IP Library › Granted Patent US 51,039

Granted Patent E1

US 51,039 · App. 18/350,653 · Granted Sep 22, 2026

Crystal of benzofuran derivative free base and preparation method

Inventors: Likun Wang (Lianyungang, CN); Zhenxing Du (Lianyungang, CN); Qiyun Shao (Lianyungang, CN); Chao Xu (Lianyungang, CN)

Assignee: Jiangsu Hengrui Medicine Co., LTD.

C07D405/14 A61K31/4545

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Quick Facts

Patent No.: US 51,039
App. No.: 18/350,653
Granted: Sep 22, 2026
Kind: E1

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Abstract

This application describes a crystal of a benzofuran derivative free base and a preparation method. Specifically, this application describes crystal A, crystal B, crystal C, and crystal D of N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran)4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide and a preparation method for the crystals. The crystals of the compound of formula (I) have great crystal stability and provides improved uses in clinical treatment.

Claims (163)

1 . A compound of formula (I):

having a crystal form selected from the group consisting of crystal form A, crystal form B, crystal form C, and crystal form D, wherein:

the crystal form A has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 11.80, 12.38, 13.52, 13.73, 14.48, 15.23, 15.99, 16.10, 16.82, 16.99, 17.35, 18.24, 20.82, 21.57, 21.91, 22.57, 22.76, 22.88, 24.29, 24.47, 25.24, 25.90, 27.23 and 27.74 using Cu-Kα radiation;

the crystal form B has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angle 2θ±0.2 of 6.31, 7.24, 10.99, 12.07, 14.56, 17.94, 19.13, 19.71, 21.48, 24.15, 27.10 and 28.83 using Cu-Kα radiation;

the crystal form C has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 12.32, 13.39, 15.52, 19.15, 19.17, 21.42 and 22.78 using Cu-Kα radiation; and

the crystal form D has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 11.38, 12.18, 13.45, 15.15, 16.73, 17.59, 17.68, 20.45, 21.51, 22.72, 24.53, 24.91 and 27.11 using Cu-Kα radiation.

2 . The compound according to claim 1 , wherein the crystal form is crystal form A.

3 . The compound according to claim 2 , wherein the crystal form A has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 10.37, 11.16, 11.80, 12.38, 12.89, 13.52, 13.73, 14.03, 14.48, 15.23, 15.99, 16.10, 16.43, 16.82, 16.99, 17.35, 18.24, 18.92, 19.17, 20.68, 20.82, 21.57, 21.91, 22.57, 22.76, 22.88, 23.53, 23.68, 24.00, 24.29, 24.47, 24.91, 25.24, 25.72, 25.90, 27.23, 27.74 and 35.63 using Cu-Kα radiation.

4 . A method for preparing the compound according to claim 2 , selected from the group consisting of:

method I, the method comprising dissolving the compound of formula (I) in a solvent, crystallizing the compound of formula (I) from the solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form A, wherein the solvent is selected from the group consisting of an amide solvent, a mixed solvent of an amide solvent and water, and a mixed solvent of a halohydrocarbon and a nitrile, the amide solvent is selected from the group consisting of N,N-dimethylformamide and N,N-dimethylacetamide, the halohydrocarbon solvent is dichloromethane, and the nitrile solvent is acetonitrile, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal;

5 . The compoundcrystal form according to claim 1 , wherein the crystal form is crystal form B.

6 . The compound according to claim 5 , wherein the crystal form B has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 7.24, 8.92, 10.38, 10.99, 12.07, 14.56, 15.10, 16.36, 17.29, 17.94, 19.13, 19.71, 21.12, 21.48, 22.59, 24.15, 25.45, 26.28, 26.52, 27.10, 28.83, 30.07, 31.37, 32.56, 33.65, 34.64, 36.09, 37.13 and 40.04 using Cu-Kα radiation.

7 . A method for preparing the compound according to claim 5 , selected from the group consisting of:

8 . The compound according to claim 1 , wherein the crystal form is crystal form C.

9 . The compound according to claim 8 , wherein the crystal form C has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 2θ±0.2 of 7.40, 8.62, 9.49, 9.96, 11.12, 12.32, 13.39, 14.21, 14.85, 15.52, 16.50, 17.67, 18.28, 19.15, 19.17, 20.06, 20.80, 21.42, 21.89, 22.20, 22.78, 23.41, 24.74, 25.34, 26.70, 27.38, 28.64, 29.63, 30.20 and 31.15 using Cu-Kα radiation.

