and excipients include, but are not limited to, sugars such as lactose, sucrose, and glucose; starches such as potato starch and corn starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, cellulose acetate, and ethyl cellulose; gelatin; tragacanth powder; talc; malt; cocoa butter and suppository waxes; oils such as peanut oil, safflower oil, cottonseed oil, olive oil, sesame oil, corn oil, and soybean oil; glycols such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; aldehydes; phosphates; phosphate buffers; non-toxic and compatible lubricants such as sodium dodecyl sulfate and magnesium stearate; colorants; coating agents; release agents; sweeteners, flavoring agents, and flavoring agents; self-emulsifying drug delivery systems (SEDDS) such as vitamin E polyethylene glycol 1000 succinate; and surfactants for pharmaceutical dosage forms such as Tween.Or other similar polymer delivery matrices; serum proteins, such as human serum albumin; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water, salts, or electrolytes, such as protamine sulfate, potassium hydrogen phosphate, disodium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based materials; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers. Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2-hydroxypropyl cyclodextrin and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives, to improve compound delivery.

[0108] The pharmaceutical compositions of the present invention can be administered in solid or liquid form, including oral administration, such as lotions (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets for oral, subcutaneous and systemic absorption), hard capsules or soft capsules, pills, syrups, powders, granules, pastes for the tongue, and duodenal route; parenteral administration, including intravenous, intra-arterial, subcutaneous, and intramuscular administration, such as in the form of creams, ointments, gels, aqueous or oily solutions or suspensions (e.g., in the form of creams, ointments, gels or vaginal suppositories, creams or stents, as per specification page 19 / 48, 22 CN 121794270 A); sublingual administration; local administration via catheter or stent; intrathecal or nasal administration (e.g., in the form of fine powders), or inhalation administration (e.g., in the form of fine powders or liquid aerosols).

[0109] Examples of suitable aqueous and non-aqueous carriers in pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Appropriate flowability is maintained by using coating materials, such as lecithin, by maintaining the desired particle size of the dispersion, and by using surfactants. These compositions may also contain excipients such as preservatives, wetting agents, emulsifiers, dispersants, lubricants, and / or antioxidants. The compounds described herein can be ensured to have a preventive effect against microorganisms by incorporating various antimicrobial and antifungal agents (e.g., parabens, chlorobutanol, phenolic sorbic acid, etc.). Isotonic agents, such as sugars, sodium chloride, etc., may also be included in the compositions. Furthermore, prolonged absorption in injectable drug forms can be achieved by including delayed absorption agents such as aluminum monostearate and gelatin.

[0110] Methods for preparing such formulations or compositions include the compounds described herein, and / or steps associated with chemotherapeutic carriers and optionally one or more excipients. Typically, this formulation is formed by homogenizing the compounds disclosed herein with a liquid carrier or a finely fragmented solid carrier, or both, and then shaping the product if desired. Methods for preparing such pharmaceutical compositions are well known in the art. Unless any conventional excipient medium is used in conjunction with the formulations provided herein...The compound is incompatible, for example, by interacting with any other component of a pharmaceutically acceptable composition to produce any undesirable biological or adverse effects; otherwise, the excipient is also intended to fall within the scope of the invention.

[0111] In some embodiments, the concentration of one or more of the disclosed compounds may be less than about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 14%, about 13%, about 12%, about 11%, about 10%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%. Approximately 0.004%, approximately 0.003%, approximately 0.002%, approximately 0.001%, approximately 0.0009%, approximately 0.0008%, approximately 0.0007%, approximately 0.0006%, approximately 0.0005%, approximately 0.0004%, approximately 0.0003%, approximately 0.0002%, or approximately 0.0001% of weight / weight ratio, weight / volume ratio, or volume / volume ratio.

[0112] In some embodiments, the concentration of one or more of the compounds disclosed herein may be greater than about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 18.5%, about 18.25%, about 17.5%, about 17.25%, about 17%, about 16.5%, about 16.25%, about 16%, about 15.5%, about 15.25%, about 15%, about 14.5%, about 14.25%, about 14%, about 13.5%, about 13.25%, about 13%, about 12.5%, about 12.25%, about 12%, about 11.5%, about 11.25%, about 11%, about 10.75%, about 10.5%. Approximately 10%, approximately 9.75%, approximately 9.5%, approximately 9.25%, approximately 9%, approximately 8.75%, approximately 8.5%, approximately 8.25%, approximately 8%, approximately 7.75%, approximately 7.5%, approximately 7.25%, approximately 7%, approximately 6.75%, approximately 6.5%, approximately 6.25%, approximately 6%, approximately 5.75%, approximately 5.5%, approximately 5.25%, approximately 5%, approximately 4.75%, approximately 4.5%, approximately 4.25%, approximately 4%, approximately 3.75%, approximately 3.5%, approximately 3%, approximately 2.75%, approximately 2.50%, approximately 2.25%, approximately 2%, approximately 1.75%, approximately 1.50%, approximately 1.25%, approximately 1%, approximately 0.9%, approximately 0.8%, approximately 0.7%, approximately 0.6%, approximately 0.5%, approximately 0.4%, approximately 0.3%, approximately 0.2%, approximately0.1%, approximately 0.09%, approximately 0.08%, approximately 0.07%, approximately 0.06%, approximately 0.05%, approximately 0.04%, approximately 0.03%, approximately 0.02%, approximately 0.01%, approximately 0.009%, approximately 0.008%, approximately 0.007%, approximately 0.006%, approximately 0.005%, approximately 0.004%, approximately 0.003%, approximately 0.002%, approximately 0.001%, approximately 0.0009%, approximately 0.0008%, approximately 0.0007%, approximately 0.0006%, approximately 0.0005%, approximately 0.0004%, approximately 0.0003%, approximately 0.0002%, or approximately 0.0001% by weight / weight, weight / volume, or volume / volume. In some embodiments, the concentration range of one or more compounds disclosed herein may be from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 20%, from about 0.09% to about 24%, from about 0.08% to about 23%, from about 0.07% to about 22%, from about 0.06% to about 24%, from about 0.2% to about 20%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% by weight / weight ratio, weight / volume ratio, or volume / volume ratio. In some embodiments, the concentration range of one or more compounds disclosed herein may be from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, or from about 0.1% to about 0.9% by weight / weight, weight / volume, or volume / volume.

[0113] In some embodiments, the amount of one or more compounds disclosed herein may be equal to or less than about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g, about 6 g, about 5.5 g, about 5 g, about 4.5 g, about 4 g, about 3.5 g, about 3 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about0.4g, about 0.35g, about 0.3g, about 0.25g, about 0.2g, about 0.15g, about 0.1g, about 0.09g, about 0.08g, about 0.07g, about 0.06g, about 0.05g, about 0.04g, about 0.03g, about 0.02g, about 0.01g, about 0.009g, about 0.008g, about 0.007g, about 0.006g, about 0.005g, about 0.004g, about 0.003g, about 0.002g, about 0.001g 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g. In some embodiments, the amount of one or more compounds disclosed herein may exceed about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095 g. Approximately 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g.

[0114] In some embodiments, the amount range of one or more compounds disclosed herein may be from about 0.0001 g to about 10 g, from about 0.0005 g to about 9 g, from about 0.001 g to about 0.5 g, from about 0.001 g to about 8 g, from about 0 g to about 0 g.0.005 g to about 7 g, 0.01 g to about 6 g, about 0.05 g to about 5 g, about 0.1 g to about 4 g, about 0.5 g to about 4 g, or about 1 g to about 3 g.

[0115] In some preferred embodiments, the pharmaceutical composition comprises a compound disclosed herein for oral administration, and a pharmaceutical excipient suitable for oral administration. In some embodiments, a pharmaceutical composition for oral administration is provided herein for: (1) optionally an effective amount of the disclosed compound; (2) an effective amount of one or more second agents; and (3) one or more pharmaceutically acceptable excipients for oral administration. In some embodiments, the pharmaceutical composition further comprises: (4) an effective amount of a third agent.

[0116] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be used as discrete dosage forms, such as capsules, flat capsules, or tablets, or liquid formulations, solutions, aerosols, or suspensions containing a predetermined amount of active ingredient in powder or granules, water or non-aqueous liquids, liquid emulsions in water, or water in a liquid emulsion. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of preparing the composition by uniformly and tightly binding the active ingredient with a liquid carrier, liposomes, or finely granulated solid carrier, or both. Typically, pharmaceutical compositions are formed by uniformly and tightly mixing the active ingredient with a liquid carrier or finely granulated solid carrier, or both, and, if desired, shaping the product into a desired form. For example, tablets may be one or more components that can be compressed or molded. Tablets can be formed by optionally mixing a free-flowing form (such as an active ingredient in powder or granules) with excipients (such as, but not limited to, binders, lubricants, inert diluents, and / or mixtures of surfactants or dispersants) and compressing in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. The tablets may optionally be uncoated, coated, or notched, and may be formulated to provide a slow or controlled release of the active ingredient therein, thereby providing sustained action over a longer period of time, such as glyceryl monostearate or glyceryl distearate. Formulations for oral use may also be hard gelatin capsules in which the active ingredient may be mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient may be mixed with an aqueous or oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0117] The active ingredient can be tightly combined with a pharmaceutically acceptable carrier using conventional pharmaceutical mixing techniques. The carrier can take many forms depending on the desired dosage form. In the preparation of pharmaceutical compositions for oral dosage forms, any commonly used...Pharmaceutical media can be used as carriers, such as water, glycols, oils, ethanol, flavoring agents, preservatives, coloring agents, and oral liquid formulations (e.g., liquid formulations, solutions, and elixirs) or aerosols, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granules, lubricants, binders, and disintegrants can be used for oral solid dosage forms. Lactose is not used in some embodiments. In some embodiments, the compound can be mixed with lactose, sucrose, starch powder, cellulose esters, alkyl cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, calcium phosphate, sodium phosphate, calcium sulfate, sodium sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol for further formulation. For example, suitable carriers also include powders, capsules, and tablets when preparing solid oral dosage forms. In some embodiments, tablets can be coated using standard aqueous or non-aqueous techniques.

[0118] Substances suitable for pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural binders and synthetic gums (such as gum arabic), sodium alginate, alginic acid, other alginates, powdered tragacanth gum, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, cellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0119] Examples of suitable fillers for pharmaceutical compositions and dosage forms include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, glucose binder, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0120] Disintegrants may be used in pharmaceutical compositions as provided herein to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant can cause tablets to disintegrate in the bottle. Too little disintegrant may be insufficient for disintegration, thereby altering the release rate and extent of the active ingredient in the dosage form. Therefore, the amount of disintegrant should be adequate, neither too little nor too much, to avoid adversely affecting the release of the active ingredient. The amount of disintegrant depends on the dosage form and route of administration and is readily implemented by those skilled in the art. About 0.5% to about 15% (by weight) or about 1% to about 5% (by weight) of disintegrant may be used in a pharmaceutical composition. Disintegrants used to form the disintegrant and dosage form of a pharmaceutical composition include, but are not limited to, agar, alginate, calcium carbonate, microcrystalline cellulose, croscarmellose, crospovidone, sodium acetate, potato or cassava starch, other starches, pre-made starches, clay, other algae, other celluloses, gums, or mixtures thereof.

