WO2021057975A1 - Mutant idh2 inhibitor and application thereof - Google Patents

Abstract

A compound (as shown in formula I) as a mutant isocitrate dehydrogenase 2 (IDH2) inhibitor, and a preparation method and a pharmaceutical composition thereof. Also disclosed is a use of the compound or pharmaceutical composition thereof in treatment of mutant IDH2-mediated diseases. The IDH2 inhibitor can inhibit generation of 2-HG in cells carrying the most common IDH2 mutant, and is an ideal target with low toxicity for efficient targeting of anti-tumor drugs.

Description

Mutant IDH2 inhibitor and its application Technical field

The present invention relates to a series of compounds as mutant isocitrate dehydrogenase 2 (IDH2) inhibitors, preparation methods and pharmaceutical compositions thereof. The present invention also relates to the use of the above-mentioned compound or its pharmaceutical composition in the treatment of diseases mediated by mutant IDH2.

Background technique

In recent years, three metabolic enzymes, fumarate dehydrogenase, succinate dehydrogenase and isocitrate dehydrogenase (IDH) have been found in tumors. The gene mutations of these enzymes change cell metabolism and may be related to the development of tumors. .

There are three types of human IDH, namely IDH1, IDH2 and IDH3. IDH1 is located in the cytoplasm and peroxisomes, and IDH2 and IDH3 are located in the mitochondria. This type of protease can oxidize isocitrate to oxalosuccinate, and then convert it to α-ketoglutarate (α-KG).

In 2009, Yan et al. discovered the IDH1 gene mutation for the first time when identifying the genetic characteristics of human glioblastoma, which opened the prelude to IDH in tumor research. A number of subsequent large-scale clinical glioma case-control studies have found that IDH1 gene mutations are more likely to occur in more than 75% of low-grade gliomas and 90% of secondary glioblastomas; IDH2 gene mutations are more likely to occur in About 20% of acute myeloid leukemias. In addition, IDH gene mutations have also been reported in cholangiocarcinoma (10%-23%), melanoma (10%) and chondroid tumors (75%). It can be seen that IDH mutations exist in a variety of tumors. Common mutation sites are the arginine residues located in the catalytic center (IDH1/R132H, IDH1/R132C, IDH2/R140Q, IDH2/R172K). The mutated IDH can catalyze the conversion of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG). Studies have shown that a-KG is structurally similar to 2-HG, and 2-HG competes with a-KG, thereby reducing the activity of a-KG-dependent enzymes, leading to hypermethylation of chromatin. This hypermethylation is It is believed that it interferes with normal cell differentiation and leads to excessive proliferation of immature cells, thereby causing cancer.

In 2013, Agios Pharmaceuticals reported the IDH2 ^R140Q inhibitor AGI-6780 and IDH2 ^R132H inhibitor AGI-5198 and another IDH2 ^R140Q inhibitor AG-221 that the company later marketed. AGI-6780 and AGI-5198 can inhibit the production of 2-HG in cells carrying common IDH1 and IDH2 mutants, respectively. In addition to inhibiting the production of 2-HG, these molecules also induced the differentiation of abnormally proliferating human cancer cells in culture. Studies have shown that AG-221 can effectively inhibit the enzymatic activity of ^{IDH2 R140Q} , and can effectively reduce the level of 2-HG in the cell supernatant and mouse plasma in the tumor xenograft model of ^{IDH2 R140Q} cells and IDH2 ^{R140Q cells.} AG-221 has completed the second phase of clinical trials to prove that 31%-40% of AML patients have a response of more than one year.

At present, drug research to inhibit mutant IDH2 for the treatment of cancer has achieved some success. However, there is still a need to develop mutant IDH2 inhibitors with stronger target inhibition and better selectivity for the treatment of related diseases mediated by mutant IDH2, and to provide a new drug option for the clinic.

Summary of the invention

The present invention relates to a compound as a mutant isocitrate dehydrogenase 2 (IDH2) inhibitor, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof. The general structural formula of the compound of the present invention is shown in formula (I):

Wherein, W is selected from N or C;

Z is selected from N or C;

M is O or chemical bond;

Ring X is a C _5-10 aromatic ring;

Ring Y is a 6-membered aryl group or a C _5-6 heteroaryl group, and the C _5-6 heteroaryl group contains 1, 2 or 3 nitrogen atoms;

R _{1 is} independently selected from H, NH ₂ , CN, -C(O)CH ₃ , hydroxyl, oxo, halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy , C _2-8 alkenyl, C _2-8 alkynyl or C _3-6 cycloalkyl, the NH ₂ , -C (O) CH ₃ or C _1-8 alkyl is optionally hydroxy, halogen, oxygen Substitute or C _1-3 alkyl substitution;

R _{2 is} selected from H, CN, halogen, C _1-8 alkyl or C _1-8 haloalkyl;

n is 1, 2 or 3.

In some embodiments, the ring X in formula (I) is a C _5-10 aromatic ring; wherein, the C _5-10 aromatic ring optionally contains 1, 2, or 3 independently selected from N, O or S Of heteroatoms.

_{In some embodiments, R 1} in formula (I) is independently selected from H, NH ₂ , CN, -C(O)CH ₃ , hydroxyl, oxo, halogen, C _1-3 alkyl, C _{1- 3} haloalkyl, C _1-3 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl or C _3-6 cycloalkyl, the NH ₂ , -C (O) CH ₃ or C _{1- The 3} alkyl group is optionally substituted with a hydroxy group, a halogen group, an oxo group or a C _1-3 alkyl group.

In some embodiments, the formula (I)

Selected from

In some embodiments, Z in formula (I) is C.

In some embodiments, the ring Y in formula (I) is a C6 heteroaryl group, and the C6 heteroaryl group contains 1, 2, or 3 nitrogen atoms.

In some embodiments, the formula (I)

for

_{In some embodiments, R 2} in formula (I) is selected from H, CN, halogen, C _1-3 alkyl or C _1-3 haloalkyl.

_{In some embodiments, R 2} in formula (I) is selected from CF ₃ , CN or Cl.

The present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

1) 2-(4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

2) 4-(6-Chloropyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

3) 4-(5-(Difluoromethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

4) 4-(2-(Difluoromethyl)-5-methylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(三(Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

5) 4-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

6) 4-(1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

7) 4-(Pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1, 3,5-Triazine-2-amine;

8) 4-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

9) 4,6-bis(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine- 2-amine;

10) 2-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)benzonitrile;

11) 4-(Indol-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

12) 4-(1-Methyldihydropyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4 -Base) -1,3,5-triazine-2-amine;

13) 4-(Chroman-6-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

14) 4-(2,3-Dihydrobenzofuran-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

15) 4-(1H-Indol-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

16) 4-(benzofuran-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1,3,5-triazine-2-amine;

17) 4-(Indoline-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

18) 2-(2-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)phenyl)propan-2-ol;

19) 4-(Isoindolin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

20) 2-(3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)phenyl)propan-2-ol;

21) 2-(6-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

22) 4-(1,3-Dihydroisobenzofuran-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

23) 4-(2-Methylisoxazol-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

24) 4-(1-Methyldihydro-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

25) 5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridin-3-ol;

26) 4-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-2-ol;

27) 4-(2-Methoxy-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

28) 4-(5-Ethynylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

29) 4-(5-chloropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

30) 4-(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

31) 4-(5-Methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

32) 4-(5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

33) 4-(6-(Trifluoromethyl)pyridin-2-yl)-6-(5-(trifluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

34) 4-(5-Cyclopropylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

35) 4-(2-Fluoro-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

36) 4-(4-(Trifluoromethyl)pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

37) 4-(6-fluoropyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

38) 4-(1-methyl-1H-pyrazol-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

39) 4-(1-methyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(tri

(Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

40)2-(5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-3-yl)propan-2-ol;

41) 4-(4-Methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

42) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-4-ol;

43) 4-(1,4-Dimethyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Yl)pyridin-4-yl)-1,3,5-triazin-2-amine;

44) 2-(3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-4-yl)propan-2-ol;

45) 4-(4-fluoropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

46) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-2(1H)-one;

47) 4-(5-Cyclopropyl-2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl )Pyridin-4-yl)-1,3,5-triazine-2-amine;

48) 1-Methyl-3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)pyridine-2(1H)-one;

49) 4-(2-Fluoro-4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

50) 4-(4,5-dimethylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

51) 4-(5-Cyclopropyl-2-fluoropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

52) 4-(2,4-dimethylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

53) 4-(2,5-dimethylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

54) 4-(2-Chloro-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

55) 4-(2-Amino-5-cyclopropylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