10 . A method for preparing the compound according to claim 8 , the method comprising:

dissolving the compound of formula (I) in a first solvent to obtain a mixture, adding an anti-solvent to the mixture, crystallizing the compound of formula (I) from the first solvent and the anti-solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form C, wherein the first solvent is an ether solvent, the ether solvent is 1,4-dioxane, the anti-solvent is selected from the group consisting of an aliphatic hydrocarbon solvent and an alicyclic hydrocarbon solvent, and the aliphatic hydrocarbon solvent is n-heptane, the alicyclic hydrocarbon solvent is cyclohexane, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal.

11 . The compound according to claim 1 , wherein the crystal form is crystal form D.

12 . The compound according to claim 11 , wherein the crystal form D has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 10.15, 11.38, 12.18, 13.45, 14.40, 15.15, 16.73, 17.59, 17.68, 18.42, 18.91, 19.22, 20.45, 21.15, 21.51, 22.11, 22.72, 24.03, 24.53, 24.91, 25.54, 26.54, 27.11, 27.61, 29.04, 30.49, 31.31, 33.00, 33.88, 35.52, 37.53, 40.46, 41.36, 42.40 and 44.02 using Cu-Kα radiation.

13 . A method for preparing the compound according to claim 11 , selected from the group consisting of:

method I, the method comprising dissolving the compound of formula (I) in a solvent, crystallizing the compound of formula (I) from the solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form D, wherein the solvent is selected from the group consisting of an alcohol solvent, an ether solvent, a mixed solvent of an alcohol and water, a mixed solvent of an ether and water, a mixed solvent of an alcohol and an aliphatic hydrocarbon, and a mixed solvent of an ether and an aliphatic hydrocarbon, the alcohol solvent is selected from the group consisting of methanol, ethanol and isopropanol, the ether solvent is selected from the group consisting of tetrahydrofuran and 1,4-dioxane, and the aliphatic hydrocarbon solvent is n-heptane, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal;

method II, the method comprising dissolving the compound of formula (I) in a first solvent to obtain a mixture, adding an anti-solvent to the mixture, crystallizing the compound of formula (I) from the first solvent and the anti-solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form D, wherein the first solvent is selected from the group consisting of an alcohol solvent and an ether solvent, the alcohol solvent is selected from the group consisting of methanol and isopropanol, the ether solvent is tetrahydrofuran, and the anti-solvent is water; or the good first solvent is an ether solvent, the ether solvent is tetrahydrofuran, the anti-solvent is selected from the group consisting of an aliphatic hydrocarbon solvent and an alicyclic hydrocarbon solvent, the aliphatic hydrocarbon solvent is n-heptane, and the alicyclic hydrocarbon solvent is cyclohexane, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal; and

method III, the method comprising adding the compound of formula (I) to a solvent to obtain a mixture, pulping the mixture to obtain a crystal, filtering and drying the crystal to obtain the crystal form D, wherein the solvent is selected from the group consisting of water, an ester, an ether, an aliphatic hydrocarbon, an alicyclic hydrocarbon, a nitroalkane solvent, an arene, an alcohol, a nitrile, a halohydrocarbon, a ketone, a sulfoxide, an amide, a mixed solvent of an alcohol and an ether, a mixed solvent of an alcohol and water, and a mixed solvent of one or more alcohol alcohols, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate and butyl acetate, the ether solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether and methyl tert- butyl tert-butyl ether, the aliphatic hydrocarbon is n-heptane, the alicyclic hydrocarbon is cyclohexane, the nitroalkane solvent is nitromethane, the arene solvent is selected from the group consisting of xylene and cumene, the alcohol solvent is selected from the group consisting of methanol, ethanol and isopropanol, the nitrile solvent is acetonitrile, the halohydrocarbon solvent is dichloromethane, the ketone solvent is acetone, the sulfoxide is dimethyl sulfoxide, the amide solvent is selected from the group consisting of N,N-dimethylformamide and N,N-dimethylacetamide, the mixed solvent of one or more alcohol alcohols is selected from the group consisting of a mixed solvent of methanol and ethanol, a mixed solvent of methanol and isopropanol, and a mixed solvent of ethanol and isopropanol.