[0121] Lubricants can be used to form pharmaceutical compositions, including but not limited to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, and hydrogenated...Vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Lubricants also include, for example, silica gel, coagulating aerosols, or mixtures thereof. (See page 22 / 48 of the specification, CN 121794270 A). Optionally, a lubricant may be added in an amount less than about 1% (by weight) of the pharmaceutical composition.

[0122] When aqueous suspensions and / or elixirs are used for oral administration, the active ingredient may be combined with various sweeteners or flavoring agents, colorants or dyes (e.g., emulsifiers and / or suspending agents), and diluents (e.g., water, ethanol, propylene glycol, glycerin, and combinations thereof).

[0123] Surfactants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. Suitable hydrophilic surfactants typically have an HLB value of at least about 10, while suitable lipophilic surfactants typically have an HLB value of less than about 10. An empirical parameter used to characterize relative hydrophilicity and hydrophobicity is the hydrophilic-lipophilic balance value (HLB value). The lower the HLB value of a surfactant, the stronger its lipophilicity or hydrophobicity, and the greater its solubility in oil; conversely, the higher the HLB value of a surfactant, the stronger its hydrophilicity, and the greater its solubility in aqueous solution. Surfactants with an HLB value greater than about 10 are generally considered hydrophilic surfactants; however, the HLB scale is generally not applicable to anionic, cationic, or zwitterionic compounds. Similarly, lipophilic (i.e., hydrophobic) surfactants are surfactants with an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guideline generally used in industrial, pharmaceutical, and cosmetic emulsion applications.

[0124] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and phospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium dodecyl; acyl lactates; monoacetylated and diacetylated monoglycerides and diglycerides of tartrate esters; succinylated monoglycerides and diglycerides; citric acid monoglycerides and diglycerides; and mixtures thereof. Ionic surfactants include, for example, lecithin, lysophosphatidylcholine, phospholipids, lysophosphatidylcholine and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; acyl lactates; monoacetylated and diacetylated monoglycerides and diglycerides of tartrate esters; succinylated monoglycerides and diglycerides; citric acid monoglycerides and diglycerides; and mixtures thereof. Hydrophilic nonionic surfactants include, but are not limited to, alkyl glycosides; alkyl maltose; alkyl thioglycosides; lauroyl polyethylene glycol.Glycerol esters; polyoxyethylene alkyl ethers, such as polyethylene glycol polyoxyethylene alkylphenols, for example, polyethylene glycol alkylphenols; polyoxyethylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyethylene dehydrated sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; and glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, polyoxyethylene sterols and their derivatives, etc.; polyoxyethyleneized vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyethylene glycol dehydrated sorbitan fatty acid esters with at least one triglyceride, vegetable oil, and hydrogenated vegetable oil polyol. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or carbohydrates. Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-40 oleate, PEG-15 stearate, PEG-32 distearate lactone, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate lactone, PEG-30 glyceryl laurate, PEG-20 glycolate, PEG-20 glyceryl oleate, PEG- PEG-30 Glycerin, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Glycerin / Capric Glycerate, PEG-8 Capric Glycerate / Capric Glycerate, Polyglycerol 1-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soy Sterol, PEG-20 Trioleate, PEG-40 Sorbitol Oleate, PEG-80 Dehydrated Sorbitol Laurate, Polysorbate 20, Polysorbate 80, POE-9 Dodecyl Ether, POE-23 Dodecyl Ether. (Instructions for Use, Page 23 / 48, 26, CN 121794270 A) Ethers, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 glyceryl stearate, PEG-100 tocopheryl succinate, PEG-24 cholesterol, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG15–100 octylphenol series and poloxamer. Suitable lipophilic surfactants include, but are not limited to, for example, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitol fatty acid esters; glycol dehydrated sorbitol fatty acid esters; sterols and sterol derivatives; polyoxyethylene sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides and diglycerides.

[0125] The pharmaceutical composition may contain a solubilizer to ensure good solubilization and / or dissolution of the compound and to minimize precipitation of the compound. This may be particularly important for pharmaceutical compositions not intended for oral use (e.g., pharmaceutical compositions for injectable pharmaceutical compositions). Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components (e.g., surfactants) or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion. Examples of suitable solubilizers include, but are not limited to: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers with a molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl PEG ether (tetrahydrofuran polyethylene glycol ether) or methoxyPEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkyl N-hydroxyalkylpyrrolidone, N-alkylpiperidine, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters, such as ethyl propionate, esters, triethyl acetyl citrate, triethyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, glyceryl triacetate, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valine ester and its isomers, butyrolactone and its isomers; and other known solubilizers, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, diethylene glycol monoethyl ether, and water. Mixtures of solubilizers may also be used.

[0126] The amount of a given solubilizer may be limited to a biologically acceptable amount, which can be readily determined by those skilled in the art. Based on the total weight of the drug and other excipients, the weight ratio of the solubilizer may be about 10%, about 25%, about 50%, about 100%, or up to about 200% (by weight). Small amounts of solubilizer may also be used, such as about 5%, 2%, 1%, or less, if desired. Typically, the solubilizer may be about 1% to about 100%, generally about 5% to about 25% (by weight).

[0127] The pharmaceutical composition may also contain one or more pharmaceutically acceptable additives and excipients, flavoring agents, coloring agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. Preservatives may include, but are not limited to, e.g.Examples include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives, and other preservatives. Antioxidants include, but are not limited to, α-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfate, and sodium sulfite. Chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), citrate monohydrate, disodium ethylenediaminetetraacetic acid, dipotassium ethylenediaminetetraacetic acid, fumaric acid, malic acid, phosphoric acid, sodium ethylenediaminetetraacetic acid, tartaric acid, and triethylenediaminetetraethyl citrate. Antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzyl chloride, benzyl alcohol, bromonitrobenzene glycol, hexadecyltrimethylammonium bromide, hexadecylpyridine chloride, chlorocresol, cresol, ethanol, glycerol, heptane, imidazoline, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, and propylene glycol. Antifungal agents include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, parabens, and phenethyl alcohol. Acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, β-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopheryl acetate, cetyltrimethylammonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium dodecyl sulfate (SLS), sodium dodecyl ether sulfate (SLES), sodium bisulfate, sodium metabisulfite, potassium sulfite, potassium metabisulfite, and methylparaben. In some embodiments, the preservative may be an antioxidant. In other embodiments, the preservative may be a chelating agent.

[0128] In some embodiments, a pharmaceutical composition for parenteral administration is provided herein: (1) an effective amount of the disclosed compound; optionally (2) an effective amount of one or more second agents; (3) one or more pharmaceutical excipients suitable for parenteral administration; and (4) an effective amount of a third agent.

[0129] The pharmaceutical composition can be administered in aqueous or oily suspensions or emulsions (sesame oil, corn oil, cottonseed oil, or peanut oil), as well as elixirs, mannitol, glucose, or sterile aqueous solutions and similar drug carriers. Saline solutions are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, benzyl alcohol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, sodium chloride, tragacanth gum, buffers, and vegetable oils may also be used. This can be achieved by using a coating (e.g., lecithin) or by using a surface...The active agent maintains the desired particle size (for dispersions) to maintain appropriate flowability. Microbial activity is prevented by using various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). The pharmaceutical composition can also be administered by injection with a suitable carrier (including physiological saline, glucose, or water), or dissolved in cyclodextrin, a cosolvent (e.g., propylene glycol), or micelles (e.g., Tween 80).

[0130] Sterile injectable solutions can be prepared by combining the required amount of the compound of the invention with the various other components described above in a suitable solvent, followed by sterile filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile carrier containing a base dispersion medium and the other suitable components described above. For sterile powders used to prepare sterile injectable solutions, some preparation methods use vacuum drying and freeze-drying techniques to obtain the active ingredient and any other sterile filtration components described above. The sterile injectable formulation can also be prepared using a solution of a non-toxic, parenteral-acceptable diluent or solvent (e.g., 1,3-butanediol solution or sterile injectable solution). Acceptable carriers and solvents that can be used include, but are not limited to, water, Ringer's solution and isotonic sodium chloride solution. Additionally, sterile nonvolatile oils are commonly used as solvents or suspension media, including, but not limited to, synthetic monoglycerides or diglycerides. Furthermore, fatty acids (e.g., oleic acid) can also be used to prepare injectables. Injectables can be sterilized by, for example, using a bacterial trap filter, or by adding a sterile solid composition containing a sterilizing agent (which can be dissolved or dispersed in sterile water or other sterile injection media). The injectable composition is about 0.1% to about 5% by weight of the compound of the present invention.

[0131] In some embodiments, compounds (or transdermal preparations) containing one or more pharmaceutical excipients (e.g., the excipients disclosed herein) are provided herein for topical administration. In some embodiments, pharmaceutical compositions for topical administration are provided herein for: (1) an effective amount of the disclosed compound; optionally (2) an effective amount of one or more second agents; (3) one or more pharmaceutical excipients suitable for topical administration; and (4) an effective amount of a third agent.

[0132] The pharmaceutical compositions provided herein can be formulated into solid, semi-solid, or liquid forms suitable for topical or external administration, such as gels, water-soluble gels, liniments, creams, lotions, suspensions, foams, powders, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, and dimethyl sulfoxide (DMSO)-based solutions. Generally, a carrier with a higher density allows for a longer exposure time to the active ingredient. Conversely, solution formulations allow for more direct contact of the selected area with the active ingredient. For example, ointment formulations may be paraffin- or water-miscible. Alternatively, the active ingredient may be formulated into an oil-in-water cream matrix. The aqueous phase of the cream matrix may include, for example, at least about 30%.w / w polyols (e.g., propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerol, polyethylene glycol, and mixtures thereof). The above pharmaceutical compositions may also contain suitable solid or gel carriers or excipients that can increase penetration or facilitate the delivery of the compound across the skin's stratum corneum barrier. Examples include urea (e.g., urea), (e.g., menthol), amines, amides, alkanes, alkanols, water, and similar substances such as isopropyl myristate and sodium sulfate, pyrrolidone, glyceryl monolaurate, sulfoxide, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers (e.g., polyethylene glycol).

[0133] The pharmaceutical compositions of the present invention can be administered in suppository form for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will melt in the rectum to release the active ingredient. These materials include, but are not limited to, polyethylene glycol, beeswax, and cocoa butter.

[0134] The pharmaceutical compositions of the present invention can be administered via nasal aerosol or inhaler. Such compositions are prepared according to techniques known in the field of pharmaceutical preparation, can be prepared as saline solutions, and can be used with benzyl alcohol or other suitable preservatives to increase the bioavailability of absorption enhancers, fluorocarbons, and other solubilizers or dispersants known in the art.

[0135] Particularly advantageous derivatives and prodrugs refer to derivatives and prodrugs that can improve the bioavailability of the compounds of the present invention in mammals (e.g., more readily absorbed by oral administration) or, relative to the parent compound, can promote the delivery of the compounds of the present invention to target tissues (e.g., the brain or central nervous system). Preferred prodrugs include derivatives obtained by attaching groups capable of improving water solubility or enhancing parenteral transport capacity to the general formula structure described herein.

[0136] The administration of the subject therapeutic agent can be directed to administration at the target site. Various techniques can be used to administer the composition to the target site, such as injection, using catheters, gels, stents, cannulas, propellants, drug-releasing polymers, or other devices for providing internal access.

[0137] According to another embodiment, the present invention provides an implantable medical device comprising a compound of the present invention or a composition comprising a compound of the present invention, such that the compound has therapeutic activity.

[0138] According to another embodiment, the present invention provides a method of injecting an implantable drug delivery device, comprising the step of contacting the drug delivery device with a compound or composition of the present invention. Implantable drug delivery devices include, but are not limited to, biodegradable polymer capsules or pills, non-degradable dispersible polymer capsules, and biodegradable polymer sheets.

[0139] In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent that, when administered alone or in combination with any compound of the general formula herein, is known to have or possess advantageous properties. Medications that can be administered in combination with these compounds include other kinase inhibitors and / or other chemotherapeutic agents for treating the aforementioned diseases and conditions. Such medications are described in detail in the art. Preferably, the second therapeutic agent is a medicament that can be used to treat or prevent cancer-related diseases or conditions via a DNA double-strand break mechanism.

[0140] In another embodiment, the present invention provides independent dosage forms in which the compounds of the present invention and the second therapeutic agent are combined with each other. As used herein, the term "combined with each other" means packaging independent dosage forms together or otherwise linking them together so that these independent dosage forms are intended to be sold or administered together (within 24 hours, consecutively, or simultaneously).

[0141] In the pharmaceutical compositions of the present invention, the compounds of the present invention are present in an effective amount. As used herein, the term "effective dose" means, when administered in a suitable dosing regimen, an amount sufficient to reduce or improve the severity, duration, or progression of the disease to be treated, to prevent the development of the disease, interruption of treatment, or to enhance or improve the preventive or therapeutic effect of another therapy.

[0142] This document describes dosage conversions between animals and humans (based on weight (mg) per square meter of body surface area). A patient's body surface area can be roughly calculated based on height and weight. The effective dose range of the compounds of the present invention is from about 0.001 to 1 mg / kg to about 500 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, and from about 0.1 mg / kg to about 2.5 mg / kg. Those skilled in the art will recognize that the effective dose can also vary depending on the disease being treated, the severity of the disease, the route of administration, the patient's age, sex, and general health condition, the excipients used, and other commonly used treatment methods (e.g., the use of other agents), as well as the judgment of the treating physician.

[0143] For pharmaceutical compositions comprising a second therapeutic agent, the effective amount of the second therapeutic agent is about 20% to 100% of the dose commonly used in monotherapy regimens using only the agent. Preferably, the effective amount is about 70% to 100% of the normal monotherapy dose. The normal monotherapy doses of these second therapeutic agents are well known in the art.

[0144] Some of the second therapeutic agents mentioned herein are expected to have a synergistic effect with the compounds of the present invention. If this synergy is present, it may be permissible to use an effective dose of the second therapeutic agent and / or the compound of the present invention lower than the dose required for monotherapy. Doing so has the advantages of minimizing minor side effects of the second therapeutic agent or the compound of the present invention, improving efficacy, making administration or use easier, and / or reducing the overall cost of compound preparation or formulation.

[0145] The treatment methods are as follows: According to another embodiment, the present invention provides a method for treating a subject suffering from or susceptible to a disease or condition or its symptoms (such as those described herein), comprising administering an effective amount of the compound or composition of the present invention to the subject in one step. These diseases are well known in the art and are also disclosed herein.

[0146] The treatment includes treatment of a disease mediated by a protein kinase (e.g., DNA-PK kinase).

[0147] In another aspect, the present invention provides a method for treating a subject's disease, comprising administering to the subject a composition comprising any of the general formulas herein.

[0148] In some embodiments, the disease is mediated by a DNA-PK kinase.

[0149] In another embodiment, the disease is cancer or a proliferative disease.

[0150] In another embodiment, as an anti-activated DNA-PK kinase inhibitor, the compound of formula (I) and its pharmaceutically acceptable salts are expected to participate in or partially mediate the activity of ATM kinase, for example, in the treatment of cancer or a medical condition. The types of cancer that can be treated with the compound shown in Formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, thymoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cell carcinoma, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain cancer, adenocarcinoma, diffuse en bloc pontine glioma (DIPG), skin cancer, or squamous cell carcinoma of the head and neck.

[0151] In another embodiment, the disease is a cancer resistant to radiotherapy.

[0152] In another embodiment, the disease is a cancer resistant to therapeutic agents that induce DNA double-strand breaks.

[0153] In another embodiment, the disease is a metastatic cancer of the central nervous system.

[0154] In another embodiment, the disease is glioma.

[0155] In another embodiment, the disease is glioblastoma.

[0156] In another embodiment, the disease is diffuse en bloc pontine glioma.

[0157] In one embodiment, the method of the present invention is used to treat a subject who has or is susceptible to a disease or condition. These diseases, conditions, or symptoms include, for example, diseases, conditions, or symptoms mediated by protein kinases (e.g., DNA-PK protein kinase). The disease or disease symptom may be, for example, cancer or a proliferative disease or condition. The disease or disease symptom may be ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, diffuse en bloc pontine glioma, melanoma, prostate cancer, leukemia, lymphoma.(GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (GIST), gastric cancer, lung cancer, liver cancer, AML, multiple myeloma, melanoma, mesothelioma, brain cancer, membranous adenocarcinoma, skin cancer, or head and neck squamous cell carcinoma. The methods described herein include subjects identified as requiring treatment (as specifically described). The identification of subjects requires treatment to be within the judgment of the subject or a healthcare professional and may be subjective (e.g., opinion) or objective (e.g., as determined by examination or diagnostic methods).

[0158] In another embodiment, compounds (and compositions thereof) of the general formula herein may be used to treat diseases or conditions that have been treated with other therapeutic agents (e.g., anticancer agents, neurotrophic agents, psychotropic drugs, cardiovascular agents, anti-obesity or diabetes agents) and have developed resistance. In one aspect, the methods described herein include administering compounds (or combinations thereof) of those general formulas to subjects resistant to treatment therein (or subjects identified as resistant to radiotherapy or chemotherapy that induces DNA double-strand breaks). In other aspects, the patient thus responds to the treatment, such that the condition is modulated or improved prior to treatment with a compound of the formula.

[0159] In another embodiment, the invention provides a method for modulating the activity of protein kinases (e.g., protein kinases listed herein) in cells, comprising contacting cells with one or more compounds of the general formula herein.

[0160] The above-described anticancer treatments may be used as monotherapy or in combination with conventional compounds, or radiotherapy, or chemotherapy, immunotherapy, and the compounds of the invention. Such chemotherapy may be administered co-, simultaneously, sequentially, or separately with the compounds of this invention, and may include, but is not limited to, one or more of the following classes of antitumor agents: for example, antiproliferative / antitumor agents, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea), antimetabolites (e.g., gemcitabine and 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and antifungal acids such as hydroxyurea); antitumor antibiotics (e.g., doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, etc.). Anthracyclines such as idarubicin, mitomycin C, gentamicin, and glimepiride; antimitotics (e.g., vinca alkaloids such as vincristine, alkaloids such as paclitaxel and tacrolimus, and equine kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxin, etoposide and dipyridylglycoside, acridine, topotecan, and camptothecin); cell growth inhibitors, such as antihormones (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, doloxifen, and zixifen), antiandrogens (e.g., pentylamine, flutamide, nilumethoxazole acetate, and cycloacetone), LHRH antagonists, or LHRH agonists (e.g., goserelin, levofloxacin, etc.).Antiprogesterone acetate (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, buxazole, and exemestane), and 5α-reductase inhibitors such as finasteride; anti-invasive agents (c-Src kinase family inhibitors such as citatinib, dasatinib, and bosutinib); and metalloproteinase inhibitors, such as equine protease, urokinase-type plasminogen activator receptor, or antibody heparinase inhibitors. Growth factor function inhibitors, for example, include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-ErbB antibody cetuximab (erbatide, C225), and growth factor receptors or growth factor receptor antibodies disclosed by Stem et al. in *Oncology / Hematology Reviews*, 2005, Vol. 54, pp. 11-29). This class of inhibitors also includes: tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family inhibitors such as gefitinib, erlotinib, icotinib, afatinib, dacomitinib, and tagrisso; erbB2 tyrosine kinase inhibitors such as lapatinib and neratinib); hepatocyte growth factor family inhibitors; platelet-derived growth factor family inhibitors, Examples include imatinib and / or nilotinib; serine / threonine kinase inhibitors (e.g., RAS / RAF signaling inhibitors such as sorafenib, tilpifalib, and lonafalib, etc., fennesyltransferase inhibitors), MEK and / or AKT kinase cell signaling inhibitors, c-kit inhibitors, abl fusion kinase inhibitors, PI3 kinase inhibitors, PLT3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors; anti-angiogenic agents, such as drugs that inhibit the action of vascular endothelial growth factor, and the antibody bevacizumab (Avastin™). And VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatarabine, sunitinib, axitinib, cabozantinib, pazopanib, and cediranib; compounds that act through other mechanisms (e.g., tricarboxyaminoquinoline, integrin αV3 function inhibitors, and angiogenesis inhibitors); antisense (nucleic acid) therapies, including, for example, replacing aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2, as described above, such as ISIS 2503, antiras gene antisense (nucleic acid) (e.g., olaparib, niraparib, rucaparib, tapolazoparib), GDEPT (gene-guided prodrug therapy) methods, such as using enzymes such as cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and increasing the patient's response to chemotherapy.Methods for treating resistance to radiotherapy, such as gene therapy and immunotherapy for multidrug resistance, include, for example, increasing the immunogenicity of the patient's tumor cells, for example, transfecting T cells with cytokines, such as interleukin-2, 4 or granulocyte-macrophage stimulating factor to reduce unresponsiveness, using transfected immune cells, such as cytokines to transfect dendritic cells, cytokines to transfect anti-idiotype antibodies to reduce the function of immunosuppressive cells (such as regulatory T cells, myeloid suppressor cells or IDO, TDO), and using proteins or peptides derived from tumor-associated antigens, such as NY-ESO-1, MAGE-3, WTI or HER2 / neu, or any other agents commonly used as a base agent or adjuvant in cancer treatment regimens (e.g., antiemetics, anti-anemia agents, etc.).

