Preparation method for aromatic heterocyclic compound used as selective JAK3 and/or JAK1 kinase inhibitor and application of aromatic heterocyclic compound

1. A compound of general formula (I),

or a pro-drug, stereoisomer, pharmaceutically acceptable salt or hydrate thereof,

wherein,

R 1 is halogen or C1-C6 alkyl;

R 2 is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylcarbonyl and C1-C6 alkylamino;

R 3 is hydrogen or halogen;

R 4 is hydrogen or C1-C4 alkyl;

X is NH, O or S;

Y is CO or S(O) 2 ;

Z is a covalent bond, CH 2 or (CH 2 ) 2 ;

n is an integer from 1 to 4; and

Ring A is a benzene ring, pyridine ring or piperidine ring.

2. The compound of general formula (I) according to claim 1 , wherein:

R 1 is halogen or C1-C6 alkyl;

R 2 is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, methyl, ethyl, methoxyl, difluoromethyl, trifluoromethyl, acetyl and dimethylamino;

R 3 is hydrogen or halogen;

R 4 is hydrogen or methyl;

X is NH or 0;

Y is CO or S(O) 2 ;

Z is a covalent bond, CH 2 or (CH 2 ) 2 ;

n is an integer from 1 to 4; and

Ring A is a benzene ring, pyridine ring or piperidine ring.

3. The compound of general formula (I) according to claim 1 , wherein:

R 1 is halogen or C1-C6 alkyl;

R 2 is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, methyl, ethyl, methoxyl, difluoromethyl, trifluoromethyl, acetyl and dimethylamino;

R 3 is hydrogen or fluoro;

R 4 is methyl;

X is NH;

Y is CO;

Z is a covalent bond;

n is an integer from 1 to 4; and

Ring A is a benzene ring, pyridine ring.

4. The compound of general formula (I) according to claim 1 , wherein:

R 1 is chloro, fluoro or methyl;

R 2 is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, methyl, ethyl, methoxyl, difluoromethyl, trifluoromethyl, acetyl and dimethylamino;

R 3 is hydrogen or fluoro;

R 4 is methyl;

X is NH;

Y is CO;

Z is a covalent bond;

n is an integer from 1 to 4; and

Ring A is a benzene ring.

5. The compound of general formula (I) according to claim 1 , wherein:

R 1 is chloro;

R 2 is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, methyl, ethyl, methoxyl, difluoromethyl, trifluoromethyl, acetyl and dimethylamino;

R 3 is hydrogen or fluoro;

R 4 is methyl;

X is NH;

Y is CO;

Z is a covalent bond;

n is an integer from 1 to 4; and

Ring A is a benzene ring.

6. The compound of general formula (I) according to claim 1 , wherein:

R 1 is chloro;

R 2 is one or more substituents selected from the group consisting of cyano, fluoro and trifluoromethyl;

R 3 is hydrogen or fluoro;

R 4 is methyl;

X is NH;

Y is CO;

Z is a covalent bond;

n=1; and

Ring A is a benzene ring.

7. The compound of general formula (I) according to claim 1 , wherein:

R 1 is chloro;

R 2 is one or more substituents selected from the group consisting of cyano;

R 3 is hydrogen or fluoro;

R 4 is methyl;

X is NH;

Y is CO;

Z is a covalent bond;

n=1; and

Ring A is a benzene ring.

8. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-cyanobenzamide;

N-(3-(2-(3-acrylamido-4-fluoro-phenylamino)-5-chloropyrimidinyl-4-amino)propyl)-4-trifluoromethylbenzamide;

N-(3-(2-(3-acrylamido-4-fluoro-phenylamino)-5-chloropyrimidinyl-4-amino)propyl)-4-fluorobenzamide;

4-fluoro-N-(3-(2-(4-fluoro-3-(N-methylacrylamido)phenylamino)-5-methylpyrimidinyl-4-amino)propyl)benzamide;

N-(3-(2-(4-fluoro-3-(N-methylacrylamido)phenylamino)-5-methylpyrimidinyl-4-amino)propyl)-4-trifluoromethylbenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-trifluoromethylbenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-fluorobenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-1-methylpiperidinyl-4-formamide;

N-(3-(2-(3-acrylamido-4-fluorophenylamino)-5-chloropyrimidinyl-4-amino)propyl)-4-cyanobenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-dimethylaminobenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-2,4,6-trifluorobenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-methoxylbenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-6-cyanonicotinamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-hydroxybenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-cyano-2-fluorobenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-cyano-3-fluorobenzamide;

4-cyano-N-(3-(2-(4-fluoro-3-(N-methylacrylamido)phenylamino)-5-methylpyrimidinyl-4-amino)propyl)-benzamide;

4-cyano-N-(3-(5-fluoro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)benzamide;

N-(5-(5-chloro-4-(3-(2-(4-cyanophenyl)acetamino)propylamino)pyrimidinyl-2-amido)-2-fluorophenyl)-N-methylacryloyl;

N-(5-(5-chloro-4-(3-(4-cyanophenylsulfonamino)propylamino)pyrimidinyl-2-amido)-2-fluorophenyl)-N-methylacryloyl;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-oxo)propyl)-4-cyanobenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-isonicotinamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-ethylbenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-methylbenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)benzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-3-trifluoromethylbenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-3-cyanobenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-3-fluoro-4-trifluoromethylbenzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-2,3,4,5-tetrafluorobenzamide;

4-acetyl-N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)benzamide;

N-(3-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)propyl)-4-difluoromethylbenzamide; and

N-(6-(5-chloro-2-(4-fluoro-3-(N-methylacrylamido)phenylamino)pyrimidinyl-4-amino)hexyl)-4-cyanobenzamide.

9. A method for preparing the compound of general formula (I) according to claim 1 , comprising reacting a compound of general formula (IV)

with a compound of general formula (V)

under organic solvent and a catalyst to form the compound of general formula (I), wherein

R 1 is halogen or C1-C6 alkyl;

R 2 is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylcarbonyl and C1-C6 alkyl amino;

R 3 is hydrogen or halogen;

R 4 is hydrogen or C1-C4 alkyl;

X is NH, O or S;

Y is CO or S(O) 2 ;

Z is a covalent bond, CH 2 or (CH 2 ) 2 ;

n is an integer from 1 to 4; and

ring A is a benzene ring, pyridine ring or piperidine ring.

10. The preparation method according to claim 9 , wherein the catalyst is selected from the group consisting of trifluoroacetic acid, hydrochloric acid and methanesulfonic acid.

11. The preparation method according to claim 9 , wherein the organic solvent is selected from the group consisting of isopropanol and n-butanol.

12. A method for preparing a compound of general formula (IV),

comprising reacting a compound of general formula (III)

with a compound of general formula (II)

under organic solvent and an alkali to form the compound of general formula (IV), wherein

R 1 is halogen or C1-C6 alkyl;

R 2 is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylcarbonyl and C1-C6 alkyl amino;

X is NH or O;

Y is CO or S(O) 2 ;

Z is a covalent bond, CH 2 or (CH 2 ) 2 ;

n is an integer from 1 to 4; and

ring A is a benzene ring, pyridine ring or piperidine ring.

13. The preparation method according to claim 12 , wherein the alkali is selected from the group consisting of triethylamine and diisopropylethylamine.

14. The preparation method according to claim 9 , wherein the organic solvent is selected from the group consisting of ethanol, methanol and n-butanol.

15. A pharmaceutical composition comprising the compound of general formula (I) according to claim 1 as the active ingredient and a pharmaceutically acceptable carrier, adjuvant or diluent.

16. The pharmaceutical composition according to claim 15 , which is in the form of tablet, capsule, powder, syrup, liquor, suspension, injection or ointment.

17. A method of treating a disease related to abnormal activities of JAK3 and/or JAK1 kinases in a human patient, comprising administering the human patient the compound according to claim 1 , wherein the disease related to abnormal activities of JAK3 and/or JAK1 kinases is selected from the group consisting of autoimmune diseases, cancers, bone resorption diseases graft-versus-host diseases.

18. A method of treating a disease related to abnormal activities of JAK3 and/or JAK1 kinases in a human patient, comprising administering the human patient the compound according to claim 1 , wherein the disease related to abnormal activities of JAK3 and/or JAK1 kinases is selected from the group consisting of psoriasis, systemic lupus erythematosus, multiple sclerosis, type I diabetes, leukaemia, and lymphoma.

19. A method of treating a disease related to abnormal activities of JAK3 and/or JAK1 kinases in a human patient, comprising administering the human patient the pharmaceutical composition according to claim 15 , wherein the disease related to abnormal activities of JAK3 and/or JAK1 kinases is selected from the group consisting of autoimmune diseases, cancers, bone resorption diseases and graft-versus-host diseases.

20. A method of treating a disease related to abnormal activities of JAK3 and/or JAK1 kinases in a human patient, comprising administering the human patient the pharmaceutical composition according to claim 15 , wherein the disease related to abnormal activities of JAK3 and/or JAK1 kinases is selected from the group consisting of rheumatoid arthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis, type I diabetes, leukaemia, and lymphoma.

21. The pharmaceutical composition according to claim 16 , wherein the formulation thereof has a unit dosage ranging from 0.0001 to 200 mg.