14 . A pharmaceutical composition comprising the compound according to claim 1 and one or more pharmaceutically acceptable carriers, diluents or excipients.

15 . A method for treating a disease associated with one or more of an EZH2 inhibitor amplification or overexpression in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 14 .

16 . The method according to claim 15 , wherein the disease associated with EZH2 inhibitor one or more of an EZH2 amplification or overexpression is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor and myeloma.

17 . The method according to claim 16 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia, and wherein the lymphoma is selected from the group consisting of non-Hodgkin lymphoma, diffuse large B-cell lymphoma and follicular lymphoma.

18. The method according to claim 17 , wherein the leukemia is chronic myeloid leukemia, acute myeloid leukemia, or mixed lineage leukemia.

19. The method according to claim 17 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

20. The method according to claim 19 , wherein the lymphoma is non Hodgkin's lymphoma.

21. The method according to claim 19 , wherein the lymphoma is diffuse large B-cell lymphoma.

22. The method according to claim 19 , wherein the lymphoma is follicular lymphoma.

23. The method according to claim 16 , wherein the tumor or cancer is an ovarian tumor or an ovarian cancer.

24. A compound of formula (I):

having a crystal form A, wherein the crystal form A has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 15.23, 15.99, and 16.82 using Cu-Kα radiation.

25. The compound according to claim 24 , wherein the crystal form A has the powder X-ray diffraction spectrum comprising characteristic peaks at different angles 2θ±0.2 of 7.60, 8.51, 13.52, 14.48, 15.23, 15.99, 16.82, and 21.91 using Cu-Kα radiation.

26. The compound according to claim 25 , wherein the crystal form A has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 11.80, 12.38, 13.52, 14.48, 15.23, 15.99, 16.10, 16.82, 21.91, 22.57, 24.29, and 24.47 using Cu-Kα radiation.

27. The compound according to claim 26 , wherein the crystal form A has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 11.80, 12.38, 13.52, 13.73, 14.48, 15.23, 15.99, 16.10, 16.82, 16.99, 17.35, 18.24, 20.82, 21.57, 21.91, 22.57, 22.76, 22.88, 24.29, 24.47, 25.24, 25.90, 27.23, and 27.74 using Cu-Kα radiation.

28. A pharmaceutical composition comprising the compound according to claim 24 and one or more pharmaceutically acceptable carriers, diluents or excipients.

29. A method for inhibiting EZH2 in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 28 .

30. A method for treating a disease associated with one or more of an EZH2 amplification or overexpression in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 28 .

31. The method according to claim 30 , wherein the disease associated with one or more of an EZH2 amplification or overexpression is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor and myeloma.

32. The method according to claim 31 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

33. The method according to claim 31 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

34. The method according to claim 33 , wherein the lymphoma is non-Hodgkin's lymphoma.

35. The method according to claim 33 , wherein the lymphoma is diffuse large B-cell lymphoma.

36. The method according to claim 33 , wherein the lymphoma is follicular lymphoma.

37. The method according to claim 31 , wherein the disease is an ovarian tumor or an ovarian cancer.

38. A compound of formula (I):

having a crystal form A, wherein the crystal form A has a powder X-ray diffraction spectrum comprising characteristic peaks at different angles 2θ±0.2 of 7.60, 8.51, 15.23, 15.99, and 16.82 using Cu-Kα radiation, prepared by a process selected from the group consisting of:

method I, the method comprising dissolving the compound of formula (I) in a solvent, crystallizing the compound of formula (I) from the solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form A, wherein the solvent is selected from the group consisting of an amide solvent, a mixed solvent of an amide solvent and water, and a mixed solvent of halohydrocarbon and a nitrile, the amide solvent is selected from the group consisting of N,N-dimethylformamide and N,N-dimethylacetamide, the halohydrocarbon solvent is dichloromethane, and the nitrile solvent is acetonitrile, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal;

39. A compound of formula (I):

having a crystal form B, wherein the crystal form B has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 10.99, 19.13, 21.48, and 24.15 using Cu-Kα radiation.

40. The compound according to claim 39 , wherein the crystal form B has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 10.99, 12.07, 14.56, 17.94, 19.13, 21.48, and 24.15 using Cu-Kα radiation.