[0161] As used herein, the term "co-administration" means that the second therapeutic agent may be administered in combination with the compounds of the present invention, partly as a single dosage form (e.g., a composition comprising the compounds of the present invention and the second therapeutic agent described above) or as a separate multi-dosage form. Alternatively, other agents may be administered before, simultaneously with, or after the application of the compound of the present invention. In this combination therapy, the compound of the present invention and the second therapeutic agent are administered by conventional methods. Administration of the composition of the present invention comprising the compound of the present invention and the second therapeutic agent to a subject does not preclude the administration of the same therapeutic agent, any other second therapeutic agent, or any compound of the present invention to the subject at other times during the treatment process. Wherein, the effect advantage derived from the use of the combination should not be lost when the second component is administered consecutively, alone, or delayed.

[0162] The effective amount of the second therapeutic agent is known to those skilled in the art. However, the optimal effective amount of the second therapeutic agent can be determined by those skilled in the art.

[0163] In one embodiment of the present invention, when the second therapeutic agent is administered to a subject, the effective amount of the compound of the present invention is lower than the effective amount of the second therapeutic agent when it is not administered. In another embodiment, the effective amount of the second therapeutic agent is lower than the effective amount of the second therapeutic agent when it is not administered. This minimizes unintended side effects caused by the administration of any high dose of the drug. Potential advantages will be apparent to those skilled in the art (including, but not limited to, improved dosing regimens and / or reduced drug costs).

[0164] In another aspect, the present invention provides the use of any compound of the general formula herein, as a single agent or in combination with one or more second therapeutic agents described herein, in a single composition or in a single dosage form, for the treatment or prevention of a subject of a disease, condition, or symptom listed herein. Another aspect of the invention is the use of a compound of the general formula herein for the treatment or prevention of a subject of a disease, condition, or symptom described herein.

[0165] In other aspects, the methods herein further include a method for monitoring a subject's response to therapeutic administration. This monitoring...This may include periodic sampling of subject tissues, body fluids, cerebrospinal fluid, samples, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of the treatment regimen. In other methods, subject needs for treatment are pre-screened or determined by assessing the suitability of the relevant markers or indicators for the treatment.

[0166] In one embodiment, the present invention provides a method for monitoring treatment progress. The method includes identifying diagnostic markers (markers) in subjects who have or are susceptible to the conditions or symptoms described herein (e.g., any target or cell type regulated by the compounds described herein) or who have been diagnosed (e.g., screened, measured), wherein the subject has been administered a therapeutic amount of the compounds of the present invention sufficient to treat the disease or its symptoms. The marker levels measured in this method may be compared with known levels in healthy controls or patients with other diseases to determine the subject's disease status. In a preferred embodiment, a second level of the marker in the subject is measured at a time point later than the first measurement level, and the two levels are compared to monitor disease progression or the effectiveness of treatment. In some preferred embodiments, the pre-treatment marker level of the subject is measured prior to the start of treatment according to the invention; the pre-treatment marker level may be the same as the marker level on page 29 / 48 of the instruction manual 32 CN 121794270 A after the start of treatment to determine the efficacy of the treatment.

[0167] In some method embodiments, the marker or marker activity level of the subject is measured at least once. This marker level is compared with another measurement (e.g., a measurement obtained by the subject before or after from the same patient, another patient, or another subject) to determine whether the therapy according to the invention has the intended effect, and thus allows for adjustment of the dose level as appropriate. The marker level can be measured using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first collected from the subject. Examples of suitable samples include blood, urine, cerebrospinal fluid, tissue, oral cavity or oral cells, and hair samples (with hair roots). Other suitable samples are well known to those skilled in the art. The determination of protein levels, ctDNA, cfDNA, and / or mRNA levels (e.g., marker levels) in a sample can be performed using any suitable technique known in the art, including but not limited to enzyme immunoassay, ELISA, radiolabeling techniques, Western blotting / chemiluminescence, real-time PCR, electrochemical signals, etc.

[0168] The present invention also provides a kit for treating the diseases, conditions, or symptoms described herein. Such a kit comprises: (1) a pharmaceutical composition containing any compound of the general formula herein or a salt thereof, or a hydrate, solvate, or polymorph thereof, wherein the pharmaceutical composition is contained in a container; and (2) the pharmaceutical composition is used to treat the diseases described herein.Instructions for use regarding the disease, condition, or symptom. The container may be any container or other sealed or sealable device capable of containing the pharmaceutical composition. Examples include bottles, single or multi-compartment reservoirs, wherein each compartment or compartment contains a single dose of the pharmaceutical composition; individual foil packages, wherein each compartment contains a single dose of the pharmaceutical composition, or individually packaged single doses of the pharmaceutical composition. The container may be any conventional shape or form known in the art and made of pharmaceutically acceptable materials, such as paper or cardboard boxes, glass or plastic bottles or jars, resealable bags (e.g., tablets can be placed in different containers when “refilling”), or single-dose blister packs that ensure accurate dosing and easy use. The container chosen may depend on the specific dosage form involved; for example, conventional cardboard boxes are not typically used for liquid suspensions. It is possible to use multiple containers in one package to contain a single dosage form at the time of sale. For example, tablets may be placed in a bottle first and then in a box. Blister packs are preferred.

[0169] The kit may also include information and / or instructions for physicians, pharmacists, or subjects. These memory aids include numbers printed on each compartment or section containing the medication (these numbers correspond to the number of days of treatment or the number of capsules to be ingested) or the number of days of a week printed on each compartment or section, or cards containing the same type of information.

[0170] The bioactivity of the compounds described herein can be evaluated using known methods (e.g., the methods described herein). Some of the compounds described herein possess excellent properties (e.g., high metabolic stability, high selectivity, low efflux rate, high permeability, non-aldehyde oxidase substrate, low hERG risk, low drug-drug interaction risk, etc.) and are high-quality candidates for potential therapeutic agents.

[0171] All references cited herein, whether in electronic, print, computer-readable or other forms, are expressly incorporated herein by reference in their entirety, including but not limited to abstracts, articles, journals, publications, textbooks, papers, technical data sheets, websites, databases, patents, patent applications and patent publications.

[0172] The invention is described in detail below with reference to embodiments. The following embodiments will help those skilled in the art to further understand the invention, but do not limit the invention in any way. It should be noted that, without departing from the spirit of this invention, those skilled in the art can make several adjustments and improvements. All of these fall within the scope of protection of this invention.

[0173] Example 1 Intermediate 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine A, the synthesis reaction formula of which is shown in Figure 2.

[0174] Step 1: Under stirring conditions, N,N-dimethylformamide dimethyl acetal (47.5 mL, 78 mmol) was added to a DMF (20.0 mL) solution of 4-methyl-5-nitropyridine-2-amine (5.0 g, 32.6 mmol) to a solution of 4-methyl-5-nitropyridine-2-amine (5.0 g, 32.6 mmol) and added ...(mmol). The reaction mixture (page 33, CN 121794270 A, page 30 / 48 of the instruction manual) was placed in a sealed tube and heated to 130°C, reacting overnight. After cooling to room temperature, the mixture was refluxed under reduced pressure to remove volatile components, yielding a red oily substance. This product was dissolved in 40.0 mL of ethanol and 10 mL of pyridine. The solution was cooled in an ice bath, and then hydroxylamine-O-sulfonic acid (4.7 g, 42.3 mmol) was added in one batch. The reaction mixture was slowly heated to room temperature and stirred overnight. After reflux under reduced pressure to remove volatile components, the residue was separated using saturated brine and ethyl acetate (EA). The aqueous phase was further extracted with EA, the organic phases were combined, and washed with saturated brine (100 mL). The mixture was then dried over magnesium sulfate, concentrated under reduced pressure, and finally yielded an orange solid crude product. Purification was performed using rapid column chromatography (silica gel; 0-4% MeOH / DCM gradient elution) to obtain 7-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (3.0 g, yield 51.7%), a pale yellow solid.

[0175] Step 2: Pd / C (300 mg, 10 wr%) was added to an EA (30 mL) solution of 7-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (3 g, 16.84 mmol). The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (2.1 g, yield 84.16%, 14.17 mmol), a yellow solid. LCMS (ESI) [M+H]+149.1. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.08 (s, 1H), 7.46 (s, 1H), 5.01 (s, 2H), 2.25 (s, 3H).

[0176] Intermediate 7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-6-amine B, the synthesis reaction formula of which is shown in Figure 3.

[0177] Step 1: Under stirring conditions, DMF-DMA (47.5 mL, 78 mmol) was added to a solution of 5-bromo-4-fluoropyridine-2-amine (5.0 g, 26.17 mmol) in DMF (20.0 mL). The reaction mixture was placed in a sealed tube and heated to 130°C overnight. After cooling to room temperature, it was refluxed under reduced pressure to remove volatile components, yielding a red oil. This product was dissolved in 40.0 mL of ethanol and 10 mL of pyridine. The solution was cooled in an ice bath, and then hydroxylamine-O-sulfonic acid (4.7 g, 42.3 g) was added in a single batch.mmol). The reaction mixture was slowly heated to room temperature and stirred overnight. Volatile components were removed by reflux under reduced pressure, and the residue was then separated using saturated brine and EA. The aqueous phase was further extracted with EA, the organic phases were combined, and washed with saturated brine (100 mL). The mixture was then dried over magnesium sulfate, concentrated under reduced pressure, and finally yielded an orange solid crude product. Purification was performed by rapid column chromatography (silica gel; 0–4% MeOH / DCM gradient elution) to give 6-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine (3.1 g, 55.3% yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J = 6.4 Hz, 1H), 8.54 (s, 1H), 8.01 (d, J = 8.9 Hz, 1H).

[0178] Step 2: To a 20 mL solution of 6-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine (500 mg, 2.29 mmol) in toluene, diphenylmethyleneimine (620 mg, 3.43 mmol), BINAP (142 mg, 0.229 mmol), Pd2(dba)3 (210 mg, 0.229 mmol), and sodium tert-butoxide (660 mg, 6.87 mmol) were added. The mixture was stirred at 130 °C for 16 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (PE:EA = 10:1~1:1) to obtain N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-diphenylmethyleneimine (130 mg, yield 17.8%), as a yellow oil. LCMS (ESI) [M+H]+317.1.

[0179] Step 3: 2 M hydrochloric acid (2 mL) was added to a THF (10 mL) solution of N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-diphenylmethyleneimine (130 mg, 0.408 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the pH of the solution was adjusted to 7 with NaHCO3. The residue was extracted with EA (10 mL × 3), and the organic phase was dried with Na2SO4 and concentrated under reduced pressure to obtain crude 7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-6-amine (65 mg), which was a yellow oil. LCMS (ESI) [M+H]+153.1.

[0180] The intermediate 7-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-amine C, the synthesis reaction formula of which is shown in Figure 4.

[0181] Step 1: Under stirring, DMF-DMA (5.27 g, 0.0443 mmol) was added to a DMF (20.0 mL) solution of 5-bromo-4-methoxypyridin-2-amine (3 g, 0.0147 mmol). The reaction mixture was placed in a sealed tube, heated to 130°C, and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude (E)-N'-(5-bromo-4-methoxypyridin-2-yl)-N,N-dimethylformamidinium (3.9 g), a pale yellow solid.

[0182] Step 2: Hydroxylamine hydrochloride (1.6 g, 0.0233 mmol) and sodium hydroxide (932 mg, 0.0233 mmol) were added to an ethanol (40 mL) solution of (E)-N'-(5-bromo-4-methoxypyridin-2-yl)-N'-dimethylformamide (3.9 g, 0.0155 mmol). The mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the mixture was concentrated. The residue was purified by rapid column chromatography (PE:EA = 10:1~3:1) to obtain N-(5-bromo-4-methoxypyridin-2-yl)-N'-hydroxyformimide (3.7 g, yield 79.61%), which was a yellow oil. LCMS (ESI) [M+H]+245.8.

[0183] Step 3: Add TFAA (3.4 g, 0.03 mmol) to a THF (200 mL) solution of N-(5-bromo-4-methoxypyridin-2-yl)-N'-hydroxyformimide (3.7 g, 0.015 mmol). Stir at room temperature for 16 hours. After the reaction is complete, add water (10 mL) to quench the reaction, and extract the residue with EA (15 mL × 3). Purify the residue by rapid column chromatography (PE:EA=5:1) to obtain 6-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (906 mg, yield 78.43%), as a yellow oil. LCMS (ESI) [M+H]+227.9. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.38 (s, 1H), 7.40 (s, 1H), 3.99 (s, 3H).

[0184] Step 4: Add diphenylimine (790 mg, 0.439 mmol) and BINAP to a toluene (20 mL) solution of 6-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (500 mg, 0.219 mmol).(140 mg, 0.0219 mmol), Pd2(dba)3 (280 mg, 0.0307 mmol) and sodium tert-butoxide (420 mg, 0.439 mmol). The mixture was stirred at 120 °C for 16 hours. After the reaction was complete, water (15 mL) was added to quench the reaction and the mixture was extracted with EtOAc (3 × 30 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (PE:EA = 3:1) to give N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-diphenylmethyleneimine (451 mg, yield 35.21%) as a yellow oil. LCMS (ESI) [M+H]+329.3.

[0185] Step 5: Add 2 M hydrochloric acid (1.7 mL) to a THF (10 mL) solution of N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-diphenylmethyleneimine (451 mg, 1.375 mmol). Stir at room temperature for 1 hour. After the reaction is complete, adjust the pH of the solution to 7 with NaHCO3. Extract the residue with EA (10 mL × 3), dry the organic phase with Na2SO4, concentrate under reduced pressure to obtain crude 7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-amine (225 mg), which is a yellow oil. LCMS (ESI) [M+H]+165.1. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.06 (d, J= 1.6 Hz, 1H), 7.04 (s, 1H), 6.31 (s, 1H), 3.91 (s, 3H).

[0186] The intermediate 7-fluoroimidazolo[1,2-a]pyridine-6-amine D, the synthesis reaction formula of which is shown in Figure 5.

[0187] Step 1: In a 250 mL round-bottom flask equipped with a magnetic stir bar, 5-bromo-4-fluoropyridine-2-amine (5 g, 26.1 mmol) was dissolved in EtOH (64 mL). Then, 50% 2-chloroacetaldehyde aqueous solution (7.8 g, 39.18 mmol) was added, and the mixture was heated to 100 °C and reacted for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the crude product was adsorbed onto silica gel. The product was purified by rapid chromatography (DCM / MeOH gradient elution) to obtain a light yellow oil (4.3 g, yield 76.7%). ¹H NMR (400 MHz, DMSO-d6) δ 10.02 (s, ¹H), 8.42 (s, ¹H), δ 8.42 (s, ¹H).1H), 8.24 (d, J = 1.9 Hz, 1H), 8.01 (s, 1H), 2.73 (s, 3H).

[0188] Step 2: Add diphenylimine (3.36 g, 18.6 mmol), BINAP (142 mg, 0.229 mmol), Pd2(dba)3 (210 mg, 0.229 mmol) and sodium tert-butoxide (5.3 g, 55.8 mmol) to a toluene (20 mL) solution of 6-bromo-7-fluoroimidazolo[1,2-a]pyridine (4.0 g, 18.6 mmol). Stir at 130 °C for 16 hours under a nitrogen atmosphere. Filter the mixture and concentrate the filtrate. The residue was purified by rapid column chromatography (PE:EA = 10:1~1:1) to obtain N-(7-fluoroimidazolo[1,2-a]pyridin-6-yl)-1,1-diphenylmethyleneimine (1.17 g, yield 20.0%), as a yellow oil. LCMS (ESI) [M+H]+317.1.

[0189] Step 3: To a THF (50 mL) solution of N-(7-fluoroimidazolo[1,2-a]pyridin-6-yl)-1,1-diphenylmethyleneimine (1.17 g, 3.71 mmol), 2 M hydrochloric acid (10 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH of the solution was adjusted to 7 with NaHCO3. The residue was extracted with EA (10 mL × 3), the organic phase was dried with Na2SO4, and concentrated under reduced pressure to obtain crude 7-fluoroimidazolo[1,2-a]pyridine-6-amine (435 mg), which was a yellow oil. LCMS (ESI) [M+H]+152.3. 1H NMR (400 MHz, CD3OD) δ 8.25 (d, J = 7.3 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 9.8 Hz, 1H).

[0190] The intermediate 7-methylimidazolo[1,2-a]pyridine-6-amine E, the synthesis reaction formula of which is shown in Figure 6.

[0191] Step 1: In a 250 mL round-bottom flask equipped with a magnetic stirrer, dissolve 4-methyl-5-nitropyridine-2-amine (5 g, 32.65 mmol) in n-butanol (64 mL). Then add 50% 2-chloroacetaldehyde aqueous solution (7.8 g, 39.18 mmol).The solvent was removed by heating to 130°C and reacting for 12 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and the crude product was adsorbed onto silica gel. The product was purified by rapid column chromatography (DCM / MeOH gradient elution) to obtain a light yellow oil (5.2 g, yield 89.9%). ¹H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.42 (s, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.01 (s, 1H), 2.73 (s, 3H).

[0192] Step 2: Pd / C (500 mg, 10 wt%) was added to an EA (30 mL) solution of 7-methyl-6-nitroimidazo[1,2-a]pyridine (5.2 g, 29.38 mmol). The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 7-methylimidazo[1,2-a]pyridine-6-amine (4.1 g, yield 95.3%) as a yellow solid. LCMS (ESI) [M+H]+148.1. 1H NMR (400 MHz, DMSO‑d6) δ 8.13 (d,J = 1.8 Hz, 1H), 8.01 (s, 1H), 7.92 (d,J= 2.0 Hz, 1H), 7.60 (s, 1H), 5.94 – 5.17 (m, 2H), 2.32 (s, 3H).

[0193] The intermediates tert-butyl 4-(2-chloro-7-(methyl-d3)-8-oxo-7,8-dihydro-9H-purin-9-yl)-3,3-difluoropiperidin-1-carboxylic acid ester F4', tert-butyl 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-3,3-difluoropiperidin-1-carboxylic acid ester F4, 2-chloro-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one F6' and 2-chloro-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one F6, are shown in Figure 7.

[0194] Step 1: At 78°C, DIPEA (245.97 g, 1906.8 mmol) was added to a THF (1500 mL) solution of tert-butyl-4-amino-3,3-difluoropiperidine-1-carboxylic acid ester (150.0 g, 635.6 mmol), followed by a THF (100 mL) solution of 2,4-dichloro-5-nitropyrimidine (112.04 g, 635.6 mmol).Solution. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with EtOAc (1500 mL), washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0–20% EtOAc / PE) to give tert-butyl-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylic acid ester (231.0 g, yield 92.4%) as a yellow solid. LC / MS (ESI) m / z: 393.8 (M+H)+. 1H NMR (400 MHz, DMSO‑d 6) δ 9.11 (s, 1H) , 8.53 (d ,J = 8.9 Hz, 1H) , 5.13 – 4.92 (m , 1H) , 4.39 – 4.16 (m , 1H) , 4.12 – 3.94 (m , 1H), 3.71 – 3.48 (m, 1H), 3.21 – 2.95 (m, 1H), 2.08 – 1.83 (m, 2H), 1.42 (s, 9H).

[0195] Step 2: Iron powder (164.58 g, 2938.93 mmol) was added to an ethanol (2300 mL)-water (50 mL) solution of tert-butyl 4-((2-chloro-5-nitropyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylic acid ester (231 g, 587.79 mmol), followed by ammonium chloride (158.70 g, 2938.93 mmol). The reaction mixture was stirred at 80 °C for 3 hours. The mixture was filtered, and the filtrate was concentrated. After the reaction was complete, EtOAc (1000 mL) was added to dilute the residue, which was then washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-50% EtOAc / PE) on pages 33 / 48 of the instruction manual (CN 121794270 A) to give tert-butyl-4-((5-amino-2-chloropyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylic acid ester (107.9 g, yield 50.56%), as a yellow solid. LC / MS (ESI) m / z: 364.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.16 (s, 2H), 4.78 (s, 1H), 4.17 (s, 1H).3.95 (s, 1H), 3.38 (s, 1H), 3.17 (s, 1H), 1.93 (d, J = 45.7 Hz, 1H), 1.65 (d, J = 10.6 Hz, 1H), 1.42 (s, 9H).

