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CN-115124554-B - Pyrrolopyrimidine compound, preparation method thereof and application thereof in medicines

CN115124554BCN 115124554 BCN115124554 BCN 115124554BCN-115124554-B

Abstract

The present disclosure relates to pyrrolopyrimidines, methods of preparation and use thereof in medicine. In particular, the present disclosure relates to a pyrrolopyrimidine compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and use thereof as a therapeutic agent, particularly as a DNA-PK inhibitor and in the preparation of a medicament for the treatment and/or prevention of cancer. Wherein each group in the general formula (I) is defined in the specification.

Inventors

  • LU BIAO
  • ZHANG CAIHUA
  • HE FENG
  • TAO WEIKANG

Assignees

  • 江苏恒瑞医药股份有限公司
  • 上海恒瑞医药有限公司

Dates

Publication Date
20260512
Application Date
20220325
Priority Date
20210326

Claims (17)

  1. 1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof: Wherein: Ring a is a3 to 6 membered heterocyclyl; R m and R n are the same or different and are each independently selected from a hydrogen atom and a C 1-6 alkyl group; Or R m and R n together with the attached carbon atom form a 3 to 6 membered cycloalkyl, said 3 to 6 membered cycloalkyl optionally substituted by one or more R 4 ; Each R 1 is the same or different and is independently a hydrogen atom or a C 1-6 alkyl group; R 2 is selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group; each R 3 is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and cyano; each R 4 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group; n is 0, 1 or 2; p is 0,1, 2,3 or 4, and The compound of formula (I) is not 。
  2. 2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II): Wherein: t is 0, 1 or 2; m is 0,1, 2,3 or 4; the rings A, R 1 to R 4 , n and p are as defined in claim 1.
  3. 3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (III): Wherein: m is 0,1, 2,3 or 4; the rings A, R 1 to R 4 , n and p are as defined in claim 1.
  4. 4. A compound of the general formula (I) according to claim 1, wherein R m and R n are the same or different and are each independently selected from a hydrogen atom and a C 1-6 alkyl group; Or R m and R n together with the attached carbon atom form a 3 to 6 membered cycloalkyl.
  5. 5. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein R m and R n are the same or different and are each independently selected from a hydrogen atom and a methyl group; Or R m and R n together with the attached carbon atom form a cyclopropane.
  6. 6. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 1 is the same or different and is each independently a hydrogen atom.
  7. 7. A compound of the general formula (I) according to claim 1, wherein R 2 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  8. 8. A compound of the general formula (I) according to claim 1, wherein R 3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  9. 9. A compound, or a pharmaceutically acceptable salt thereof, selected from the following structures: 、 、 、 And 。
  10. 10. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises: The compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IB) or the salt thereof undergo a coupling reaction to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof, Wherein: x is halogen; The rings A, R m 、R n 、R 1 to R 3 , n and p are as defined in claim 1.
  11. 11. The method of claim 10, wherein X is a chlorine atom.
  12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  13. 13. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for inhibiting DNA-PK.
  14. 14. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 12 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition selected from leukaemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumour, retinoblastoma, neuroblastoma, germ cell tumour, teratoma, gastric cancer, oesophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, sarcoma and pediatric cancer.
  15. 15. The use of claim 14, wherein the sarcoma is selected from the group consisting of chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, and kaposi's sarcoma.
  16. 16. The use according to claim 14, wherein the colorectal cancer is colon cancer or rectal cancer.
  17. 17. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 12 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition selected from the group consisting of embryonic dysplastic neuroepithelial tumors, glioblastoma multiforme, medulloblastoma, salivary gland carcinoma, gastrointestinal stromal tumors.

