阅读说明：本技术 用于治疗癌症的5-乙酰氨基甲基-噁唑烷酮衍生物 (5-acetamidomethyl-oxazolidinone derivatives for the treatment of cancer ) 是由 詹姆斯·哈里森 于 2019-09-06 设计创作，主要内容包括：本文提供了用于治疗、缓解或预防癌症的化合物,或其药学上可接受的盐或溶剂化物。(Provided herein are compounds, or pharmaceutically acceptable salts or solvates thereof, for use in the treatment, alleviation or prevention of cancer.)

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment, alleviation or prevention of cancer:

wherein X is O, S, SO or SO₂；

R¹Is hydrogen, except that when X is O, then R¹Can be hydrogen, CN, CO₂R⁶OR optionally by OR⁶、OCOR⁶、N(R⁶)₂Or NHCOR⁶Substituted C_1-2An alkyl group;

R²is hydrogen, except when X is O and R¹Is CH₃When then R is²Can be H or CH₃；

R³And R⁴Independently hydrogen, F or Cl;

R⁵is hydrogen, optionally substituted by one or more R⁷Substituted C_1-8Alkyl radical, C_3-6Cycloalkyl, amino, C_1-8Alkylamino radical, C_1-8Dialkylamino or C_1-8An alkoxy group;

each R⁶Independently hydrogen, optionally substituted by one or more R⁷Substituted C_1-8Alkyl radical, C_3-6Cycloalkyl, amino, C_1-8Alkylamino radical, C_1-8Dialkylamino or C_1-8An alkoxy group;

each R⁷Independently F, Cl, OH, C_1-8Alkoxy radical, C_1-8Acyloxy or O-CH₂-Ph；

And n is 0, 1 or 2.

2. The compound for use according to claim 1, wherein X is O.

3. A compound for use according to claim 1 or claim 2, wherein R¹Is hydrogen, CN, CO₂R⁶OR optionally by OR⁶、OCOR⁶、N(R⁶)₂Or NHCOR⁶Substituted C_1-2An alkyl group.

4. A compound for use according to any one of the preceding claims, wherein R¹Is hydrogen, CN, CO₂H or optionally substituted by OH, OCOH, NH₂Or NHCOH substituted C_1-2An alkyl group.

5. A compound for use according to any one of the preceding claims, wherein R¹Is hydrogen or C_1-2An alkyl group.

6. A compound for use according to any one of the preceding claims, wherein R²Is hydrogen.

7. A compound for use according to any one of the preceding claims, wherein R³And R⁴Is F or Cl.

8. A compound for use according to any one of the preceding claims, wherein R³And R⁴One of F or Cl and the other is hydrogen, optionally R³And R⁴One of which is F and the other is hydrogen.

9. A compound for use according to any one of the preceding claims, wherein R⁵Is hydrogen or optionally substituted by one or more R⁷Substituted C_1-8An alkyl group.

10. A compound for use according to any one of the preceding claims, wherein R⁵Is hydrogen or optionally substituted by one or more R⁷Substituted C_1-5An alkyl group.

11. A compound for use according to any one of the preceding claims, wherein R⁵Is CH₃。

12. A compound for use according to any one of the preceding claims, wherein n is 1.

13. The compound for use according to any one of the preceding claims, wherein the compound of formula (I) is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

14. the compound for use according to any one of the preceding claims, wherein the cancer is a solid tumor or a solid cancer.

15. A compound for use according to any preceding claim, wherein the cancer is intestinal, brain, breast, endometrial, gastric, liver, lung, ovarian, pancreatic, prostate or skin cancer.

16. The compound for use according to claim 15, wherein: (i) the intestinal cancer is colon cancer or rectal cancer; (ii) the brain cancer is glioma or glioblastoma; (iii) the breast cancer is HER2 positive breast cancer or HER2 negative breast cancer; (iv) the liver cancer is hepatocellular carcinoma; (v) the lung cancer is non-small cell lung cancer or small cell lung cancer; or (vi) the skin cancer is melanoma.

17. A compound for use according to any preceding claim, wherein the compound of formula (I) is used in combination with one or more chemotherapeutic drugs, optionally wherein the compound of formula (I) is used after the chemotherapeutic drug.

18. The compound for use according to claim 17, wherein the chemotherapeutic drug comprises bleomycin, capecitabine, carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, epirubicin, eribulin, etoposide, 5-fluorouracil, leucovorin, gemcitabine, methotrexate, mechlorethamine, oxaliplatin, paclitaxel, prednisolone, procarbazine, vinblastine, vincristine, and/or vinorelbine.

19. The compound for use according to any one of the preceding claims, wherein the compound of formula (I) is used in combination with a DNA damaging or DNA damaging response process (DDR) interfering drug.

20. A compound for use according to claim 19, wherein the compound of formula (I) is for use in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor, an ATM inhibitor, an ATR inhibitor, a checkpoint inhibitor, a Vascular Endothelial Growth Factor (VEGF) inhibitor or a wee1 inhibitor.

21. The compound for use according to claim 20, wherein (i) the PARP inhibitor is a PARP1 inhibitor; or (ii) the checkpoint inhibitor is a programmed cell death protein 1(PD-1) inhibitor, a programmed death-ligand 1(PD-L1) inhibitor or a cytotoxic T-lymphocyte-associated protein 4(CTLA-4) inhibitor.

22. The compound for use according to claim 21, wherein the PARP1 inhibitor is gold thiomalate, Aurothioglucose (ATG), lucapanib, olaparib, nilapali, tarazol panini, viliparib, pamidrarib, 2X-121, or auranofin.

23. The compound for use of claim 22, wherein the PARP1 inhibitor comprises a gold complex, optionally wherein the PARP1 inhibitor comprises gold thiomalate, ATG, or auranofin.

24. A pharmaceutical composition for use in the treatment of cancer, which comprises a compound of formula (I) as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable vehicle.

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition further comprises a drug that damages DNA or interferes with DNA damage response processes (DDR), optionally wherein the DDR drug is a poly (ADP-ribose) polymerase (PARP) inhibitor, an ATM inhibitor, an ATR inhibitor, a checkpoint inhibitor, a Vascular Endothelial Growth Factor (VEGF) inhibitor, or a wee1 inhibitor.

26. The pharmaceutical composition of claim 25 wherein (i) the PARP inhibitor is a PARP1 inhibitor; or (ii) the checkpoint inhibitor is a programmed cell death protein 1(PD-1) inhibitor, a programmed death-ligand 1(PD-L1) inhibitor or a cytotoxic T-lymphocyte-associated protein 4(CTLA-4) inhibitor.

27. The pharmaceutical composition of claim 26, wherein said PARP1 inhibitor comprises a gold complex, or is gold thiomalate (ATM), Aurothioglucose (ATG), lucapanib, olaparib, nilapali, tarapanib, viliparib, pamidride, 2X-121, or auranofin.

28. The pharmaceutical composition of claim 27, wherein said PARP1 inhibitor comprises gold thiomalate, ATG, or auranofin.

29. A method for the preparation of a composition according to any one of claims 24 to 28, which method comprises contacting a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable vehicle.