[0196] Step 3: Add CDI (250.80 g, 1780.0 mmol) to an EA (1000 mL) solution of tert-butyl 4-((5-amino-2-chloropyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylic acid ester (107.9 g, 296.60 mmol). Stir the mixture at 85 °C for 10 hours. After the reaction was complete, the mixture was washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-50% EtOAc / PE) to give tert-butyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-3,3-difluoropiperidine-1-carboxylic acid ester (100 g, yield 90.82%) as a white solid. LCMS (ESI) [M+H]+389. 1H NMR (400 MHz, DMSO‑d 6) δ 11.81 (s, 1H) , 8.21 (s, 1H) , 5.03 – 4.80 (m, 1H) , 4.23 (ddd,J = 45.8, 23.9, 4.6 Hz, 2H) , 3.71 – 3.37 (m, 1H) , 3.24 – 2.96 (m, 2H) , 1.99 (d,J = 12.1 Hz, 1H) , 1.44 (s, 9H).

[0197] Step 4: At 0°C, NaH (60%, 12.93 g, 323.26 mmol) was added to a DMF (1000 mL) solution of tert-butyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-3,3-difluoropiperidine-1-carboxylic acid ester (105.0 g, 269.38 mmol). The mixture was stirred at 0°C for 20 minutes, and then a DMF (80 mL) solution of MeI (57.378 g, 404.07 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was diluted with EtOAc (1000 mL), washed with water and saturated brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-70% EtOAc / PE) to obtain tert-butyl.4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-3,3-difluoropiperidine-1-carboxylic acid ester (73.5 g, yield 67.57%) is a white solid. LCMS (ESI) [M+H]+403.8. 1H NMR (400 MHz, DMSO-d 6) δ 8.44 (d, J = 6.4 Hz, 1H), 5.05 – 4.84 (m, 1H), 4.19 (d, J = 56.6 Hz, 2H), 3.54 (d, J = 24.4 Hz, 1H), 3.39 (s, 3H), 3.25 – 2.92 (m, 2H), 2.05 – 1.96 (m, 1H), 1.41 (d, J = 24.6 Hz, 9H).

[0198] Step 4': Same as step 4, but using CD3I instead of MeI to obtain intermediate F4'. LCMS (ESI) [M+H]+ 407.1. Step 5: At 0 °C, TFA (100 mL) was added to a DCM (500.0 mL) solution of tert-butyl-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-3,3-difluoropiperidin-1-carboxylic acid ester (73.5 g, 182.01 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to dryness to give 2-chloro-9-(3,3-difluoropiperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (55.28 g, 100% yield) as a yellow solid. LCMS (ESI) [M+H]+ 304.1.

[0199] Step 6: At 0°C, formaldehyde (37%, 70.5 g, 864 mmol) was added to a methanol (2000 mL) solution of 2-chloro-9-(3,3-difluoropiperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (54 g, 167.8 mmol). The mixture was stirred at room temperature for 1 hour, and then NaBH3CN (21.9 g, 337 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, DCM (2000 mL) was added to dilute the mixture, then it was washed with water and saturated brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give 2-chloro-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (50 g, yield 93.78%) as a white solid. LCMS(ESI) [M+H]+318.1. 1H Specification 34 / 48 pages 37 CN 121794270 A NMR (400 MHz, DMSO-d 6) δ 8.42 (s, 1H), 4.70 – 4.55 (m, 1H), 3.39 (s, 3H), 3.21 – 3.09 (m, 2H), 2.93 (d, J = 11.9 Hz, 1H), 2.55 (d, J = 11.8 Hz, 1H), 2.30 (s, 3H), 2.25 (d, J = 11.2 Hz, 1H), 1.91 (dd, J = 8.6, 4.3 Hz, 1H).

[0200] Step 6': Operate in the same way as step 4, using CD3I instead of MeI to obtain intermediate F5'. LCMS (ESI) [M+ H]+321.1. General method for chiral resolution of racemic products 1~14, as shown in Figure 8.

[0201] Dissolve the sample in about 150 mL of EtOH, inject 7 mL each time, and separate the enantiomers using a chiral Pre-SFC column (Waters SFC 150, 250*25 mm 10 μm DAICELCHIRALPAK ®AS SFC column) (mobile phase: supercritical CO2-EtOH=55:45, flow rate: 70 g / min, detection wavelength: 214 nm).

[0202] A typical example of chiral resolution of racemic products using the general method is shown in Figure 9.

[0203] Following the general method for chiral resolution of racemic products, 9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (100 mg) was chirally separated to obtain (R)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (40 mg, 99%, yellow solid). LCMS (ESI) [M+H]+484. 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.00 (s, 1H), 4.74 – 4.51 (m, 1H), 3.56 – 3.47 (m, 1H), 3.45 (s, 3H), 3.34 – 3.22 (m, 1H), 3.19 – 3.03 (m, 1H), 2.61 – 2.49 (m, 1H), 2.46 (s, 3H), 2.35 – 2.24 (m, 1H), 1.97 – 1.88 (m, 1H). SFC: 99%, and (S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (44 mg, 99%, yellow solid). LCMS (ESI) [M+ H]+484. 1H NMR (400 MHz, CDCl3)δ 9.90 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 6.99 (s, 1H), 4.78 – 4 .51 (m, 1H), 3.57 – 3.46 (m, 1H), 3.46 (s, 3H), 3.32 – 3.22 (m, 1H), 3.15 – 3.08 (m, 1H), 2.69 – 2.48 (m, 1H), 2.45 (s, 3H) , 2.35 – 2.23 (m, 1H), 1.97 – 1.87 (m, 1H). SFC: 99%.

[0204] Example 2 Synthesis of (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (1), the synthetic reaction formula of which is shown in Figure 10.

[0205] To a 1,4-dioxane (500 mL) solution of 2-chloro-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (intermediate F6, 25 g, 178.5 mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (intermediate A, 17.5 g, 120 mmol) was added, followed by Cs2CO3 (65 g, 118 mmol), Ruphos (7.35 g, 15.5 mmol), and Ruphos Pd G3 (7.25 g, 8.5 mmol). The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, the mixture was diluted with EtOAc (500 mL) and then with water and saturated brine.The sample was washed, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give compound 1,9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (19.5 g, 45.4 mmol, yield 37.9%) as a yellow solid. LCMS (ESI) [M+H]+430.2. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H) , 8.25 (s, 1H) , 7.94 (s, 1H) , 7.56 (s, 1H) , 6.71 (s, 1H) , 4.72 – 4.56 (m, 1H), 3.60 – 3.49 (m, 1H), 3.45 (s, 3H), 3.32 – 3.23 (m, 1H), 3.16 – 3.09 (m, 1H), 2.60 – 2.51 (m, 1H), 2.50 (s , 3H) , 2.47 (s , 3H) , 2.33 – 2.25 Specification 35 / 48 pages 38 CN 121794270 A (m, 1H) , 1.94 – 1.89 (m, 1H).

[0206] Example 3 Synthesis of (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (11), the synthesis reaction formula is shown in Figure 11.

[0207] Step 1: 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (intermediate A, 350 mg, 2.4 mmol) was added to a 1,4-dioxane (10 mL) solution of tert-butyl-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-3,3-difluoropiperidine-1-carboxylic acid ester (intermediate F4, 635 mg, 1.57 mmol), followed by Cs2CO3 (1.3 g, 2.36 mmol), Ruphos (147 mg, 0.31 mmol), and Ruphos Pd G3 (145 mg, 0.17 mmol). The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, EtOAc (20 mL) was added to dilute the mixture, and then...The sample was washed with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give tert-butyl 3,3-difluoro-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidine-1-carboxylic acid ester (150 mg, yield 18.65%) as a yellow solid. LC / MS (ESI) m / z: 516.2 (M+H)+.

[0208] Step 2: At 0°C, TFA (1.5 mL) was added to a DCM (5 mL) solution of tert-butyl 3,3-difluoro-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidine-1-carboxylic acid ester (150 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was purified by preparative high performance liquid chromatography (C18, 0.1% formic acid-acetonitrile (0~90%)-water) to give compound 11 (25.0 mg, yield 20.68%) as a white solid. LCMS (ESI) [M+H]+416.1. 1H NMR (400 MHz, DMSO‑d 6) δ 9.25 (s, 1H), 8.65 (s, 1H), 8.37 (s, 1H), 8.15 (d,J = 13.7 Hz, 2H), 7.70 (s , 1H) , 4.80 – 4.67 (m , 1H) , 3.34 (s , 3H) , 3.17 – 2.91 (m, 4H) , 2.79 – 2.71 (m, 1H) , 2.40 (s, 3H) , 1.97 – 1.88 (m, 1H).

[0209] Example 4 Synthesis of (R / S)-9-(1-ethyl-3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (2), the synthetic reaction formula of which is shown in Figure 12.

[0210] NaBH3CN (18 mg, 0.28 mmol) was added to a solution of compound 11 (100 mg, 0.24 mmol) in acetaldehyde (10 mL). The mixture was stirred at 30 °C for 5 hours. After the reaction was completed, water (20 mL) was added, and EtOAc (20 mL × 3) was used.Extraction and concentration of the organic phase under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=30:1) to give compound 2 (50 mg, yield 47%) as a white solid. LCMS (ESI) [M+H]+444.2. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 6.71 (s, 1H) , 4.72 – 4.56 (m, 1H) , 3.60 – 3.51 (m, 1H) , 3.45 (s, 3H) , 3.32 – 3.25 (m, 1H) , 3.16 – 3.11 (m, 1H) , 2.60 –2.47 (m, 9H) , 2.33 – 2.27 (m, 1H), 1.94 – 1.89 (m, 1H).

[0211] Example 5 Synthesis of (R / S)-9-(3,3-difluoro-1-isopropylpiperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (3), the synthetic reaction formula of which is shown in Figure 13.

[0212] NaBH3CN (22 mg, 0.35 mmol) was added to a solution of compound 11 (100 mg, 0.24 mmol) in acetone (10 mL). The reaction mixture was stirred at 30 °C for 5 hours. After the reaction was completed, water (20 mL) was added, and the organic phase was concentrated by extraction with EtOAc (20 mL × 3). The residue was purified by column chromatography (DCM:MeOH=30:1) to obtain compound 3 (60 mg, yield 54.7%), a white solid. LC-MS: (ESI) m / z=458.2 [M+H]. (Pages 36 / 48, CN 121794270 A) 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 6.71 (s, 1H), 4.72 – 4.56 (m, 1H), 3.60 – 3.49 (m, 1H) , 3.45 (s, 3H) , 3.32 – 3.25 (m, 1H) , 3.16 – 3.11 (m, 1H) , 2.60 – 2.46 (m, 11H) ,2.33 – 2.25 (m, 1H), 1.94 – 1.89 (m, 1H).

[0213] Example 6 Synthesis of (R / S)-9-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (4), the synthetic reaction formula of which is shown in Figure 14.

