Alkenyl pyrimidine compound, preparation method therefor, and application thereof

1 . A compound having the following general formula:

or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof,

wherein:

R 1 is selected from:

1)

 Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each are independently selected from the following groups, and Y, Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time:

(1) H, F, Cl, Br, I, nitro, cyano,

(2) C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluorine-containing alkoxy, C 3 -C 6 cycloalkyl,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N—(N-methyl-4-piperidyl) piperazinyl, N—(N-ethyl-4-piperidyl) piperazinyl, 4-(N-methyl-azetidin-3-yl) piperazinyl,

(4) 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl,

(5) 4-N,N-dimethylaminopiperidyl, 4-N,N-diethylaminopiperidyl, 4-N,N-diisopropylaminopiperidyl, 4-(piperazinyl-1-) piperidyl, 4-(N-methylpiperazinyl-1-) piperidyl, 4-(N-ethylpiperazinyl-1-) piperidyl, 4-(N-isopropylpiperazinyl-1-) piperidyl,

(6) cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, benzyl,

(7) 4-(N-methyl-1-piperazinyl) piperidyl-1-formyl, 4-(N-ethyl-1-piperazinyl) piperidyl-1-formyl,

(8) amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, 2-N,N-dimethylaminoethylamino, 3-N,N-dimethylaminopropylamino, 3-N,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino,

(9)

2)

 wherein Y 1 , Y 3 , Y 4 , Y 5 each are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 4-(N-methylpiperazinyl-1-) piperidyl, 4-(N-ethylpiperazinyl-1-) piperidyl, or 4-(N-isopropylpiperazinyl-1-) piperidyl, and Y, Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

3)

 wherein, Y 1 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, F, Cl, Br, or C 1 -C 6 fluorine-containing alkoxy, Y 2 , Y 5 are H, R y is selected from C 1 -C 6 alkyl;

4)

 wherein, Y 1 , Y 2 , Y 5 are H, R z , R each are independently selected from C 1 -C 6 alkyl;

5) 3-pyrazolyl, 1-methyl-3-pyrazolyl, 1-ethyl-3-pyrazolyl, 1-isopropyl-3-pyrazolyl, 1,5-dimethyl-3-pyrazolyl, 1,5-diethyl-3-pyrazolyl, 1,5-diisopropyl-3-pyrazolyl, 1-methyl-5-ethyl-3-pyrazolyl, 1-methyl-5-isopropyl-3-pyrazolyl, 1-ethyl-5-methyl-3-pyrazolyl, 1-ethyl-5-isopropyl-3-pyrazolyl, 1-isopropyl-5-methyl-3-pyrazolyl, 1-isopropyl-5-ethyl-3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 1-ethyl-4-pyrazolyl, 1-isopropyl-4-pyrazolyl, 1,3-dimethyl-4-pyrazolyl, 1,3-diethyl-4-pyrazolyl, 1,3-diisopropyl-4-pyrazolyl, 1-methyl-3-ethyl-4-pyrazolyl, 1-methyl-3-isopropyl-4-pyrazolyl, 1-ethyl-3-methyl-4-pyrazolyl, 1-ethyl-3-isopropyl-4-pyrazolyl, 1-isopropyl-3-methyl-4-pyrazolyl, 1-isopropyl-3-ethyl-4-pyrazolyl;

Z 3 , Z 4 each are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 fluorine-containing alkyl, or C3-C 6 cycloalkyl;

R 3 , R 4 , R 5 each are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl; or,

R 3 , R 4 and carbon atoms linked thereto together form

 R 5 being selected from H, or C 1 -C 6 alkyl.

2 . A compound having the following general formula:

or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof,

wherein:

R 1 is selected from:

1)

 wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each are independently selected from the following groups, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time:

(1) H, F, Cl, Br, I, nitro, cyano,

(2) C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluorine-containing alkoxy, C 3 -C 6 cycloalkyl,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl,

(4) 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl,

(5) 4-N,N-dimethylaminopiperidyl, 4-N,N-diethylaminopiperidyl, 4-N,N-diisopropylaminopiperidyl, 4-(N-methylpiperazinyl-1-) piperidyl, 4-(N-ethylpiperazinyl-1-) piperidyl, 4-(N-isopropylpiperazinyl-1-) piperidyl,

(6) cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(7) 4-(N-methyl-1-piperazinyl) piperidyl-1-formyl, 4-(N-ethyl-1-piperazinyl) piperidyl-1-formyl,

2)

 wherein:

Y 1 , Y 3 , Y 4 , Y 5 each are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 4-(N-methylpiperazinyl-1-) piperidyl, 4-(N-ethylpiperazinyl-1-) piperidyl, or 4-(N-isopropylpiperazinyl-1-) piperidyl, and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

Z 5 is selected from C 1 -C 6 alkyl;

R 3 , R 4 , R 5 each are independently selected from H, or C 1 -C 6 alkyl.

3 . A compound having the following general formula:

or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof,

wherein:

R 1 is selected from:

1)

 wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each are independently selected from the following groups, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time:

(1) H, F, Cl, Br, I, nitro, cyano,

(2) C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluorine-containing alkoxy, C 3 -C 6 cycloalkyl,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl,

(4) 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl,

(5) 4-N,N-dimethylaminopiperidyl, 4-N,N-diethylaminopiperidyl, 4-N,N-diisopropylaminopiperidyl, 4-(N-methylpiperazinyl-1-) piperidyl, 4-(N-ethylpiperazinyl-1-) piperidyl, 4-(N-isopropylpiperazinyl-1-) piperidyl,

(6) cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(7) 4-(N-methyl-1-piperazinyl) piperidyl-1-formyl, 4-(N-ethyl-1-piperazinyl) piperidyl-1-formyl,

2)

 wherein:

Y 1 , Y 3 , Y 4 , Y 5 each are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 4-(N-methylpiperazinyl-1-) piperidyl, 4-(N-ethylpiperazinyl-1-) piperidyl, or 4-(N-isopropylpiperazinyl-1-) piperidyl, and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

Z 6 is selected from C 1 -C6 alkyl;

R 3 , R 4 , R 5 each are independently selected from H, or C 1 -C 6 alkyl.

4 . A compound selected from:

No.

Structure

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

II-1

II-2

II-3

II-4

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

II-35

II-36

II-37

II-38

II-39

II-40

II-41

II-42

II-43

II-44

II-45

II-46

II-47

II-48

II-49

II-50

II-51

II-52

II-53

II-54

II-55

II-56

II-57

II-58

II-5

II-6

II-7

II-8

II-9

II-10

II-11

II-12

II-13

II-14

II-15

III-1

III-2

III-3

III-4

III-5

III-6

III-7

II-59

II-60

II-61

II-62

II-63

II-64

II-65

II-66

II-67

II-68

II-69

II-70

II-71

II-72

II-73

II-74

II-75

II-76

II-77

II-78

III-8

III-9

III-10

III-11

III-12

III-13

III-14

III-15

III-16

III-17

III-18

III-19

III-20

III-21

IV-1

IV-2

IV-3

IV-4

IV-5

IV-6

IV-7

IV-8

IV-9

IV-10

IV-11

IV-12

IV-13

IV-14

IV-15

IV-16

IV-17

IV-18

I-25

or stereoisomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the above compounds.

5 . A compound having the following general formula or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof:

wherein:

R 1 is selected from:

1)

 wherein:

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each are independently selected from the following groups, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time:

H, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy, cyclopropylmethylene, N-methylpiperazinyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-N,N-dimethylaminopiperidyl, 4-(N-methylpiperazinyl-1-) piperidyl, or N-methyl-4-piperidyl;

2)

 wherein:

Y 1 , Y 3 , Y 4 , Y 5 each are independently selected from H, methyl, ethyl, methoxy, or 4-(N-methylpiperazinyl-1-) piperidyl, and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time,

3)

 wherein, Y 1 is F, Y 2 , Y 5 are H, R y is methyl;

 wherein, Y 1 , Y 2 , Y 5 are H, R z is methyl, R is H;

Z 1 , Z 2 each are independently selected from C1-C 6 alkyl;

R 3 , R 4 , R 5 each are independently selected from:

1) H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C 6 cycloalkyl;

2) substituted or unsubstituted aryl, the substituents being selected from halogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl;

3) R 3 , R 4 and carbon atoms linked thereto together form

 R 5 being selected from H, or C 1 -C 6 alkyl; and wherein the compound having the general formula (I) does not include

6 . The compound according to claim 1 or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein:

R 1 is selected from:

1)

 wherein:

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each are independently selected from the following groups, and Y 1 , Y 2 , Y 3 , Y 4 ,

Y 5 are not hydrogen at the same time:

H, F, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy, cyclopropylmethylene, benzyl, N-methylpiperazinyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-N,N-dimethylaminopiperidyl 4-(N-methylpiperazinyl-1-)piperidyl, 4-(N-methyl-1-piperazinyl) piperidyl-1-formyl, 2-hydroxyethylamino, 2-N,N-dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, 4-(piperazinyl-1-) piperidyl, N—(N-methyl-4-piperidyl) piperazinyl, 4-(N-methyl-azetidin-3-yl) piperazinyl,

2)

 wherein:

Y 1 , Y 3 , Y 4 , Y 5 each are independently selected from H, ethyl, methoxy, or 4-(N-methylpiperazinyl-1-) piperidyl, and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time,

3)

 wherein, Y 1 is selected from H, methyl, methoxy, F, Cl, or trifluoromethoxy, Y 2 , Y 5 are H, R y is methyl;

4)

 wherein, Y 1 , Y 2 , Y 5 are H, R z , R are methyl;

5) 3-pyrazolyl, 1-ethyl-3-pyrazolyl, 1-isopropyl-3-pyrazolyl, 1,5-dimethyl-3-pyrazolyl, 1-methyl-5-ethyl-3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 1-ethyl-4-pyrazolyl, 1-isopropyl-4-pyrazolyl, 1-ethyl-3-methyl-4-pyrazolyl.

7 . The compound according to claim 1 or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein: R 3 , R 4 , R 5 each are independently selected from H, methyl, cyclopropyl, or phenyl; or, R 3 , R 4 and carbon atoms linked thereto together form

R 5 being H.

8 . The compound according to claim 2 or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from:

1)

 wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each are independently selected from the following groups, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time:

H, F, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy, cyclopropylmethylene, N-methylpiperazinyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-N,N-dimethylaminopiperidyl, 4-(N-methylpiperazinyl-1-) piperidyl, or 4-(N-methyl-1-piperazinyl) piperidyl-1-formyl;

2)

 wherein:

Y 1 , Y 3 , Y 4 , Y 5 each are independently selected from H, ethyl, methoxy, or 4-(N-methylpiperazinyl-1-) piperidyl, and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time.

9 . The compound according to claim 2 or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein: R 3 , R 4 , R 5 are H.

10 . The compound according to claim 3 or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from:

1)

 wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each are independently selected from the following groups, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time:

H, F, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy, cyclopropylmethylene, N-methylpiperazinyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-N,N-dimethylaminopiperidyl, 4-(N-methylpiperazinyl-1-) piperidyl, or 4-(N-methyl-1-piperazinyl) piperidyl-1-formyl;

2)

 wherein:

Y 1 , Y 3 , Y 4 , Y 5 each are independently selected from H, ethyl, methoxy, or 4-(N-methylpiperazinyl-1-) piperidyl, and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time.

11 . The compound according to claim 3 or a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein: R 3 , R 4 , R 5 are H.