56) 4-(2-Amino-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

57) 4-(2-Aminopyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

58) 4-(6-Methoxypyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

59) 2-(6-amino-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-3-yl)propan-2-ol;

60) 4-(2-Amino-5-chloropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

61) 4-(2-Amino-5-(trifluoromethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

62) 4-(6-Fluoro-4-methylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

63) 6-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-2-ol;

64) 6-chloro-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1, 3,5-triazin-2-yl)pyridin-3-ol;

65) 4-(2-Fluoro-5-methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

66) 4-(2-Fluoro-5-methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

67) 4-Methyl-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-Triazine-2-yl)pyridin-3-ol;

68) 6-Methyl-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-Triazine-2-yl)pyridin-3-ol;

69) 6-amino-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1, 3,5-triazin-2-yl)nicotinonitrile;

70) 4-(2-(Difluoromethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

71) 4-(5-(Difluoromethyl)-6-fluoropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

72) 4-(5-(1,1-Difluoroethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

73) 1-(5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-3-yl)ethan-1-one;

74) 4-(3-Aminopyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

75) 4-(2-(1,1-Difluoroethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

76) 4-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)-2-cyanopyridine;

77) 4-(2-Methylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

78) 4-(5-Fluoro-2-methyl-pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

79) 4-(1,3-Dimethyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Yl)pyridin-4-yl)-1,3,5-triazin-2-amine;

80)2,2,2-Trifluoro-1-(5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine-4 -Amino)-1,3,5-triazin-2-yl)pyridin-3-yl)ethan-1-one;

81) 4-(5-(Dimethylamino)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

82)2-Methyl-1-(5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)pyridin-3-yl)propan-2-ol;

83) 4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-( 2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

84) 4-(4-Cyclopropylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

85) 4-(6-chloropyridin-2-yl)-6-(5-cyclopropylpyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1, 3,5-Triazine-2-amine;

86) 4-(5-(prop-1-yn-1-yl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(three (Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

87) 4-(4-(Trifluoromethyl)pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

88) 4-(4-methylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

89) 4-(6-(Trifluoromethyl)pyridin-2-yl)-N,6-bis(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine- 2-amine;

90)4-(4,6-dimethylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

91) 4-(5-(Difluoromethyl)-2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(三(Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

92) 4-(5-Amino-2-cyclopropylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

93) 4-(5-Amino-2-chloropyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

94) 4-(3-Amino-2-fluoro-6-methyl-pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(tri (Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

95) 4-(2-Cyclopropylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

96) 2-(4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)butan-2-ol;

97) 4-(6-(Trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(2-vinylpyridin-4-yl )-1,3,5-triazine-2-amine;

98) 2-(5-Fluoro-4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-2-yl)propan-2-ol;

99)2-(2-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-4-yl)propan-2-ol;

100)2-(5-chloro-4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-2-yl)propan-2-ol;

101)1-(4-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)ethan-1-ol;

102) 4-(6-Chloro-4-methylpyridin-2-yl)-6-(6-chloropyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

103) 4-(6-Chloro-4-(trifluoromethyl)pyridin-2-yl)-6-(6-chloropyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

104) 4-(6-Chloropyridin-2-yl)-6-(2-(2,2-difluoroethyl)pyridin-4-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

105)(4-(4-(6-chloropyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazine-2 -Base)pyridin-2-yl)methanol;

106) 4-(2-Methoxypyrimidin-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

107) 4-(2-Aminopyrimidin-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

108) 4-(5-Methoxy-4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

109) 2-(2-Chloro-6-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-4-yl)propan-2-ol;

110)4-(4-chloropyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

111) 5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl) nicotinonitrile;

112) 4-(6-Cyclopropylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

113) 1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine 2(1H)-one;

114) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)oxazole-2(3H)-one;

115) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)thiazol-2(3H)-one;

116) 3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)benzo[d]oxazole-2(3H)-one;

117) 3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)-1,-3,4-oxadiazole-2(3H)-one;

118) 1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyrimidine 2(1H)-one;

119) 5-(trifluoromethyl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl) Amino)-1,3,5-triazin-2-yl)pyridine-2(1H)-one;

120) 5-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)pyridine-2(1H)-one;

121) 2-(5-methyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)-4H-1,2,4-triazol-3-yl)propan-2-ol;

122)2-(5-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)-1H-1,2,4-triazol-3-yl)propan-2-ol;

123) 4-(1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1,3,5-triazine-2-amine;

124) 4-(1H-1,2,3-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

125)4-(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

126) 4-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1,3,5-triazine-2-amine;

127) 2-(1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazine-2-yl)-1H-imidazol-2-yl)propan-2-ol;

128)2-(1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)-1H-pyrrol-2-yl)propan-2-ol;

129) 2-(1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)-1H-1,2,4-triazol-5-yl)propan-2-ol;

130) 5-cyclopropyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)- 1,3,5-triazin-2-yl)pyridine-2(1H)-one;

131)5-(1,1-difluoroethyl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine- 4-yl)amino)-1,3,5-triazin-2-yl)pyridin-2(1H)-one

132) 5-Acetyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)pyridine-2(1H)-one;

133) 4-(3-Methyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

134) 5-(trifluoromethyl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl) Amino)-1,3,5-triazin-2-yl)pyrimidin-2(1H)-one;

135) 5-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-Triazin-2-yl)pyrimidine-2(1H)-one;

136) 5-(2-hydroxypropane-2-yl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine- 4-yl)amino)-1,3,5-triazin-2-yl)pyrimidin-2(1H)-one;

137) 4-(3-(Difluoromethyl)-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Yl)pyridin-4-yl)-1,3,5-triazin-2-amine;

138)4-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

139) 2-(1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)-1H-pyrrol-2-yl)propan-2-ol;

140)1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazine-2-yl)-1H-pyrrole-2-carbonitrile;

141) 4-(2,4-Dimethyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

142)3,5-Dimethyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)-1H-pyrrole-2-carbaldehyde;

143) 4-(2-(Difluoromethyl)-3,5-dimethyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N -(2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

144)1-(3,5-Dimethyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine-4- (Yl)amino)-1,3,5-triazin-2-yl)-1H-pyrrol-2-yl)ethan-1-ol;

145) 2-(4-(4-((2-(trifluoromethoxy)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1, 3,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

146) 2-(6-(4-((2-(trifluoromethoxy)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1, 3,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

147) 4-(6-chloropyridin-2-yl)-N-(2-(trifluoromethoxy)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl )-1,3,5-triazine-2-amine;

148) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethoxy)pyridin-4-yl)-6-(6-(trifluoromethyl) (Pyridin-2-yl)-1,3,5-triazine-2-amine;

149) 2-(2-(4-((2-(trifluoromethoxy)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1, 3,5-triazin-2-yl)pyridin-4-yl)propan-2-ol;

150)2-(2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyrimidin-2-yl)-1,3 ,5-Triazin-2-yl)pyridin-4-yl)propan-2-ol;

151) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyrimidine -2-yl)-1,3,5-triazine-2-amine;

152) 2-(4-(4-(6-(trifluoromethyl)pyrazin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1, 3,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

153) 2-(4-(4-(2-(trifluoromethyl)pyridin-4-yl)amino)-6-(2-(trifluoromethyl)pyrimidin-4-yl)-1,3, 5-triazin-2-yl)pyridin-2-yl)propan-2-ol;

154) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)pyrimidine -2-yl)-1,3,5-triazine-2-amine;

155) 4-(5-(Difluoromethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

156) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(2-(trifluoromethyl)pyrimidine -4-yl)-1,3,5-triazine-2-amine;

157) 2-(4-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-Triazinepyridin-2-yl)pyridin-2-yl)propan-2-ol;

158) 4-(5-(Difluoromethyl)pyridin-3-yl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,-1,3,5-triazine-2-amine; or

159)4,6-bis(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5 -Triazine-2-amine.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned compounds and at least one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition in which the weight ratio of the compound represented by the structural formula (I) to the excipient is 0.0001-10.

The present invention provides the application of the compound or pharmaceutical composition represented by the structural formula (I) in the preparation of medicines.

The present invention further provides a preferred technical solution for the application:

Preferably, the application is to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis.

Preferably, the application is used to treat diseases mediated by mutant IDH2.

Preferably, the disease is cancer.

Preferably, the cancer is selected from melanoma, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, glioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin Lymphoma and so on. In a specific embodiment, the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myelodysplastic neoplasm (MPN), acute myelogenous leukemia (AML) , Sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma or angioimmunoblastic lymphoma. In a more specific embodiment, the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML) ), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin’s lymphoma (NHL).

Preferably, the application is used as a mutant IDH2 inhibitor.