[0214] Following the preparation method of compound 1, 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (intermediate A, 15 mg, 0.1 mmol) was added to a 1,4-dioxane (5 mL) solution of intermediate F6′ (50 mg, 0.16 mmol), followed by the addition of Cs2CO3 (130 mg, 0.24 mmol), Ruphos (13 mg, 0.027 mmol), and Ruphos Pd G3 (13 mg, 0.015 mmol). After the reaction was complete, compound 4 (21 mg, yield 48.6%) was obtained as a white solid. LCMS (ESI) [M+H]+433.2. 1H NMR (400 MHz, DMSO‑d 6) δ 9.21 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 7.69 (s, 1H), 4 .78 – 4.67 (m, 1H), 3.34 (s, 3H), 3.15–2.72 (m, 5H), 2.42 (s, 3H), 1.97 – 1.88 (m, 1H).

[0215] Example 7 Synthesis of (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (5), the synthetic reaction formula is shown in Figure 15.

[0216] According to the preparation method of compound 1, intermediate F4′ was first treated with TFA to remove the Boc protecting group, then subjected to a reductive amination reaction, and then coupled with intermediate A to finally obtain compound 5, which is a white solid. LCMS (ESI) [M+H]+433.2. 1H NMR (400 MHz, DMSO‑d 6) δ 9.23 (s , 1H) , 8.65 (s , 1H) , 8.36 (s , 1H) , 8.17 (s , 1H) , 7.71 (s , 1H) , 4.79 – 4.67 (m, 1H), 3.17–2.71 (m, 5H), 2.49 (s, 3H), 2.42 (s, 3H), 1.95–1.89 (m, 1H).

[0217] Example 8 Synthesis of (R / S)-9-(3,3-difluoro-1-(oxacyclobutane-3-yl)piperidin-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (6), the synthetic reaction formula is shown in Figure 16.

[0218] NaBH3CN (23.2 mg, 0.369 mmol) was added to a DCM (10 mL) solution of compound 11 (153 mg, 0.369 mmol) and 3-oxetane (53.2 mg, 0.738 mmol). The mixture was stirred at 30 °C for 5 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3) to concentrate the organic phase. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give compound 6 (76 mg, yield 43.9%) as a white solid. LCMS (ESI) [M+H]+472.2. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 6.72 (s, 1H), 4.63 (dd, , 2.49 (d , J = 13.5 Hz, 7H), 2.30 (t, J = 13.1 Hz, 1H), 1.93 (d, J = 12.6 Hz, 1H).

[0219] Example 9 Specification 37 / 48 pages 40 CN 121794270 A (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (7), the synthesis reaction formula of which is shown in Figure 17.

[0220] To intermediate F6 (250 mg, 0.79 mmol) 17-fluoro-[1,2,4]triazolo[1,5-a]pyridine-6-amine (132 mg, 0.87 mmol) was added to a 5 mL solution of 4-dioxane, followed by Cs₂CO₃ (641 mg, 1.97 mmol), Ruphos (73 mg, 0.16 mmol), and Ruphos Pd G₃ (66 mg, 0.08 mmol). The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, the mixture was diluted with 10 mL of EtOAc, washed with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give compound 7 (120 mg, 35% yield) as a yellow solid. LCMS (ESI) [M +H]+434.1H NMR (400 MHz, CDCl3) δ 10.10 (d ,J = 6.9 Hz, 1H) , 8.27 (s, 1H) , 8.00 (s , 1H) , 7.45 (d ,J = 10.6 Hz, 1H) , 7 .18 (s , 1H) , 4.66 (s , 1H) , 3.62 – 3.53 (m , 1H) , 3.47 (s , 3H) , 3.37 – 3.27 (m , 1H) , 3.23 – 3.12 (m , 1H) , 2.51 (s , 3H) , 2.40 – 2.26 (m, 1H), 1.99 – 1.90 (m, 1H), 1.69 – 1.65 (m, 1H). Example 10 Synthesis of (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (8), the synthetic reaction formula of which is shown in Figure 18.

[0221] 7-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-amine (63 mg, 0.38 mmol) was added to a 1,4-dioxane (10 mL) solution of intermediate F6 (100 mg, 0.31 mmol), followed by the addition of Cs₂CO₃ (256 mg, 0.79 mmol), Ruphos (29 mg, 0.06 mmol), and Ruphos Pd G₃ (26 mg, 0.03 mmol). The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, EtOAc (10 mL) was added.The mixture was diluted (mL), washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give compound 8 (82 mg, yield 59.4%) as a yellow solid. LCMS (ESI) [M+H]+446.0.1H NMR(400 MHz, CDCl3) δ 10.04 (s, 1H) , 8.19 (s, 1H) , 8.02 – 7.95 (m, 1H) , 7.52 (s, 1H) , 7.06 (s, 1H) , 4.72 – 4.58 (m, 1H) , 4.10 (s, 3H) , 3.58 (dt, J = 13.0, 9.6 Hz, 1H) , 3.45 (s , 3H) , 3.35 – 3.25 (m , 1H) , 3.22 – 3.11 (m , 1H), 2.53 (s, 1H), 2.51 (s, 3H), 2.39 – 2.28 (m, 1H), 1.97 – 1.89 (m, 1H). Example 11 Synthesis of (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-2-((7-fluoroimidozop[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (9), the synthetic reaction formula is shown in Figure 19.

[0222] 7-Fluorimidazolo[1,2-a]pyridine-6-amine (357 mg, 2.36 mmol) was added to a 1,4-dioxane (10 mL) solution of intermediate F6 (500 mg, 1.57 mmol), followed by Cs₂CO₃ (1.28 g, 3.93 mmol), Ruphos (147 mg, 0.31 mmol), and Ruphos Pd G₃ (132 mg, 0.16 mmol). The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, EtOAc (20 mL) was added to dilute the mixture, followed by washing with water and saturated brine, drying with anhydrous Na₂SO₄, filtering, and concentrating to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give compound 9 (255 mg, yield 37.6%) as a yellow solid. LCMS (ESI) [M+H]+ 433.1H NMR (400 MHz, CDCl3) δ 9.72 (d, J = 7.3 Hz, 1H), 8.00 (s, 1H).7.68 (s, 1H), 7.58 (s, 1H), 7.47 (d, J = 11.2 Hz, 1H), 7.13 (s, 1H), 4.73 – 4.60 (m, 1H), 3.57 – 3.47 (m, 1H), 3.47 (s, 3H), 3.34 – 3.26 (m, 1H), 3.11 – 3.04 (m, 1H), 2.56 – 2.45 (m, 4H), 2.31 – 2.24 (m, 1H), 1.91 – 1.87 (m, ... (See specification pages 38 / 48, CN 121794270 A for more details) 1H). Example 12 Synthesis of (R / S)-9-(3,3-difluoro-1-methylpiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (10), the synthetic reaction formula of which is shown in Figure 10.

[0223] 7-methylimidazo[1,2-a]pyridin-6-amine (347 mg, 2.36 mmol) was added to a 1,4-dioxane (10 mL) solution of intermediate F6 (500 mg, 1.57 mmol), followed by the addition of Cs2CO3 (1.28 g, 3.93 mmol), Ruphos (147 mg, 0.31 mmol) and Ruphos Pd G3 (132 mg, 0.16 mmol). The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, EtOAc (20 mL) was added to dilute the mixture, which was then washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give compound 10 (288 mg, yield 42.8%) as a yellow solid. LCMS (ESI) [M+H]+ 429. 1H NMR (400 MHz, CDCl3) δ 9.45 (s , 1H) , 7.95 (s , 1H) , 7.65 (s , 1H) , 7.55 (s , 1H) , 7.49 (s , 1H) , 6.69 (s, 1H), 4.69 – 4.57 (m, 1H), 3.58 – 3.48 (m, 1H), 3.45 (s, 3H), 3.32 – 3.23 (m, 1H), 3.08 – 3.03 (m, 1H), 2.60 – 2.49(m, 1H), 2.48 (s, 3H), 2.44 (s, 3H), 2.28 – 2.22 (m, 1H), 1.90 – 1.86 (m, 1H).

[0224] Example 13 Synthesis of (R / S)-9-(3,3-difluoropiperidin-4-yl)-7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one (12), the synthetic reaction formula is shown in Figure 21.

[0225] To a 1,4-dioxane (10 mL) solution of intermediate F4 (635 mg, 1.57 mmol), 7-methylimidazo[1,2-a]pyridine-6-amine (347 mg, 2.4 mmol) was added, followed by Cs₂CO₃ (1.3 g, 2.36 mmol), Ruphos (147 mg, 0.31 mmol), and Ruphos Pd G₃ (145 mg, 0.17 mmol). The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, EtOAc (20 mL) was added to dilute the mixture, followed by washing with water and saturated brine, drying with anhydrous Na₂SO₄, filtering, and concentrating to dryness. The residue was purified by rapid column chromatography (silica gel, 0–100% EtOAc / PE) to give tert-butyl 3,3-difluoro-4-(7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidin-1-carboxylic acid ester (240 mg, yield 29.66%), as a yellow solid. LC / MS (ESI) m / z: 515.3 (M+H)+. At 0 °C, TFA (3 mL) was added to a DCM (10 mL) solution of tert-butyl 3,3-difluoro-4-(7-methyl-2-((7-methylimidazo[1,2-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidine-1-carboxylic acid ester (240 mg, 0.47 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was purified by preparative high-performance liquid chromatography (C18, 0.1% formic acid-acetonitrile (0-90%)-water) to give product 12 (110 mg, yield 56.9%) as a white solid. LCMS (ESI) [M+H]+ 415.1. 1H NMR (400 MHz, DMSO‑d 6) δ 9.14 (s, 1H) , 8.76 (s, 1H) , 8.26 – 8.15 (m, 2H) , 8.06 (d ,J =2.0 Hz, 1H), 7.81 (s, 1H), 5.13 – 4.94 (m, 1H), 3.89 – 3.81 (m, 1H), 3.69 – 3.51 (m, 2H), 3.36 (s, 3H), 3.31 – 3 .22 (m, 3H), 2.47 (s, 3H), 2.32 – 2.17 (m, 1H).

[0226] Example 14 Synthesis of (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (13), the synthetic reaction formula is shown in Figure 22.

[0227] According to the preparation method of compound 11, intermediate F4 was first coupled with intermediate B, and then the Boc protecting group was removed to obtain compound 13, which is a yellow solid. LCMS (ESI) [M+H]+420.1. 1H NMR (400 MHz, DMSO-d₆) δ 8.89 (d, J = 6.9 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 10.6 Hz, 1H), 7.18 (s, 1H), 4.68 (s, 1H), 3.37 (s, 3H), 3.17 – 2.92 (m, 2H), 2.60 – 2.46 (m, 2H), 1.99 – 1.90 (m, 2H). (See specification pages 39 / 48, CN 121794270 A for details.) 1.79 – 1.75 (m, 1H).