41. The compound according to claim 40 , wherein the crystal form B has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 7.24, 10.99, 12.07, 14.56, 17.94, 19.13, 19.71, 21.48, 24.15, 27.10, and 28.83 using Cu-Kα radiation.

42. The compound according to claim 41 , wherein the crystal form B has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 7.24, 8.92, 10.38, 10.99, 12.07, 14.56, 15.10, 17.94, 19.13, 19.71, 21.48, 24.15, 26.52, 27.10, and 28.83 using Cu-Kα radiation.

43. A pharmaceutical composition comprising the compound according to claim 39 and one or more pharmaceutically acceptable carriers, diluents or excipients.

44. A method for inhibiting EXH2 in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 43 .

45. A method for treating a disease associated with one or more of an EZH2 amplification or overexpression in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 43 .

46. The method according to claim 45 , wherein the disease associated with one or more of an EZH2 amplification or overexpression is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor and myeloma.

47. The method according to claim 46 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

48. The method according to claim 46 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

49. The method according to claim 48 , wherein the lymphoma is non-Hodgkin's lymphoma.

50. The method according to claim 48 , wherein the lymphoma is diffuse large B-cell lymphoma.

51. The method according to claim 48 , wherein the lymphoma is follicular lymphoma.

52. The method according to claim 46 , wherein the disease is an ovarian tumor or an ovarian cancer.

53. A compound of formula (I):

54. A compound of formula (I):

having a crystal form C, wherein the crystal form C has a powder X-ray diffraction spectrum comprising characteristic peaks a diffraction angles 2θ±0.2 of 7.40, 9.49, 12.32, 13.39, and 15.52 using Cu-Kα radiation.

55. The compound according to claim 54 , wherein the crystal form C has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 12.32, 13.39, 15.52, 22.78 using Cu-Kα radiation.

56. The compound according to claim 55 , wherein the crystal form C has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 12.32, 13.39, 15.52, 19.15, 19.17, 21.42, and 22.78 using Cu-Kα radiation.

57. The compound according to claim 56 , wherein the crystal form C has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 9.96, 12.32, 13.39, 14.21, 15.52, 17.67, 18.28, 19.15, 19.17, 21.42, 22.78, 24.74, and 25.34 using Cu-Kα radiation.

58. A pharmaceutical composition comprising the compound according to claim 54 and one or more pharmaceutically acceptable carriers, diluents or excipients.

59. A method for inhibiting EZH2 in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 58 .

60. A method for treating a disease associated with one or more of an EZH2 amplification or overexpression in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 58 .

61. The method according to claim 60 , wherein the disease associated with one or more of an EZH2 amplification or overexpression is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor and myeloma.

62. The method according to claim 61 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

63. The method according to claim 61 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

64. The method according to claim 63 , wherein the lymphoma is non-Hodgkin's lymphoma.

65. The method according to claim 63 , wherein the lymphoma is diffuse large B-cell lymphoma.

66. The method according to claim 63 , wherein the lymphoma is follicular lymphoma.

67. The method according to claim 61 , wherein the disease is an ovarian tumor or an ovarian cancer.

68. A compound of formula (I):

having a crystal form C, wherein the crystal form C has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 9.49, 12.32, 13.39, and 15.52 using Cu-Kα radiation, prepared by a process comprising dissolving the compound of formula (I) in a first solvent to obtain a mixture, adding and anti-solvent to the mixture, crystallizing the compound of formula (I) from the first solvent and the anti-solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form C, wherein the first solvent is an ether solvent, the ether solvent is 1,4-dioxane, the anti-solvent is selected from the group consisting of an aliphatic hydrocarbon solvent and an alicyclic hydrocarbon solvent, and the aliphatic hydrocarbon solvent is n-heptane, the alicyclic hydrocarbon solvent is cyclohexane, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal.

69. A compound of formula (I):

having a crystal form D, wherein the crystal form D has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 13.45, 17.59, 21.51, and 24.91 using Cu-Kα radiation.

70. The compound according to claim 69 , wherein the crystal form D has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 13.45, 15.15, 17.59, 17.68, 21.51, 24.91, and 27.11 using Cu-Kα radiation.

71. The compound according to claim 70 , wherein the crystal form D has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 11.38, 12.18, 13.45, 15.15, 16.73, 17.59, 17.68, 20.45, 21.51, 22.72, 24.53, 24.91 and 27.11 using Cu-Kα radiation.

72. The compound according to claim 71 , wherein the crystal form D has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 11.38, 12.18, 13.45, 14.40, 15.15, 16.73, 17.59, 17.68, 18.42, 20.45, 21.15, 21.51, 22.11, 22.72, 24.03, 24.53, 24.91, 25.54, 26.54, 27.11, 27.61, and 29.04 using Cu-Kα radiation.

73. A pharmaceutical composition comprising the compound according to claim 69 and one or more pharmaceutically acceptable carriers, diluents or excipients.

74. A method for inhibiting EZH2 in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 73 .

75. A method for treating a disease associated with one or more of an EZH2 amplification or overexpression in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 73 .

76. The method according to claim 75 , wherein the disease associated with one or more of an EZH2 amplification or overexpression is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor and myeloma.

77. The method according to claim 76 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

78. The method according to claim 76 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-call lymphoma, or follicular lymphoma.

79. The method according to claim 78 , wherein the lymphoma is non-Hodgkin's lymphoma.

80. The method according to claim 78 , wherein the lymphoma is diffuse large B-cell lymphoma.

81. The method according to claim 78 , wherein the lymphoma is follicular lymphoma.

82. The method according to claim 76 , wherein the disease is an ovarian tumor or an ovarian cancer.

83. A compound of formula (I):

method I, the method comprising dissolving the compound of formula (I) in a solvent, crystallizing the compound of formula (I) from the solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form D, wherein the solvent is selected from the group consisting of an alcohol solvent, an ether solvent, a mixed solvent of an alcohol and water, a mixed solvent of an ether and water, a mixed solvent of an alcohol and an aliphatic hydrocarbon, and a mixed solvent of an ether and an aliphatic hydrocarbon, the alcohol solvent is selected from the group consisting of methanol, ethanol and isopropanol, the ether solvent is selected from the group consisting of tetrahydrofuran and 1,4-dioxane, and the aliphatic hydrocarbon solvent is n-heptane, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal;

method II, the method comprising dissolving the compound of formula (I) in a first solvent to obtain a mixture, adding an anti-solvent to the mixture, crystallizing the compound of formula (I) from the first solvent and the anti-solvent using a crystallization method to obtain a crystal, filtering and drying the crystal to obtain the crystal form D, wherein the first solvent is selected from the group consisting of an alcohol solvent and an ether solvent, the alcohol solvent is selected from the group consisting of methanol and isopropanol, the ether solvent is tetrahydrofuran, and the anti-solvent is water; or the first solvent is an ether solvent, the ether solvent is tetrahydrofuran, the anti-solvent is selected from the group consisting of an aliphatic hydrocarbon solvent and an alicyclic hydrocarbon solvent, the aliphatic hydrocarbon solvent is n-heptane, and the alicyclic hydrocarbon solvent is cyclohexane, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal; and

method III, the method comprising adding the compound of formula (I) to a solvent to obtain a mixture, pulping the mixture to obtain crystal, filtering and drying the crystal to obtain the crystal form D, wherein the solvent is selected from the group consisting of water, an ester, an ether, an aliphatic hydrocarbon, an alicyclic hydrocarbon, a nitroalkane solvent, an arene, an alcohol, a nitrile, a halohydrocarbon, a ketone, a sulfoxide, an amide, a mixed solvent of an alcohol and an ether, a mixed solvent of an alcohol and water, and a mixed solvent of one or more alcohols, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate and butyl acetate, the ether solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether and methyl tert- butyl ether, the aliphatic hydrocarbon is n-heptane, the alicyclic hydrocarbon is cyclohexane, the nitroalkane solvent if nitromethane, the arene solvent is selected from the group consisting of xylene and cumene, the alcohol solvent is selected from the group consisting of methanol, ethanol and isopropanol, the nitril solvent is acetonitrile, the halohydrocarbon solvent is dichloromethane, the ketone solvent is acetone, the sulfoxide is dimethyl sulfoxide, the amide solvent is selected from the group consisting of N,N-dimethylformamide and N,N-dimethylacetamide, the mixed solvent of one or more alcohols is selected from the group consisting of a mixed solvent of methanol and ethanol, a mixed solvent of methanol and isopropanol, and a mixed solvent of ethanol and isopropanol.

84. A method for treating a tumor or cancer in a subject in need thereof, wherein the treating is associated with an EZH2 inhibitor and the tumor or cancer is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor and myeloma, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I):

having a crystal form selected from the group consisting of crystal form A, crystal form B, crystal form C, and crystal form D, wherein:

the crystal form A has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 15.23, 15.99, and 16.82 using Cu-Kα radiation;

the crystal form B has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 10.99, 12.07, 14.56, 17.94, 19.13, 21.48, and 24.15 using Cu-Kα radiation;

the crystal form C has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 9.49, 12.32, 13.39, and 15.52 using Cu-Kα radiation; and

the crystal form D has a powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 13.45, 17.59, 21.51, and 24.91 using Cu-Kα radiation.

85. The method according to claim 84 , wherein the crystal form is crystal form A.

86. The method according to claim 85 , wherein the crystal form A has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 13.52, 14.48, 15.23, 15.99, 16.82, and 21.91 using Cu-Kα radiation.

87. The method according to claim 86 , wherein the crystal form A has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 11.80, 12.38, 13.52, 14.48, 15.23, 15.99, 16.10, 16.82, 21.91, 22.57, 24.29, and 24.47 using Cu-Kα radiation.

88. The method according to claim 87 , wherein the crystal form A has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 11.80, 12.38, 13.52, 13.73, 14.48, 15.23, 15.99, 16.10, 16.82, 16.99, 17.35, 18.24, 20.82, 21.57, 21.91, 22.57, 22.76, 22.88, 24.29, 24.47, 25.24, 25.90, 27.23 and 27.71 using cu-Kα radiation.

89. The method according to claim 88 , wherein the crystal form A has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.60, 8.51, 10.37, 11.16, 11.80, 12.38, 12.89, 13.52, 13.73, 14.03, 14.48, 15.23, 15.99, 16.10, 16.43, 16.82, 16.99, 17.35, 18.24, 18.92, 19.17, 20.68, 20.82, 21.57, 21.91, 22.57, 22.76, 22.88, 23.53, 23.68, 24.00, 24.29, 24.47, 24.91, 25.24, 25.72, 25.90, 27.23, 27.74 and 35.63 using Cu-Kα radiation.

90. The method according to claim 85 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

91. The method according to claim 85 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

92. The method according to claim 91 , wherein the lymphoma is non-Hodgkin's lymphoma.

93. The method according to claim 91 , wherein the lymphoma is diffuse large B-cell lymphoma.

94. The method according to claim 91 , wherein the lymphoma is follicular lymphoma.

95. The method according to claim 85 , wherein the tumor or cancer is an ovarian tumor of an ovarian cancer.

96. The method according to claim 84 , wherein the crystal form is crystal form B.

97. The method according to claim 96 , wherein the crystal form B has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 10.99, 12.07, 14.56, 17.94, 19.13, 21.48, and 24.15 using Cu-Kα radiation.

98. The method according to claim 97 , wherein the crystal form B has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 7.24, 10.99, 12.07, 14.56, 17.94, 19.13, 19.71, 21.48, 24.15, 27.10 and 28.83 using Cu-Kα radiation.

99. The method according to claim 98 , wherein the crystal form B has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 7.24, 8.92, 10.38, 10.99, 12.07, 14.56, 15.10, 17.94, 19.13, 19.71, 21.48, 24.15, 26.52, 27.10, and 28.83 using Cu-Kα radiation.

100. The method according to claim 99 , wherein the crystal form B has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 6.31, 7.24, 8.92, 10.38, 10.99, 12.07, 14.56, 15.10, 16.36, 17.29, 17.94, 19.13, 19.71, 21.12, 21.48, 22.59, 24.15, 25.45, 26.28, 26.52, 27.10, 28.83, 30.07, 31.37, 32.56, 33.65, 34.64, 36.09, 37.13 and 40.04 using Cu-Kα radiation.

101. The method according to claim 96 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

102. The method according to claim 96 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

103. The method according to claim 102 , wherein the lymphoma is non-Hodgkin's lymphoma.

104. The method according to claim 102 , wherein the lymphoma is diffuse large B-cell lymphoma.

105. The method according to claim 102 , wherein the lymphoma is follicular lymphoma.

106. The method according to claim 96 , wherein the tumor or cancer is an ovarian tumor or an ovarian cancer.

107. The method according to claim 84 , wherein the crystal form is crystal form C.

108. The method according to claim 107 , wherein the crystal form C has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 12.32, 13.39, 15.52, and 22.78 using Cu-Kα radiation.

109. The method according to claim 108 , wherein the crystal form C has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 12.32, 13.39, 15.52, 19.15, 19.17, 21.42 and 22.78 using Cu-Kα radiation.

110. The method according to claim 109 , wherein the crystal form C has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 9.96, 12.32, 13.39, 14.21, 15.52, 17.67, 18.28, 19.15, 19.17, 21.42, 22.78, 24.74, and 25.34 using Cu-Kα radiation.

111. The method according to claim 110 , wherein the crystal form C has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 7.40, 8.62, 9.49, 9.96, 11.12, 12.32, 13.39, 14.21, 14.85, 15.52, 16.50, 17.67, 18.28, 19.15, 19.17, 20.06, 20.80, 21.42, 21.89, 22.20, 22.78, 23.41, 24.74, 25.34, 26.70, 27.38, 28.64, 29.63, 30.20 and 31.15 using Cu-Kα radiation.

112. The method according to claim 107 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

113. The method according to claim 107 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

114. The method according to claim 113 , wherein the lymphoma is non-Hodgkin's lymphoma.

115. The method according to claim 113 , wherein the lymphoma is diffuse large B-cell lymphoma.

116. The method according to claim 113 , wherein the lymphoma is follicular lymphoma.

117. The method according to claim 107 , wherein the tumor or cancer is an ovarian tumor or an ovarian cancer.

118. The method according to claim 84 , wherein the crystal form is crystal form D.

119. The method according to claim 118 , wherein the crystal form D has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 13.45, 15.15, 17.59, 17.68, 21.51, 24.91, and 27.11 using Cu-Kα radiation.

120. The compound according to claim 119 , wherein the crystal form D has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 11.38, 12.18, 13.45, 15.15, 16.73, 17.59, 17.68, 20.45, 21.51, 22.72, 24.53, 24.91 and 27.11 using Cu-Kα radiation.

121. The compound according to claim 120 , wherein the crystal form D has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 11.38, 12.18, 13.45, 14.40, 15.15, 16.73, 17.59, 17.68, 18.42, 20.45, 21.15, 21.51, 22.11, 22.72, 24.03, 24.53, 24.91, 25.54, 26.54, 27.11, 27.61, and 29.04 using Cu-Kα radiation.

122. The method according to claim 121 , wherein the crystal form D has the powder X-ray diffraction spectrum comprising characteristic peaks at diffraction angles 2θ±0.2 of 8.41, 8.85, 10.15, 11.38, 12.18, 13.45, 14.40, 15.15, 16.73, 17.59, 17.68, 18.42, 18.91, 19.22, 20.45, 21.15, 21.51, 22.11, 22.72, 24.03, 24.53, 24.91, 25.54, 26.54, 27.11, 27.61, 29.04, 30.49, 31.31, 33.00, 33.88, 35.52, 37.53, 40.46, 41.36, 42.40 and 44.02 using Cu-Kα radiation.

123. The method according to claim 118 , wherein the leukemia is selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia and mixed lineage leukemia.

124. The method according to claim 118 , wherein the lymphoma is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma.

125. The method according to claim 124 , wherein the lymphoma is non-Hodgkin's lymphoma.

126. The method according to claim 124 , wherein the lymphoma is diffuse large B-cell lymphoma.

127. The method according to claim 124 , wherein the lymphoma is follicular lymphoma.

128. The method according to claim 118 , wherein the tumor or cancer is an ovarian tumor or an ovarian cancer.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 31, 2026

From: WANG, LIKUN; DU, ZHENXING; SHAO, QIYUN; XU, CHAO

To: JIANGSU HENGRUI MEDICINE CO., LTD.

Reel/Frame 074230/0650 →

Priority Claims (1)

CN 201710350574.5 · May 18, 2017 · national

Continuity (1)

Reissue 16612168 · May 17, 2018

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