The present invention also provides a method for administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula (I) to a subject to treat and/or prevent diseases mediated by IDH2.

Preferably, in the above method, the IDH2-mediated disease is cancer.

The present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula (I) to a subject. In some embodiments, the present invention relates to a method for treating cancer characterized by the presence of mutant IDH2, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula I or an isomer thereof, or a pharmacologically Acceptable salts, crystals, solvates or prodrugs, or pharmaceutical compositions containing them, wherein the cancer is selected from melanoma, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, glial Tumors, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin’s lymphoma, etc.

Preferably, in the above method, the subject to be treated is a human being.

The general chemical terms used in the above general structural formula have their usual meanings. For example, unless otherwise specified, the term "halogen" used in the present invention refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include fluorine, chlorine and bromine.

In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similar, "C _1-8 alkyl""C_1-8" means comprising 7 or 8 carbon atoms, a straight-chain or branched-chain arranged in the form of Group.

Alkenyl and alkynyl include straight-chain or branched alkenyl and alkynyl. Similarly, "C _2-8 alkenyl" and "C _2-8 alkynyl" refer to alkenyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain. Or alkynyl.

"Alkoxy" refers to the oxyether form of the aforementioned linear or branched alkyl group, that is, -O-alkyl.

In the present invention, "a", "an", "the", "at least one" and "one or more" can be used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

The term "aromatic ring" in the present invention, unless otherwise specified, refers to unsubstituted or substituted monocyclic, fused or fused ring aromatic groups including carbon atoms, or unsubstituted or substituted heteroatoms, such as A monocyclic, condensed or condensed N, O or S aromatic group, when it is a condensed or condensed ring, at least one ring has aromaticity. Preferably, the aromatic ring is a 5- to 10-membered monocyclic or bicyclic aromatic ring group. Examples of these aromatic rings include, but are not limited to, phenyl, pyridyl, pyrazolyl, pyrimidinyl, chromatic dihydrofuran, indolyl.

The term "heterocyclic group", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-8 membered stable monomer consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S A ring system in which nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of these heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolane, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone and tetrahydro Oxadiazolyl.

Unless otherwise specified, the term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms, and at least one ring is aromatic. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

The term "heteroaryl" in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo Condensed heteroaromatic ring system or bicyclic heteroaromatic ring system, which consists of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms can be selectively Upon oxidation, the nitrogen heteroatoms can be selectively quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene And thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.

The term "cycloalkyl" refers to a cyclic saturated alkyl chain having 3-10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "substituted" means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C _1-8 alkyl, C _3-12 cycloalkyl, -OR ₁ , -SR ₁ , =0, =S, -C (O)R ₁ , -C(S)R ₁ , =NR ₁ , -C(O)OR ₁ , -C(S)OR ₁ , -NR ₁ R ₂ , -C(O)NR ₁ R ₂ , Cyano, nitro, -S(O) ₂ R ₁ , -OS(O ₂ )OR ₁ , -OS(O) ₂ R ₁ , -OP(O)(OR ₁ )(OR ₂ ); where R ₁ And R _{2 are} independently selected from -H, C _1-6 alkyl, and C _1-6 haloalkyl. In some embodiments, the substituents are independently selected from the group comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Group, isobutoxy, tert-butoxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde, -C(OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl Groups of amino group, methylthio group, sulfonyl group and acetyl group.

Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

Examples of substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.

In certain embodiments, the ring A is

, Can become

when

When the N in the amide bond in the structure is further substituted, it also falls into the protection scope of the present invention; similarly,

Can become

Other similar structures can be deduced by analogy.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium and sodium. Pharmaceutically acceptable non-toxic organic bases that can be derivatized into salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

When the compound provided by the present invention is a base, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydroiodic acid, perchloric acid, hydrochloric acid, isethionic acid, propionic acid, glycolic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pantothenic acid, phosphoric acid , Succinic acid, sulfuric acid, 2-naphthalenesulfonic acid, cyclohexylamine sulfonic acid, salicylic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, a purity of at least 60%, a more suitable purity of at least 75%, and a particularly suitable purity of at least 98% (% is weight ratio).

The prodrug of the compound of the present invention is included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. For example, any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues. Particularly preferred derivatives or prodrugs are those compounds that can improve the bioavailability of the compounds of the present application when administered to patients (for example, can make oral compounds more easily absorbed into the blood), or promote the transfer of parent compounds to biological organs or Those compounds delivered at the site of action (for example, the brain or lymphatic system). Therefore, the term "administration" in the treatment method provided by the present invention refers to the administration of the compound disclosed in the present invention that can treat different diseases, or although it is not clearly disclosed but can be transformed into the present disclosure in vivo after administration to a subject Compound compound. The conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs" (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).

Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substituted forms of the compounds of the present invention through the existing technical means and the methods described in the present invention to obtain chemically stable and easy-to-synthesize compounds.

The compounds of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

The above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of racemization or epimerization known to those skilled in the art, the product obtained may be a mixture of stereoisomers.

When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.

When the compound represented by formula (I) and its pharmaceutically acceptable salt have solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "composition", in the present invention, refers to a product containing a specified amount of each specified ingredient, and any product produced directly or indirectly from a combination of specified amounts of each specified ingredient. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound of the present invention are also part of the present invention. In addition, some crystalline forms of the compound may exist in polymorphs, and this polymorph is included in the present invention. In addition, some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.

The pharmaceutical composition provided by the present invention includes as an active component a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.

In fact, according to conventional drug mixing technology, the compound represented by formula (I) of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used as an active component and mixed with a drug carrier to form a drug combination Things. The pharmaceutical carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may adopt a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into the desired appearance.

Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomers, tautomers, polymorphs, solvates, and pharmaceutically acceptable Salt and its prodrugs. The combination of the compound represented by formula (I) or its pharmaceutically acceptable salt and one or more other compounds with therapeutic activity is also included in the pharmaceutical composition of the present invention.

The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include, but are not limited to, lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include but are not limited to syrup, peanut oil, olive oil and water. Gas carriers include but are not limited to carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any pharmacologically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.

The tablet containing the compound or pharmaceutical composition of the present invention can be compressed or molded, and optionally, can be made into a tablet together with one or more auxiliary components or adjuvants. The active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to make compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to make a molded tablet. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a formulation intended for oral administration to humans contains about 0.5 mg to about 5 g of the active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition. The unit dosage form generally contains about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water. A suitable surfactant such as hydroxypropyl cellulose may be included. In glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared. Further, a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared into a sterile powder form for immediate preparation of sterile injections or dispersions. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferred that the pharmaceutical composition be stored under conditions of anti-microbial contamination such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. Using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. As an example, a cream or ointment is prepared by adding about 5 wt% to 10 wt% of a hydrophilic material and water to produce a cream or ointment with the desired consistency.

The pharmaceutical composition provided by the present invention may use a solid as a carrier and is suitable for rectal administration. The unit dose suppository is the most typical dosage form. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, then cooling and moulding.

In addition to the above-mentioned adjuvant components, the above formulations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and enhancers. Thickeners, lubricants and preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can be prepared in the form of a powder or a concentrated solution.

In general, to treat the conditions or discomforts shown above, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies/asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS), the effective treatment drug dosage level is 0.01 mg/kg body weight to 50 mg/kg body weight per day, or 0.5mg to 3.5g per patient per day.

However, it is understood that lower or higher dosages than those mentioned above may be required. The specific dosage level and treatment plan for any particular patient will depend on many factors, including the activity of the specific compound used, age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, drug combination The condition and the severity of the specific disease being treated.

Description of the drawings

Figure 1 shows the progression of 2-HG concentration in the plasma of mice in each group after inoculation with U87-IDH2-R140Q cells in the tumor BALB/c mouse model. The abscissa is the time after cell inoculation (h), and the ordinate is the small The concentration of 2-HG in rat plasma (ng/ml) includes the control group AG-221 and the compound groups of Examples 1, 3, and 21.

detailed description

In order to make the above content clearer and clearer, the present invention will use the following embodiments to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific implementations of the present invention, so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.

Unless otherwise specified, all parts and percentages in the present invention are calculated by weight, and all temperatures refer to degrees Celsius.

The following abbreviations are used in the examples:

Pd(dppf)Cl ₂ .CH ₂ Cl ₂ : [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex;

DMF: N,N-dimethylformamide;

DMSO: dimethyl sulfoxide;

EA: ethyl acetate;

THF: Tetrahydrofuran;

a-KG: α-ketoglutarate;

2-HG: 2-hydroxyglutaric acid;

LC-MS or LCMS: liquid chromatography-mass spectrometry.

Preparation of intermediate M1:

Under the protection of nitrogen, add compound M1-1 (30.10g, 0.13mol), double pinacol borate (10.73g, 0.2mol), potassium acetate (39.21g, 0.4mol) to dioxane, After replacing the system with nitrogen, Pd(dppf)Cl _{2 .CH 2} Cl ₂ (5.45 g, 0.0067 mol) was added to the system, and the temperature was raised to 90° C. to react for 5 hours. Water and ethyl acetate were added to the reaction system for dilution, liquid separation, the aqueous phase was extracted twice with ethyl acetate, the combined organic phase was dried and concentrated in vacuo, and then the residue was purified by silica gel column chromatography to obtain 25.65 g Compound M1 (0.094 mol, 70.8%).

LC-MS [M+H ⁺ ]274.

Preparation of intermediate M2:

Compound M2-1 (5.00g, 30.84mmol), sodium bicarbonate (5.18g, 61.68mmol) and 2,4,6-trichloro-1,3,5-triazine (5.97g, 32.38mmol) were added to In tetrahydrofuran (70 mL), react at room temperature for 16 h. After filtration, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and then the residue was purified by silica gel column chromatography to obtain 8.12 g of compound M2 (26.19 mmol, 84.9%).

LC-MS [M+H ⁺ ] 310.

Preparation of intermediate M3:

method 1:

Step 1: Preparation of compound M3-2

The biuret (3.02 g, 29.25 mmol) was dissolved in ethylene glycol dimethyl ether (80 mL), sodium hydride (5.85 g, 243.75 mmol) was added in batches, and the mixture was heated at 50° C. and stirred for 1 h. M3-1 (5.00 g, 24.37 mmol) was added, and the reaction was heated at 85°C for 16 h. The reaction solution was poured into 400 mL ice water, and the pH was adjusted with concentrated hydrochloric acid. A solid was precipitated, stirred for 0.5 h, filtered, and the filter cake was rinsed with water and dried to obtain 3.68 g of compound M3-2 (14.25 mmol, 58.5%).

LC-MS [M+H ⁺ ] 259.

Step 2: Preparation of compound M3-3

Compound M3-2 (3.68 g, 14.25 mmol) was dissolved in 25 mL of phosphorus oxychloride, phosphorus pentachloride (11.87 g, 57.02 mmol) was added, and the reaction was heated at 105° C. for 16 h. The reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain 3.10 g of compound M3-3 (10.51 mmol, 73.8%).

LC-MS [M+H ⁺ ] 295.

Step 3: Preparation of compound M3

Dissolve compound M3-3 (3g, 10.17mmol) in tetrahydrofuran (30mL), add 2-trifluoromethyl-4-aminopyridine (1.81g, 11.18mmol), sodium carbonate (2.16g, 20.34mmol), and heat React at 75°C for 16h. After filtration, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and then the residue was purified by silica gel column chromatography to obtain 1.94 g of compound M3 (4.61 mmol, 45.4%).

LC-MS [M+H ⁺ ]421.

Method 2:

Step 1: Preparation of compound M3-2

Under the protection of N ₂ , sodium ethoxide (13.2 g, 194.0 mmol) was added to ethanol (80 mL), and the mixture was heated at 50° C. and stirred for 10 min. Add biuret (5.00g, 48.51mmol), heat at 50°C and stir for 0.5h. Compound M3-1 (9.95g, 48.51mmol) was added, and the mixture was heated at 85°C to react for 16h. The reaction solution was poured into 600 mL ice water, and the pH was adjusted with concentrated hydrochloric acid. A solid was precipitated, stirred for 0.5 h, filtered, and the filter cake was rinsed with water and dried to obtain 4.5 g of compound M3-2 (17.43 mmol, 36.0%).

LC-MS [M+H ⁺ ] 259.

Step 2: Preparation of compound M3-3

Compound M3-2 (4.5 g, 17.43 mmol) was dissolved in phosphorus oxychloride (40 mL), phosphorus pentachloride (14.52 g, 69.73 mmol) was added, and the reaction was heated at 100° C. for 4 h. The reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain 5.05 g of compound M3-3 (17.12 mmol, 98.2%).

LC-MS [M+H ⁺ ] 295.

Step 3: Preparation of compound M3

Dissolve compound M3-3 (5.05g, 17.12mmol) in tetrahydrofuran (50mL), add 2-trifluoromethyl-4-aminopyridine (2.77g, 17.12mmol), sodium carbonate (3.63g, 34.23mmol), Heat at 75°C for 16h. After filtration, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and then the residue was purified by silica gel column chromatography to obtain 3.88 g of compound M3 (9.22 mmol, 53.9%).

LC-MS [M+H ⁺ ]421.

Preparation of intermediate M4:

Step 1: Preparation of compound M3-2

Under the protection of N ₂ , sodium ethoxide (2.64 g, 38.8 mmol) was added to ethanol (50 mL), and the mixture was heated at 50° C. and stirred for 10 min. Add biuret (1.00g, 9.70mmol), heat at 50°C and stir for 0.5h. Compound M3-1 (3.98 g, 19.40 mmol) was added, and the mixture was heated at 85° C. to react for 16 h. The reaction solution was poured into 400 mL ice water, and the pH was adjusted with concentrated hydrochloric acid. A solid was precipitated, stirred for 0.5 h, filtered, and the filter cake was rinsed with water and dried to obtain 2.15 g of compound M3-2 (8.33 mmol, 86.0%).

LC-MS [M+H ⁺ ] 259.

Step 2: Preparation of compound M3-3

Compound M3-2 (1.72 g, 6.66 mmol) was dissolved in phosphorus oxychloride (12 mL), phosphorus pentachloride (5.55 g, 26.65 mmol) was added, and the reaction was heated at 100° C. for 16 h. The reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain 1.90 g of compound M3-3 (6.44 mmol, 96.4%).

LC-MS [M+H ⁺ ] 295.

Step 3: Preparation of compound M4

Dissolve compound M3-3 (828mg, 2.81mmol) in tetrahydrofuran (15mL), add 2-trifluoromethoxy-4-aminopyridine (500mg, 2.81mmol), sodium carbonate (595mg, 5.61mmol), heat 75 React at ℃ for 16h. After filtration, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and then the residue was purified by silica gel column chromatography to obtain 600 mg of compound M4 (1.37 mmol, 49.1%).

LC-MS [M+H ⁺ ]437.

Preparation of intermediate M5:

Step 1: Preparation of compound M5-2

M5-1 (4g, 20.82mmol) was added to methanol (50mL), and SOCl ₂ (4.95g, 41.65mmol) was slowly dropped into it, protected by nitrogen, and reacted at 65°C for 6h. The reaction solution was directly concentrated, diluted with EA, washed once with water and brine, dried and concentrated. M5-2 (3.482 g, 81%) was obtained.

LC-MS [M+H ⁺ ]207.

Step 2: Preparation of compound M5-3

Under the protection of N ₂ , sodium ethoxide (4.08 g, 59.96 mmol) was added to ethanol (50 mL), and the mixture was heated at 50° C. and stirred for 15 min. Add biuret (1.03g, 10mmol), heat at 50°C and stir for 0.5h. M5-2 (2.06g, 10mmol) was added and heated at 85°C to react for 16h. The reaction solution was concentrated, water was added, the pH was adjusted to neutral with a 6N hydrochloric acid aqueous solution, and the solution was concentrated and toluene was taken twice. Used directly in the next reaction.

LC-MS [M+H ⁺ ]260.

Step 3: Preparation of compound M5-4

Dissolve M5-3 (2.59g, 10mmol) in 50mL of phosphorus oxychloride, add phosphorus pentachloride (10.41g, 50mmoI), protect with nitrogen, and heat at 110°C to react for 4h. The reaction solution was concentrated, diluted with EA, poured into ice water, adjusted to neutral with sodium bicarbonate, extracted with EA, washed with water and brine, dried with anhydrous sodium sulfate, and concentrated to obtain the title compound M5-4 (1.17g, 39.5%) ).

LC-MS [M+H ⁺ ] 296.

Step 4: Preparation of compound M5

Dissolve M5-4 (1.17g, 3.95mmol) in 25mL of tetrahydrofuran, add 2-trifluoromethyl-4-aminopyridine (705mg, 4.35mmol), sodium carbonate (838mg, 7.90mmol), heat at 60℃ to react for 5h . Add water, extract with EA, wash the organic phase with water and brine once, dry and concentrate. The residue was purified by silica gel column chromatography to obtain the title compound M5 (415 mg, 24.9%).

LC-MS [M+H ⁺ ]422.

Example 1: Compound 1 (2-(4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)pyridin-2-yl)propan-2-ol) preparation

Step 1: Preparation of compound 1b

Under the protection of nitrogen, compound 1a (150mg, 0.690mmol, 1.0eq), double pinacol borate (264mg, 1.04mmol, 1.5eq), potassium acetate (204mg, 2.08mmol, 3.0eq) were added to the dioxygen After replacing the system with nitrogen in the hexacyclic ring (2 mL), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (57 mg, 0.07 mmol, 0.1 eq) was added to the system, and the temperature was raised to 90° C. to react for 2 hours. Drop the temperature directly to the next step reaction. 125 mg of compound 1b was obtained.

LC-MS [M+H ⁺ ]182.

Step 2: Preparation of compound 1

Under nitrogen protection, compound M3 (70mg, 0.16mmol, 1.0eq) and potassium carbonate aqueous solution (0.5ml, 2.0N) were added to the compound 1b system. After the system was replaced with nitrogen, Pd(dppf)Cl ₂ was added to the system. CH ₂ Cl ₂ (13 mg, 0.016 mmol, 0.1 eq), heated to 120° C. for microwave reaction for 0.5 h. Water and ethyl acetate were added to the reaction system for dilution, liquid separation, the organic phase was dried and concentrated in vacuo, and then the residue was purified by silica gel column chromatography to obtain 39 mg of compound 1 (0.074 mmol, 44.9%).

LC-MS [M+H ⁺ ]522.

¹ H NMR (500MHz, DMSO-d6) δ 11.52 (s, 1H), 8.95 (d, J = 7.9 Hz, 1H) of compound 1, 8.84-8.74 (m, 2H), 8.71-8.61 (m, 1H) ), 8.44 (t, J = 7.9 Hz, 1H), 8.24 (dd, J = 20.6, 6.4 Hz, 2H), 8.07 (d, J = 27.4 Hz, 1H), 5.45 (s, 1H), 1.54 (s ,6H).

Example 2: Compound 2 (4-(6-chloropyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine) preparation

Under nitrogen protection, compound M3 (50mg, 0.12mmol), compound 2a (43mg, 0.18mmol) and potassium carbonate (49mg, 0.36mmol) were added to dioxane (3mL) and water (0.3mL) and replaced with nitrogen After the system, Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (10 mg, 0.012 mmol) was added to the system, and the temperature was raised to 120° C. for microwave reaction for 1 h. Water and ethyl acetate were added to the reaction system to dilute, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried and concentrated in vacuo. Then the residue was purified by silica gel column chromatography to obtain 18.6 mg title compound 2 (0.037 mmol, 31.5%).

LC-MS [M+H ⁺ ]498.

Example 3: Compound 3 (4-(5-(difluoromethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(tri (Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine) preparation

Step 1: Preparation of compound 3b

Under the protection of nitrogen, compound 3a (200mg, 0.96mmol, 1.0eq), pinacol diborate (366mg, 1.44mmol, 1.5eq), potassium acetate (283mg, 2.88mmol, 3.0eq) were added to the dioxane (6mL), after replacing the system with nitrogen, add Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (78 mg, 0.096 mmol, 0.1 eq) to the system, and react in a microwave at 100° C. for 1 h. After diluting with ethyl acetate, washing with water once, separating the liquids, and concentrating the organic phase. 125 mg of compound 3b (0.072 mmol, 74.9%) were obtained.

LC-MS [M+H ⁺ ]174.

Step 2: Preparation of compound 3

Under nitrogen protection, compound M3 (268mg, 0.64mmol, 1.0eq), compound 3b (166mg, 0.96mmol, 1.5eq) and potassium carbonate (266mg, 1.93mmol) were added to dioxane (5mL) and water (0.5 mL), after the system was replaced with nitrogen, Pd(dppf)Cl _{2 .CH 2} Cl ₂ (52.5 mg, 0.064 mmol) was added to the system, and the temperature was raised to 100° C. for microwave reaction for 1 h. Water and ethyl acetate were added to the reaction system for dilution, liquid separation, the organic phase was dried and concentrated in vacuo, and then the residue was purified by silica gel column chromatography to obtain 71.4 mg of compound 3 (0.14 mmol, 21.7%).

LC-MS [M+H ⁺ ]514.

Compound 3 ¹ H NMR (500MHz, DMSO-d6) δ 11.51 (s, 1H), 9.83 (s, 1H), 9.09 (s, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.98 ( s, 1H), 8.68 (d, J = 5.4 Hz, 1H), 8.41 (t, J = 7.9 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H), 7.35 ( t, J=55.2 Hz, 1H).

Example 4: Compound 4(4-(2-(Difluoromethyl)-5-methylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N- (2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine) preparation

Step 1: Preparation of compound 4b

Compound 4a (100 mg, 0.5 mmol) and diethylaminosulfur trifluoride (161.2 mg, 1.00 mmol) were added to dichloromethane (10 mL) and reacted at room temperature for 2 hours. The reaction was quenched by adding sodium bicarbonate aqueous solution, extracted with dichloromethane, washed once with water, dried over anhydrous sodium sulfate, and concentrated the organic phase to obtain 80 mg of the title compound 4b (0.36 mmol, 72.7%).

LC-MS [M+H ⁺ ]222.

Step 2: Preparation of compound 4c

Under the protection of nitrogen, compound 4b (80mg, 0.36mmol), double pinacol borate (137.3mg, 0.54mmol) and potassium acetate (106.1mg, 1.08mmol) were added to dioxane (10mL), After replacing the system with nitrogen, Pd(dppf)Cl _{2 .CH 2} Cl ₂ (29.5 mg, 0.036 mmol) was added to the system, and the temperature was raised to 90° C. to react for 2 hours. Water and ethyl acetate were added to the reaction system for dilution, liquid separation, the aqueous phase was extracted twice with ethyl acetate, the combined organic phase was dried and concentrated in vacuo to obtain 90 mg of the title compound 4c (0.33 mmol, 92.7%).

LC-MS [M+H ⁺ ]270.

Step 3: Preparation of compound 4

Under nitrogen protection, add M3 (65mg, 0.15mmol), 4c (83.2mg, 0.31mmol) and potassium carbonate (64mg, 0.46mmol) to dioxane (3mL) and water (0.3mL), and replace the system with nitrogen _{Afterwards, Pd(dppf)Cl 2} .CH ₂ Cl ₂ (12.6 mg, 0.015 mmol) was added to the system, and the temperature was raised to 120° C. for microwave reaction for 0.5 h. Water and ethyl acetate were added to the reaction system for dilution, liquid separation, the aqueous phase was extracted twice with ethyl acetate, the combined organic phase was dried and concentrated in vacuo, and then the residue was purified by silica gel column chromatography to obtain 34 mg The title compound 4 (0.064 mmol, 41.9%).

LC-MS [M+H ⁺ ]528.

The example compounds in Table 1 were synthesized according to the methods of Examples 1-4 above using commercially available raw materials.

Table 1

Example 113: Compound 182 (1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)pyridine 2(1H)-one) preparation

Under nitrogen protection, compound M3 (50mg, 0.12mmol), compound 113a (17mg, 0.18mmol), cuprous iodide (2mg, 0.012mmol), o-phenanthroline (2mg, 0.024mmol) and cesium carbonate (116mg, 0.36mmol) was added to dioxane (4mL), and the system was replaced with nitrogen, and the temperature was raised to 120° C. for microwave reaction for 0.5 h. Water and ethyl acetate were added to the reaction system to dilute, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried and concentrated in vacuo, and then the residue was purified by silica gel column chromatography to obtain 38.8 mg title compound 113 (0.081 mmol, 68.1%).

LC-MS [M+H ⁺ ]480.

The compounds in the examples in Table 2 were prepared according to the methods in the above examples using commercially available raw materials.

Table 2

Example 145: Compound 145 (2-(4-(4-((2-(trifluoromethoxy)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridine-2- (Base)-1,3,5-triazin-2-yl)pyridin-2-yl)propan-2-ol) preparation

Under nitrogen protection, compound M4 (200mg, 0.46mmol), compound 3b (124mg, 0.69mmol) and potassium carbonate (190mg, 1.37mmol) were added to dioxane (5mL) and water (0.5mL) and replaced with nitrogen After the system, Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (37.5 mg, 0.046 mmol) was added to the system, and the temperature was raised to 100° C. for microwave reaction for 0.5 h. Water and ethyl acetate were added to the reaction system for dilution, liquid separation, the aqueous phase was extracted twice with ethyl acetate, the combined organic phase was dried, concentrated in vacuo, and then the residue was purified by silica gel column chromatography to obtain 56.5 mg title compound 145 (0.11 mmol, 22.8%).

LC-MS [M+H ⁺ ]538.

Commercially available raw materials were used to prepare the compounds in the examples in Table 3 according to the methods in the foregoing examples.

table 3

Example 150: Compound 150 (2-(2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyrimidin-2-yl )-1,3,5-triazin-2-yl)pyridin-4-yl)propan-2-ol) preparation

Compound M5 (105mg, 0.25mmol), K ₂ CO ₃ (415mg, 3mmol), H ₂ O (2.5mL), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (41mg, 0.05mol) were added to the reaction of compound 3b In the liquid, under nitrogen protection, react at 100°C for 1 hour. Add EA, wash with water and brine once, dry, concentrate, mix the sample, and purify by silica gel column chromatography to obtain the title compound 150 (13 mg, 10%).

LC-MS [M+H ⁺ ]523.

The compounds in the examples in Table 4 were prepared according to the methods in the above examples using commercially available raw materials.

Table 4

Example 157: Compound 157 (2-(4-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((2-(trifluoromethyl)pyridine-4 -Yl)amino)-1,3,5-triazinepyridin-2-yl)pyridin-2-yl)propan-2-ol) preparation

Step 1: Preparation of compound 157a

M2 (4.60g, 14.89mmol), potassium carbonate (6.17g, 44.67mmol) and 3-(trifluoromethyl)pyrazole (1.62g, 11.91mmol) were added to DMF (40mL), and reacted with ice-water bath at 0°C 2h. After filtration, the filter cake was rinsed with ethyl acetate, the filtrate was washed 3 times with water, and purified by column chromatography to obtain 1.22 g of target compound 157a (2.98 mmol, 25.0%).

LC-MS [M+H ⁺ ]410.

Step 2: Preparation of compound 157

Intermediate 157a (100mg, 325μmol), potassium carbonate (135mg, 876.89μmol), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (26.54mg, 32.5μmol) were added to 1,4-dioxane: water = In a 10:1 mixed solution (5ml), microwave at 120°C for 0.5h. After cooling, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with water, dried, and separated and purified by column chromatography to obtain 20 mg (39.2 μmol, 12.06%) of compound 157.

LC-MS [M+H ⁺ ]511.

The compounds in the examples in Table 5 were prepared according to the methods in the above examples using commercially available raw materials.

table 5

Example 159: Compound 159 (4,6-bis(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1,3,5-triazine-2-amine) preparation

Compound M2 (100mg, 325μmol), potassium carbonate (135mg, 876.89μmol) and 3-(trifluoromethyl)pyrazole (88mg, 651μmol) were added to DMF (3mL) and reacted at room temperature for 2h. After filtration, the filter cake was rinsed with ethyl acetate, the filtrate was washed 3 times with water, dried, and concentrated under reduced pressure. Separation and purification by column chromatography yielded 37 mg of target compound 159 (72 μmol, 22.35%).

LC-MS [M+H ⁺ ]510.

Pharmacological experiment

Example A:

Enzyme activity inhibition test

^{The inhibitory ability of the test compound on the enzyme activities of IDH2 R140Q} and IDH2 ^R172K , respectively, is expressed as a half inhibitory concentration (IC ₅₀ ) value. AG-221 was used as a positive control compound. In this experiment, we use fluorescence methods ^{to screen compounds on IDH2 R140Q} and IDH2 ^R172K enzymes, starting at 10000nM, 3 times dilution, 10 concentrations, single-well detection; compound screening ^{on IDH2 R172K enzymes} , Starting concentration 3000nM, 3 times dilution, 10 concentrations, single-well detection.

(1) Prepare 1×Assay buffer.

(2) Compound concentration gradient preparation: the test compound has a ^{starting concentration of 10000nM on IDH2 R140Q} enzyme; the initial concentration on IDH2 ^R172 K enzyme is 3000nM, which is diluted to 50 times the final concentration of 100 in a 96-well plate. %DMSO solution, 3 times dilution compound with Precision, 10 concentrations.

(3) Add 1μL of DMSO and 1μL of the diluted compound to the reaction plate.

(4) Add 25μL enzyme Mix and 1*buffer(max), and incubate for 60 minutes.

(5) Add 25μL substrate mix and incubate for a certain period of time (IDH2 ^R140Q 120 minutes, IDH2 ^R172K 90 minutes).

(6) Add 25μL Detection buffer and shake for 1 minute.

(7) Synergy 2, Ex544/Em590 cutoff 590 is used for reading.

(8) Calculation of inhibition rate, formula: %Inhibition=(RFU_sample-RFU_min)/(RFU_max-RFU_min)*100%. Among them: RFU-sample is the fluorescence intensity of the sample; RFU-min is the average value of the negative control wells, representing the fluorescence intensity of the enzyme; RFU-max is the average value of the positive control wells, representing the fluorescence intensity of the no enzyme. Curve fitting using Graphpad Prism software, to give ₅₀ value IC.

Cell 2-HG experiment

The compound was tested for its inhibitory effect on the 2-HG production ability in the U87 cell line stably transfected with IDH2-R140Q and the TF-1 cell culture supernatant stably transfected with IDH2-R140Q or IDH2-R172K.

1. Collect the cultured cells by centrifugation, then suspend them in cell culture medium. After counting the cells, inoculate the cells in a 96-well cell culture plate, 160 μL cell suspension/well (U87-IDH2-R140Q is 20000 cells/well, TF- 1-IDH2-R140Q and TF-1-IDH2-R172K are 10,000 cells/well).

2. Take a 96-well dilution plate, dilute the test compound with DMSO and cell culture medium, and then take 40 μL of the test compound after the gradient dilution and put it in a 96-well culture plate with cells. The final concentration of the compound is 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5, 0nM (the final concentration of DMSO is 0.2%), the final volume of each well is 200μL, and finally it is placed at 37℃ with 5% CO ₂ incubator.

3. After the compound was incubated with the cells for 72 hours, the cell culture plate was taken out, centrifuged at 2500 rpm for 5 minutes, and then 100 μL of the medium supernatant was drawn for 2-HG determination.

4. Dilute the supernatant with purified water, take 50μL of the diluted sample into a 1.5ml centrifuge tube, add 200μL of internal standard solution, vortex to mix, and centrifuge at 4°C and 13000rpm for 15 minutes. Take 80 μL of the supernatant solution in a 96-well plate and detect with LC-MS. The ratio of Analyse Peak Area to IS Peak Area (Analyte IS Ratio) represents the 2-HG level.

5. Calculation of inhibition rate, formula: %Inhibition=(1-Analyte IS Ratio_sample/Analyte IS Ratio_max)*100%. Curve fitting using Graphpad Prism software, to give ₅₀ value IC.

Experimental inhibition of enzyme activity assay and results of the experiments 2-HG cells ₅₀ represented by IC, such as shown in Table 6. The compounds of the present invention illustrated in the examples show that the IC ₅₀ values are in the following range: "A" represents "IC ₅₀ ≤100nM";"B" represents "100nM<IC ₅₀ <500nM";"C" represents "IC _50" ≥500nM".

Table 6

Note: "-" stands for "not tested".

Example B: Mouse PO-Cassette experimental method

1. Prepare the compound (solvent: 15% DMSO/10% Solutol/75% physiological saline).

2. Mice were administered intragastrically (dose: 5mg/kg), blood was collected 0.5, 2, and 4 hours after administration, and the plasma supernatant was collected by centrifugation at 4000 rpm and 10 minutes.

3. Take 30μL of plasma supernatant sample and add 200μL of internal standard solution. After centrifugation at 3000rpm for 10 minutes, take 100μL of supernatant solution and dilute 1:1 with water for injection. The injection volume is 5μL. LC-MS was used to detect the drug concentration in plasma.

4. Calculate various parameters (t _1/2 , C _max , AUC _last ) with Winnonln software.

Table 7

Example C: Drug effect experiment of mouse tumor model

The purpose of this experiment is to study the in vivo pharmacodynamics of different compounds on U87-IDH2-R140Q cell subcutaneous xenograft tumor BALB/c mouse model.

experimental method

1. Establishment of U87-IDH2-R140Q subcutaneous xenograft tumor model

(1) Cell culture

U87-IDH2-R140Q cells are cultured in a monolayer in vitro, and the culture conditions are 1640 medium plus 10% heat-inactivated fetal bovine serum, and culture in an incubator _{containing 5% CO 2 at 37°C.} Digestion with trypsin-EDTA twice a week for passage. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.

(2) Tumor cell inoculation and animal grouping

Before cell inoculation, animals were weighed and randomly grouped according to body weight (random block design). U87-IDH2-R140Q cells were inoculated subcutaneously on the right back of each mouse.

(3) Experimental indicators

The experimental index is the change of the level of 2-HG in the plasma of the animal after administration.

2. Drug treatment and sample collection

When the tumor volume of the mouse was about 400mm ³ , the administration was started, and the administration was administered once, and blood was collected from the venous plexus of the fundus of the mouse at 0, 6, and 24 hours after the administration. The amount of blood collected was 100 uL, and after anticoagulation with 2.0% EDTA, the blood was centrifuged at 4000 rpm for 10 minutes to obtain the plasma supernatant. Take 10uL centrifugation to take the plasma supernatant sample, add 20uL ddH ₂ O, add 100uL sample internal standard solution, centrifuge at 3000rpm for 10 minutes, take the supernatant solution 50uL supernatant solution diluted 1:4 with water, and then inject the sample. 5uL. The concentration of 2-HG in plasma was detected by LC-MS.

Experimental results

(1) Concentration of 2-HG in plasma after administration

In the U87-IDH2-R140Q transplanted tumor mouse model, when the tumor volume of the mouse is about 400mm ³ , the mice will be administered by gavage, and blood will be collected at 0, 6 and 24 hours after the administration. The plasma is detected by LC-MS Concentration of 2-HG in. The results are shown in the figure below. After a single administration of 15 mg/kg of AG221, Compound 3, Compound 21 and Compound 1, the concentration of 2-HG in plasma decreased. The effect of the compound 3 group was similar to that of AG-221, the lowest 2-HG value appeared at 24 hours after administration; the lowest 2-HG value of compound 21 and compound 1 appeared at 6 hours after administration.

Tumor efficacy model data show that compared with the control compound AG221, compound 3, compound 21 and compound 1 can effectively reduce the level of 2-HG in plasma and have excellent in vivo efficacy.

Although the present invention has been fully described through its implementation modes, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the appended claims of the present invention.

Claims (23)

1. The compound represented by formula I, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof,

   

   Wherein, W is selected from N or C;

   Z is selected from N or C;

   M is O or chemical bond;

   Ring X is a C _5-10 aromatic ring;

   Ring Y is a 6-membered aryl group or a C _5-6 heteroaryl group, and the C _5-6 heteroaryl group contains 1, 2 or 3 nitrogen atoms;

   R _{1 is} independently selected from H, NH ₂ , CN, -C(O)CH ₃ , hydroxyl, oxo, halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy , C _2-8 alkenyl, C _2-8 alkynyl or C _3-6 cycloalkyl, the NH ₂ , -C (O) CH ₃ or C _1-8 alkyl is optionally hydroxy, halogen, oxygen Substitute or C _1-3 alkyl substitution;

   R _{2 is} selected from H, CN, halogen, C _1-8 alkyl or C _1-8 haloalkyl;

   n is 1, 2 or 3.
2. The compound of claim 1, wherein the ring X is a C _5-10 aromatic ring; wherein the C _5-10 aromatic ring optionally contains 1, 2, or 3 independently selected from N, O Or S heteroatom.
3. The compound of claim 1 or 2, wherein R _{1 is} independently selected from H, NH ₂ , CN, -C(O)CH ₃ , hydroxyl, oxo, halogen, C _1-3 alkyl , C _1-3 haloalkyl, C _1-3 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl or C _3-6 cycloalkyl, the NH ₂ , -C(O)CH ₃ Or C _1-3 alkyl is optionally substituted with hydroxy, halogen, oxo or C _1-3 alkyl.
4. The compound according to any one of claims 1-3, characterized in that:

   

   Selected from

   

   

   
5. The compound of any one of claims 1-4, wherein Z is C.
6. The compound according to any one of claims 1 to 5, wherein the ring Y is a C ₆ heteroaryl group, and the C ₆ heteroaryl group contains 1, 2 or 3 nitrogen atoms.
7. The compound according to any one of claims 1-6, characterized in that:

   

   for

   

   
8. The compound according to any one of claims 1-7, wherein R _{2 is} selected from H, CN, halogen, C _1-3 alkyl or C _1-3 haloalkyl.
9. The compound according to any one of claims 1-8, wherein R _{2 is} selected from CF ₃ , CN or Cl.
10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

    1) 2-(4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

    2) 4-(6-Chloropyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    3) 4-(5-(Difluoromethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    4) 4-(2-(Difluoromethyl)-5-methylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(三(Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    5) 4-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    6) 4-(1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    7) 4-(Pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1, 3,5-Triazine-2-amine;

    8) 4-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    9) 4,6-bis(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine- 2-amine;

    10) 2-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)benzonitrile;

    11) 4-(Indol-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    12) 4-(1-Methyldihydropyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4 -Base) -1,3,5-triazine-2-amine;

    13) 4-(Chroman-6-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    14) 4-(2,3-Dihydrobenzofuran-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    15) 4-(1H-Indol-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    16) 4-(benzofuran-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1,3,5-triazine-2-amine;

    17) 4-(Indoline-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    18) 2-(2-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)phenyl)propan-2-ol;

    19) 4-(Isoindolin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    20) 2-(3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)phenyl)propan-2-ol;

    21) 2-(6-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

    22) 4-(1,3-Dihydroisobenzofuran-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    23) 4-(2-Methylisoxazol-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    24) 4-(1-Methyldihydro-7-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    25) 5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridin-3-ol;

    26) 4-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-2-ol;

    27) 4-(2-Methoxy-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

    28) 4-(5-Ethynylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

    29) 4-(5-chloropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    30) 4-(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

    31) 4-(5-Methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    32) 4-(5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

    33) 4-(6-(Trifluoromethyl)pyridin-2-yl)-6-(5-(trifluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    34) 4-(5-Cyclopropylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    35) 4-(2-Fluoro-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    36) 4-(4-(Trifluoromethyl)pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    37) 4-(6-fluoropyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    38) 4-(1-methyl-1H-pyrazol-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    39) 4-(1-methyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    40)2-(5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-3-yl)propan-2-ol;

    41) 4-(4-Methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    42) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-4-ol;

    43) 4-(1,4-Dimethyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Yl)pyridin-4-yl)-1,3,5-triazin-2-amine;

    44) 2-(3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-4-yl)propan-2-ol;

    45) 4-(4-fluoropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    46) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-2(1H)-one;

    47) 4-(5-Cyclopropyl-2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl )Pyridin-4-yl)-1,3,5-triazine-2-amine;

    48) 1-Methyl-3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)pyridine-2(1H)-one;

    49) 4-(2-Fluoro-4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    50) 4-(4,5-dimethylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    51) 4-(5-Cyclopropyl-2-fluoropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    52) 4-(2,4-dimethylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    53) 4-(2,5-dimethylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    54) 4-(2-Chloro-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    55) 4-(2-Amino-5-cyclopropylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    56) 4-(2-Amino-5-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    57) 4-(2-Aminopyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    58) 4-(6-Methoxypyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    59) 2-(6-amino-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-3-yl)propan-2-ol;

    60) 4-(2-Amino-5-chloropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    61) 4-(2-Amino-5-(trifluoromethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    62) 4-(6-Fluoro-4-methylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    63) 6-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine-2-ol;

    64) 6-chloro-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1, 3,5-triazin-2-yl)pyridin-3-ol;

    65) 4-(2-Fluoro-5-methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    66) 4-(2-Fluoro-5-methoxypyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    67) 4-Methyl-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-Triazine-2-yl)pyridin-3-ol;

    68) 6-Methyl-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-Triazine-2-yl)pyridin-3-ol;

    69) 6-amino-5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1, 3,5-triazin-2-yl)nicotinonitrile;

    70) 4-(2-(Difluoromethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    71) 4-(5-(Difluoromethyl)-6-fluoropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    72) 4-(5-(1,1-Difluoroethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    73) 1-(5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-3-yl)ethan-1-one;

    74) 4-(3-Aminopyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    75) 4-(2-(1,1-Difluoroethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    76) 4-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)-2-cyanopyridine;

    77) 4-(2-Methylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

    78) 4-(5-Fluoro-2-methyl-pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    79) 4-(1,3-Dimethyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Yl)pyridin-4-yl)-1,3,5-triazin-2-amine;

    80)2,2,2-Trifluoro-1-(5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine-4 -Amino)-1,3,5-triazin-2-yl)pyridin-3-yl)ethan-1-one;

    81) 4-(5-(Dimethylamino)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    82)2-Methyl-1-(5-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)pyridin-3-yl)propan-2-ol;

    83) 4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-( 2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    84) 4-(4-Cyclopropylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    85) 4-(6-chloropyridin-2-yl)-6-(5-cyclopropylpyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1, 3,5-Triazine-2-amine;

    86) 4-(5-(prop-1-yn-1-yl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(three (Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    87) 4-(4-(Trifluoromethyl)pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1,3,5-triazine-2-amine;

    88) 4-(4-methylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl )-1,3,5-triazine-2-amine;

    89) 4-(6-(Trifluoromethyl)pyridin-2-yl)-N,6-bis(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine- 2-amine;

    90)4-(4,6-dimethylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    91) 4-(5-(Difluoromethyl)-2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(三(Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    92) 4-(5-Amino-2-cyclopropylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    93) 4-(5-Amino-2-chloropyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    94) 4-(3-Amino-2-fluoro-6-methyl-pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(tri (Fluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    95) 4-(2-Cyclopropylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    96) 2-(4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)butan-2-ol;

    97) 4-(6-(Trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(2-vinylpyridin-4-yl )-1,3,5-triazine-2-amine;

    98) 2-(5-Fluoro-4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-2-yl)propan-2-ol;

    99)2-(2-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-4-yl)propan-2-ol;

    100)2-(5-chloro-4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-2-yl)propan-2-ol;

    101)1-(4-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)pyridin-2-yl)ethan-1-ol;

    102) 4-(6-Chloro-4-methylpyridin-2-yl)-6-(6-chloropyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    103) 4-(6-Chloro-4-(trifluoromethyl)pyridin-2-yl)-6-(6-chloropyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    104) 4-(6-Chloropyridin-2-yl)-6-(2-(2,2-difluoroethyl)pyridin-4-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    105)(4-(4-(6-chloropyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazine-2 -Base)pyridin-2-yl)methanol;

    106) 4-(2-Methoxypyrimidin-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    107) 4-(2-Aminopyrimidin-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    108) 4-(5-Methoxy-4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

    109) 2-(2-Chloro-6-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-triazin-2-yl)pyridin-4-yl)propan-2-ol;

    110)4-(4-chloropyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazine-2-amine;

    111) 5-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl) nicotinonitrile;

    112) 4-(6-Cyclopropylpyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Group) -1,3,5-triazine-2-amine;

    113) 1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyridine 2(1H)-one;

    114) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)oxazole-2(3H)-one;

    115) 3-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)thiazol-2(3H)-one;

    116) 3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)benzo[d]oxazole-2(3H)-one;

    117) 3-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)-1,-3,4-oxadiazole-2(3H)-one;

    118) 1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazin-2-yl)pyrimidine 2(1H)-one;

    119) 5-(trifluoromethyl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl) Amino)-1,3,5-triazin-2-yl)pyridine-2(1H)-one;

    120) 5-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)pyridine-2(1H)-one;

    121) 2-(5-methyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)-4H-1,2,4-triazol-3-yl)propan-2-ol;

    122)2-(5-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)-1H-1,2,4-triazol-3-yl)propan-2-ol;

    123) 4-(1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1,3,5-triazine-2-amine;

    124) 4-(1H-1,2,3-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    125)4-(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    126) 4-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1,3,5-triazine-2-amine;

    127) 2-(1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazine-2-yl)-1H-imidazol-2-yl)propan-2-ol;

    128)2-(1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)-1H-pyrrol-2-yl)propan-2-ol;

    129) 2-(1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)-1H-1,2,4-triazol-5-yl)propan-2-ol;

    130) 5-cyclopropyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)- 1,3,5-triazin-2-yl)pyridine-2(1H)-one;

    131)5-(1,1-difluoroethyl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine- 4-yl)amino)-1,3,5-triazin-2-yl)pyridin-2(1H)-one

    132) 5-Acetyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)pyridine-2(1H)-one;

    133) 4-(3-Methyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- 4-yl)-1,3,5-triazine-2-amine;

    134) 5-(trifluoromethyl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl) Amino)-1,3,5-triazin-2-yl)pyrimidin-2(1H)-one;

    135) 5-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1 ,3,5-Triazin-2-yl)pyrimidine-2(1H)-one;

    136) 5-(2-hydroxypropane-2-yl)-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine- 4-yl)amino)-1,3,5-triazin-2-yl)pyrimidin-2(1H)-one;

    137) 4-(3-(Difluoromethyl)-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) (Yl)pyridin-4-yl)-1,3,5-triazin-2-amine;

    138)4-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

    139) 2-(1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 ,5-Triazin-2-yl)-1H-pyrrol-2-yl)propan-2-ol;

    140)1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Triazine-2-yl)-1H-pyrrole-2-carbonitrile;

    141) 4-(2,4-Dimethyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) )Pyridin-4-yl)-1,3,5-triazine-2-amine;

    142)3,5-Dimethyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino )-1,3,5-triazin-2-yl)-1H-pyrrole-2-carbaldehyde;

    143) 4-(2-(Difluoromethyl)-3,5-dimethyl-1H-pyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N -(2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine;

    144)1-(3,5-Dimethyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridine-4- (Yl)amino)-1,3,5-triazin-2-yl)-1H-pyrrol-2-yl)ethan-1-ol;

    145) 2-(4-(4-((2-(trifluoromethoxy)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1, 3,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

    146) 2-(6-(4-((2-(trifluoromethoxy)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1, 3,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

    147) 4-(6-chloropyridin-2-yl)-N-(2-(trifluoromethoxy)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl )-1,3,5-triazine-2-amine;

    148) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethoxy)pyridin-4-yl)-6-(6-(trifluoromethyl) (Pyridin-2-yl)-1,3,5-triazine-2-amine;

    149) 2-(2-(4-((2-(trifluoromethoxy)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1, 3,5-triazin-2-yl)pyridin-4-yl)propan-2-ol;

    150)2-(2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyrimidin-2-yl)-1,3 ,5-Triazin-2-yl)pyridin-4-yl)propan-2-ol;

    151) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyrimidine -2-yl)-1,3,5-triazine-2-amine;

    152) 2-(4-(4-(6-(trifluoromethyl)pyrazin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1, 3,5-Triazin-2-yl)pyridin-2-yl)propan-2-ol;

    153) 2-(4-(4-(2-(trifluoromethyl)pyridin-4-yl)amino)-6-(2-(trifluoromethyl)pyrimidin-4-yl)-1,3, 5-triazin-2-yl)pyridin-2-yl)propan-2-ol;

    154) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)pyrimidine -2-yl)-1,3,5-triazine-2-amine;

    155) 4-(5-(Difluoromethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N-(2-(trifluoromethyl) (Pyridin-4-yl)-1,3,5-triazine-2-amine;

    156) 4-(5-(Difluoromethyl)pyridin-3-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-6-(2-(trifluoromethyl)pyrimidine -4-yl)-1,3,5-triazine-2-amine;

    157) 2-(4-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino) -1,3,5-Triazinepyridin-2-yl)pyridin-2-yl)propan-2-ol;

    158) 4-(5-(Difluoromethyl)pyridin-3-yl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(2-(trifluoro (Methyl)pyridin-4-yl)-1,-1,3,5-triazine-2-amine; or

    159)4,6-bis(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5 -Triazine-2-amine.
11. A pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound according to any one of claims 1-10 and at least one pharmaceutically acceptable excipient.
12. The pharmaceutical composition according to claim 11, wherein the mass percentage of the compound and pharmaceutically acceptable excipients is 0.0001:1-10.
13. Use of the compound of any one of claims 1-10 or the pharmaceutical composition of claim 11 or 12 in the preparation of medicines.
14. The application according to claim 13, wherein the drug is used to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis.
15. The application according to claim 13 or 14, wherein the drug is used to treat diseases mediated by mutant IDH2.
16. The use according to claim 15, wherein the disease is cancer.
17. The use according to claim 16, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, glioma, glioblastoma multiforme Tumor, acute myeloid leukemia, non-Hodgkin’s lymphoma.
18. The application according to claim 13, wherein the drug is used as a mutant IDH2 inhibitor.
19. A method for treating and/or preventing a disease mediated by mutant IDH2, characterized in that a therapeutically effective amount of the compound according to any one of claims 1-10 or the compound according to claim 11 or 12 is administered to a subject to be treated Pharmaceutical composition.
20. The method according to claim 19, wherein the disease mediated by the mutant IDH2 is cancer.
21. The method of claim 20, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, glioma, glioblastoma multiforme Tumor, acute myeloid leukemia, non-Hodgkin’s lymphoma.
22. A method for treating cancer, comprising administering a therapeutically effective amount of the compound according to any one of claims 1-10 or the pharmaceutical composition according to claim 11 or 12 to a subject, characterized in that the cancer is black Tumor, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, glioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin’s lymphoma.
23. The method according to any one of claims 19-22, wherein the subject to be treated is a human.

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