[0228] Example 15 Synthesis of (R / S)-9-(3,3-difluoropiperidin-4-yl)-2-((7-fluoroimidazolo[1,2-a]pyridin-6-yl)amino)-7-methyl-7,9-dihydro-8H-purine-8-one (14), the synthetic reaction formula of which is shown in Figure 23.

[0229] According to the preparation method of compound 12, intermediate F4 was first coupled with intermediate D, and then the Boc protecting group was removed to obtain compound 14, which is a yellow solid. LCMS (ESI) [M+H]+419.2. 1H NMR (400 MHz, DMSO‑d 6) δ 9.42 (d,J = 7.3 Hz, 1H) , 8.46 (s, 1H) , 8.00 (s, 1H) , 7.68 (s, 1H) , 7.58 (s, 1H) , 7.47 (d,J = 11.2 Hz,1H) , 5.23 – 5.01 (m, 1H) , 3.87 – 3.79 (m, 1H) , 3.69 – 3.51 (m, 2H) , 3.38 (s, 3H) , 3.31 – 3.26 (m, 2H) , 2.31 – 2.24 (m, 1H) , 1.91 – 1.87 (m, 1H).

[0230] Example 16 The following enantiomeric pure compounds 15–42 were obtained by separation according to the general chiral resolution method for racemic products 1–14: Specification 40 / 48 pages 43 CN 121794270 A Specification 41 / 48 pages 44 CN 121794270 A Specification 42 / 48 pages 45 CN 121794270 A Specification 43 / 48 pages 46 CN 121794270 A Specification 44 / 48 pages 47 CN 121794270 A Specification 45 / 48 pages 48 CN 121794270 A

[0231] Example 17. Biological test data The inhibitory activity of compound (I) against DNA-PK kinase was detected by the TR-FRET method. The experimental procedure is as follows: Prepare 4× serially diluted compounds using 1× reaction buffer, and add 2.5 μL of each 4× serially diluted compound to each well of a 384-well plate (6008280, PerkinElmer); prepare 4× p53 using pre-chilled 1× reaction buffer, and add 2.5 μL of 4× p53 to each well; prepare 4× DNA-PK enzyme solution using pre-chilled dilution buffer, and add 2.5 μL of 4× DNA-PK enzyme solution to each well; prepare 4× ATP using pre-chilled ddH2O, and add 2.5 μL of 4× ATP to each well; centrifuge the 384-well plate at 1000 rpm for 1 minute and incubate at room temperature in the dark for 30 minutes. Add 5 μL of stop solution to each well, and then add 5 μL of the detection mixture (antiphosphorylated p53 (ser15)-K and anti-GST-d2) to each well. Centrifuge the 384-well plate at 1000 rpm for 1 minute and incubate at room temperature in the dark. Results were read using a BMG microplate reader at wavelengths of 665 nm and 615 nm.

[0232] In the DNA-PK kinase inhibition assay, the compounds of the present invention showed good inhibitory effects on DNA-PK kinase.

[0233] Table 1: Inhibitory activity of representative compounds against DNA-PK kinase (IC50 units are nM)

[0234] The phosphorylation level of DNA-PK protein was detected using HT-29 cells with an ODYSSEY CLx (LI-COR) microplate. HT-29 cells were seeded in 384-well cell culture plates and incubated at 37°C and 5%...The cells were cultured under CO2 conditions for 24 hours. Using an Echo 550, the appropriate concentrations of the compound were added to 384-well plates containing HT-29 cells (see page 46 / 48, CN 121794270 A in the instruction manual). The final concentrations of the tested compounds were 10000, 3333, 1111, 370, 123, 41, 13, 4.57, 1.52, and 0.51 nM. The HT-29 cells were then irradiated with 10 Gy of gamma rays. The plates were cultured at 37°C and 5% CO2 for 1 hour. At room temperature (approximately 22°C), the cells were fixed with paraformaldehyde for 20 minutes. The cells were then permeabilized with 1×PBS containing 0.1% Triton X-100. 50 µL of Odyssey Blocking Buffer was added to the 384-well plates, and the plates were blocked at room temperature for 1.5 hours. The blocking buffer was removed using a plate washer (BioTek ELx405 Select CW). Add 20 µL of primary antibody (containing anti-DNA PKcs (phosphorylated S2056) antibody (Abcam, ab124918) and anti-DNA PKcs antibody (Abcam, ab44815)) to each well of a 384-well plate. Incubate overnight at 4°C. Then wash the plate with washing buffer containing 0.1% Tween-20. Add 20 µL of secondary antibody (containing IRDye 800CW goat anti-rabbit IgG (LI-COR, 926-32211) and IRDye 680CW goat anti-mouse IgG (H+L) (LI-COR, 926-68070)) to each well. Incubate at room temperature in the dark for 1 hour. Wash cells with 1×PBS containing 0.1% Tween-20. For best results, scan the plate immediately after washing using an ODYSSEY CLx (LI-COR).

[0235] In the cellular-level inhibition assay of DNA-PK phosphorylation, the compounds of the present invention effectively inhibited the pDNA-PK signaling pathway in HT-29 cells, thus possessing the potential to overcome resistance to radiotherapy or chemotherapy by inhibiting DNA-PK protein-induced DNA damage repair.

[0236] Table 2: Inhibitory activity of representative compounds against pDNA-PK in HT-29 cells (IC50 units in nM)

[0237] Blood-brain barrier permeability: To determine whether the compounds could cross the blood-brain barrier (BBB), the test compounds were administered to rats or mice. Animals were sacrificed 4 hours after administration, and blood and brain tissue were collected to analyze the concentration of the test compounds. Brain permeability was defined as the ratio of the concentration of the compound in brain tissue to the concentration of the compound in plasma. In some embodiments, some compounds exhibited brain penetration ability with a low efflux rate. For example, compound 7 had a blood-brain barrier permeability of 0.24, and therefore it may have the ability to penetrate the brain to achievePotential for effective concentrations.

[0238] Susceptibility to aldehyde oxidase: Human aldehyde oxidase (hAOX) is a cytoplasmic drug-metabolizing enzyme expressed in the human liver. Similar to CYP, it contributes to the oxidation of large amounts of quinoline derivatives (which does not require NADPH coenzyme factor). AOX substrate drugs typically exhibit high metabolic clearance, leading to reduced human exposure and thus reduced drug efficacy (Lepri et al., PNAS, 2017, pp. E3178-E3187). The compounds of the present invention are not substrates of human aldehyde oxidase and have long half-lives, thus possessing the potential for effective drug efficacy and low metabolic clearance in the treatment and / or prevention of cancer, cancer with brain metastases, cancer with meningeal metastases, glioma, glioblastoma, DIPG, and other central nervous system diseases.

[0239] Table 3: Aldehyde Oxidase Susceptibility of Representative Compounds Specification 47 / 48 pages 50 CN 121794270 A

[0240] Although several embodiments have been described in this invention, the basic embodiments of this invention may be modified to provide other embodiments utilizing the compounds and methods of this invention. Therefore, the scope of protection of this invention should be determined by the appended claims, and not limited to the specific embodiments shown as examples. Instruction manual 48 / 48 pages 51 CN 121794270 A Figure 1A Instruction manual Figure 1 / 10 page 52 CN 121794270 A Figure 1B Instruction manual Figure 2 / 10 page 53 CN 121794270 A Figure 1C Instruction manual Figure 3 / 10 page 54 CN 121794270 A Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Instruction manual Figure 4 / 10 page 55 CN 121794270 A Figure 7 Figure 8 Instruction manual Figure 5 / 10 page 56 CN 121794270 A Figure 9 Figure 10 Figure 11 Instruction manual Figure 6 / 10 page 57 CN 121794270 A Figure 12 Figure 13 Figure 14 Instruction manual Figure 7 / 10 page 58 CN 121794270 A Figure 15 Figure 16 Figure 17 Instruction manual Figure 8 / 10 page 59 CN 121794270 A Figure 18 Figure 19 Figure 20 Drawings from the Specification 9 / 10 Page 60 CN 121794270 A Figure 21 Figure 22 Figure 23 Drawings from the Specification 10 / 10 Page 61 CN 121794270 A Abstract The present invention discloses substituted2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9- dihydro-8H-purin-8-one compounds having the structural formula represented by formula (I): (I) The substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purin-8-one compounds, derivatives and pharmaceutically acceptable salts thereof of the present invention are capable of acting as a drug characteristic of a protein kinase inhibitor, and in particular, inhibit the expression of a protein induced by DNA-dependent protein kinase (DNA-PK) and can be used to treat or prevent disorders associated with abnormal protein kinase activity, such as cancer, cancer with brain metastases, cancer with meningeal metastases, glioma, glioblastoma, DIPG, and the like, either as monotherapy or in combination with other treatments, such as radiation therapy or chemotherapy.

Claims

1. A compound comprising the structure shown in formula (I), (I) R1 is independently selected from hydrogen, methyl, ethyl, isopropyl, deuterated methyl or oxetane; R2 is independently selected from methyl or deuterated methyl; R3 is independently selected from fluorides, methyl groups, or OCH3; X is independently selected from CH or nitrogen.

2. A pharmaceutical composition comprising the compound of claim 1, or a salt thereof, a solvate thereof, a hydrate thereof, or a polymorph thereof, and a pharmaceutically acceptable excipient or adjuvant thereof.

3. A DNA-PK inhibitor, characterized in that, The active ingredient of the inhibitor is the compound according to claim 1; the inhibitor is capable of crossing the blood-brain barrier.

4. Use of the compound of claim 1, or the pharmaceutical composition of claim 2, or the inhibitor of claim 3, in the preparation of a medicament for treating or preventing diseases related to DNA-PK activation induced by DNA-PK protein.

5. The use according to claim 4, characterized in that, The protein in question is a DNA-dependent protein kinase.

6. The use according to claim 4, characterized in that, The disease is a metastatic cancer of the central nervous system, brain cancer, proliferative disease or cancer, wherein the compound shown in formula (I) is administered simultaneously, separately or sequentially with radiotherapy.

7. The use according to claim 4, for the treatment of the cancer of claim 6, wherein the compound of formula (I) is administered simultaneously, separately, or sequentially with at least one other antitumor drug that may cause DNA double-strand breaks, said antitumor drug being selected from: cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amiroboracin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, rucapab, niraparib, taprazolepanib, pamipanib, pembrolizumab, nivolumab, cimipril, spartalizumab, sintilimab, tislelizumab, dostalimab, atezolizumab, avelumab, durvalumab, osimertinib, and WSD0922.

8. The use according to claim 6, characterized in that, The diseases mentioned are glioblastoma, diffuse en bloc pontine glioma, astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma, vestibular schwannoma, and medulloblastoma.

9. A method of treating cancer in a warm-blooded animal requiring the treatment, comprising administering to the warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and administering it simultaneously, separately, or sequentially with other treatments.