Description

Pyrrolopyrimidine compound, preparation method thereof and application thereof in medicines Technical Field The present disclosure relates to a pyrrolopyrimidine compound, a preparation method thereof and application thereof in medicine, which belongs to the field of medicine. In particular, the disclosure relates to pyrrolopyrimidine compounds represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds as DNA-PK inhibitors in preparation of medicines for treating and/or preventing cancers. Background The DNA-dependent protein kinase (DNA-PK) is a serine/hydroxybutyrate kinase complex composed of a heterodimer of catalytic subunits DNA-PKcs and Ku protein (Ku 70/Ku 80), is an important protein in the DNA damage repair process (Cancer Discovery,2014,4,1126-1139), and plays an important role in maintaining the stability of telomerase, participating in natural immunity and V (D) J recombination, transcriptional regulation and the like (Curr Opin ALLERGY CLIN Immunol,2009,9,503-509). Eukaryotic DNA repair is mainly of 4 types, nucleotide Excision Repair (NER), base Excision Repair (BER), mismatch repair (MMR) and Double Strand Break Repair (DSBR). NER can cleave large fragments of DNA lesions, BER can repair individual base lesions, MMR can repair base mismatches, and DSBR can include two mechanisms, non-homologous end joining (NHEJ) and Homologous Recombination (HR). NHEJ is directly linked to the stump without the need for a template, HR requires the use of the intact sister chromatid as a repair template. NHEJ is the predominant repair pathway, which occurs in all phases of the cell cycle. While HR occurs primarily in the G2/M phase of the cell cycle (CHEMMEDCHEM, 2017,12,895-900). Three kinases of the PI3K related kinase (PIKK) family, DNA-dependent protein kinases (DNA-PKs), ataxia telangiectasia mutated kinase (ATM), and ATM and Rad3 related kinases (ATR), play a leading role in DNA damage repair. DNA-PK is mainly involved in the NHEJ pathway, ATM is mainly involved in the HR pathway, and ATR mainly repairs single-stranded DNA lesions (NAT REV CLIN Oncol.,2019,81-104). When a DNA double strand breaks, the cyclic Ku70/Ku80 heterodimer recognizes and binds to the broken DNA end, recruiting DNA-PKcs. The recruitment of DNA-PKcs facilitates the movement of the Ku heterodimer into the DNA duplex, allowing the DNA-PKcs to act as a tether to break the DNA ends and prevent exonuclease degradation. At the same time, binding to DNA promotes activation of the catalytic activity of DNA-PKcs, the major autophosphorylation sites being Ser2056 and Thr2609.DNA-PKcs also result in the phosphorylation of a range of downstream proteins, including Artemis, DNA ligase 4, histone H2A variants (H2 AX), and the like, which together complete DNA double-strand repair (NAT REV CLIN Oncol.,2019,81-104). DNA-PK is highly expressed in many types of tumor tissue and can cause tumor metastasis by stimulating angiogenesis and tumor cell migration (CLIN CANCER RES,2019,25,5623-5637). Moreover, an increase in DNA-PK activity is closely related to drug resistance to chemotherapeutic agents and to a poor prognosis. Studies have shown that DNA-PK inhibitors significantly increase the sensitivity of tumor cells to x-ray radiation (IR) and chemotherapeutics, and increase the tumor-inhibiting effect of the PAPR inhibitor olaharib (Nat Commun.,2019,10,5065-5079;Mol Cancer Res,2019,17,2457-2468). Several patents for DNA-PK inhibitors (WO 2019238929A1, WO2018114999A1, WO2014183850A1, etc.) are currently issued by companies typified by AstraZeneca and Merck, and there is room for improvement in both in vitro activity and selectivity of these structural classes of compounds. Wherein the small molecule DNA-PK inhibitor of AstraZeneca entered clinical stage 10 in 2019. At present, no DNA-PK inhibitor drugs are approved for marketing, and thus there is a significant unmet medical need in the relevant patient population. Disclosure of Invention The purpose of the present disclosure is to provide a compound represented by general formula (I): Wherein: Ring a is a3 to 14 membered cycloalkyl or a3 to 14 membered heterocyclyl; R m and R n are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl; Or R m and R n together with the attached carbon atom form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 4; Each R 1 is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, and hydroxyalkyl; R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl