Aryl-fused isoselenazole compound containing tetrazine substituent, synthesis method therefor, and use thereof

1 . An aryl-fused isoselenazole compound containing a tetrazine substituent represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein A 1 , A 2 , A 3 and A 4 are identical or different and are each independently selected from CR and N, with the proviso that no more than one of A 1 , A 2 , A 3 and A 4 is N;

wherein R is selected from hydrogen, cyano, hydroxy, halogen, and nitro, or R is selected from amino, sulfhydryl, amido, alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl and heteroaryl, which are substituted with one or more Ra, each Ra is independently selected from hydrogen, cyano, hydroxy, halogen, amino, nitro, sulfhydryl, alkyl, cycloalkyl, alkoxy, aryl, and heteroaryl; and

R 1 is alkylene.

2 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound has a structure represented by formula (II):

wherein A 1 is selected from CH and N; and n is 1, 2, 3, 4, 5, or 6.

3 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the pharmaceutically acceptable salt is an acid addition salt formed from the compound and an inorganic or organic acid,

the inorganic acid being selected from at least one of hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, and nitric acid, and

the organic acid being selected from at least one of formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, and thiocyanic acid;

or,

the pharmaceutically acceptable salt is an alkali metal salt, alkaline earth metal salt or ammonium salt of the compound, or a salt formed from the compound and an organic base providing physiologically acceptable cations.

4 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:

R is selected from hydrogen, cyano, hydroxy, halogen, and nitro, or from amino, sulfhydryl, amido, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, 3-10 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, which are substituted with one or more Ra, each Ra is independently from each other selected from hydrogen, cyano, hydroxy, halogen, amino, nitro, sulfhydryl, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, 3-10 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl; R 1 is selected from C 1-10 alkylene.

5 . The compound or the pharmaceutically acceptable salt thereof according to claim 4 , wherein:

R is selected from hydrogen, halogen, or from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, phenyl and pyridyl, which are substituted with one or more Ra, each Ra is independently from each other selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, phenyl, and pyridyl; and

R 1 is selected from C 1-6 alkylene.

6 . The compound or the pharmaceutically acceptable salt thereof according to claim 5 , wherein:

R is selected from hydrogen, halogen, C 1-6 alkyl, and C 1-6 alkoxy.

7 . The compound or the pharmaceutically acceptable salt thereof according to claim 6 , wherein:

R is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and isopentoxy.

8 . The compound or the pharmaceutically acceptable salt thereof according to claim 2 , wherein:

R is selected from hydrogen, halogen, C 1-6 alkyl, and C 1-6 alkoxy.

9 . The compound or the pharmaceutically acceptable salt thereof according to claim 8 , wherein:

R is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and isopentoxy.

10 . The compound or the pharmaceutically acceptable salt thereof according to claim 9 , selected from compounds 1 to 8 listed in the following table:

No.

Structure

1

2

3

4

5

6

7

8

11 . The compound or the pharmaceutically acceptable salt thereof according to claim 3 , wherein the pharmaceutically acceptable salt is a salt formed from the compound and at least one selected from sodium ion, potassium ion, calcium ion, magnesium ion, morpholine, piperidine, triethylamine, tripropylamine, tributylamine, diisopropylamine, diisopropylethylenediamine, pyridine, dimethylamine, diethylamine, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, and 1-amino-2,3,4-butanetriol.

12 . A preparation method for the compound according to claim 1 , comprising the following steps:

1) diazotizing an amino group in a compound A, followed by reacting with Na 2 Se 2 to prepare a compound B:

wherein A 1 , A 2 , A 3 , A 4 , R and R 1 have the definitions described in claim 1 ;

2) reacting the compound B with thionyl chloride to prepare a compound C:

3) reacting the compound C with H 2 N—R 1 —NHBoc to prepare a compound D:

wherein Boc represents tert-butyloxycarbonyl;

4) deprotection of the Boc protective group of the compound D in the presence of an acid to prepare a compound E:

and

5) reacting the compound E with a compound F to prepare the compound represented by formula (I):

wherein in the compound F, R 2 is selected from chlorine, bromine, hydroxy, and —OR 3 , wherein R 3 is selected from C 1-6 alkyl, succinimidyl, tert-butyloxycarbonyl, methylsulfonyl, p-nitrobenzenesulfonyl, p-toluenesulfonyl, and isobutyloxycarbonyl.

13 . The preparation method according to claim 12 , characterized in that, the compound F is commercially available or can be obtained by using a conventional method in the art, or is prepared through the following steps:

a) allowing compound TMZ (i.e. temozolomide) to react under the action of sulfuric acid and sodium nitrite to give a compound F-1:

and optional step b): reacting the compound F-1 with thionyl chloride or dibromosulfoxide in the presence of a catalytic amount of DMF to give a compound F-2:

or optional step c): allowing the compound F-1 to further react to give the compound F in which R 2 is —OR 3 , wherein R 3 is C 1-6 alkyl, succinimidyl, tert-butoxycarbonyl, methanesulfonyl, p-nitrobenzenesulfonyl, p-toluenesulfonyl, or isobutyloxycarbonyl;

step c) is selected from step c-1), step c-2), step c-3), step c-4) and step c-5) below;

step c-1): reacting the compound F-1 with R 4 OH under the action of an acid to give a compound F-3:

wherein R 4 is C 1-6 alkyl;

step c-2): reacting the compound F-1 with R 5 Cl under the action of a base to give a compound F-4:

wherein R 5 is methylsulfonyl, p-nitrobenzenesulfonyl or p-toluenesulfonyl;

step c-3): reacting the compound F-1 with N-hydroxysuccinimide to give a compound F-5:

step c-4): reacting the compound F-1 with di-tert-butyl dicarbonate to give a compound F-6

and

step c-5): reacting the compound F-1 with isobutyl chloroformate to give a compound F-7:

14 . A pharmaceutical composition, wherein the pharmaceutical composition comprises the compound or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

15 . The pharmaceutical composition according to claim 14 , wherein the compound or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable sustained/controlled-release carrier can be prepared into a sustained/controlled-release preparation according to a conventional preparation method for sustained/controlled-release preparations.

16 . The pharmaceutical composition according to claim 14 , wherein the pharmaceutical composition is suitable for enteral, topical or parenteral administration.

17 . The pharmaceutical composition according to claim 16 , wherein the pharmaceutical composition is administrated by oral administration, injection, implantation, topical application, spray, or inhalation.

18 . The pharmaceutical composition according to claim 17 , wherein the pharmaceutical composition is administrated by oral administration, the oral pharmaceutical composition in the form of a tablet, a capsule, a pill, an oral liquid preparation, granules, an injection, a topical preparation, or a powder.

19 . A method for treating a tumor, comprising administrating the compound or the pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof, wherein the tumor is selected from brain glioma, liver cancer, and pancreatic cancer.