Use of benzisoselenazole derivatives for preparing anti-coronavirus medicaments
阅读说明：本技术 苯并异硒唑衍生物用于制备抗冠状病毒药物的用途 (Use of benzisoselenazole derivatives for preparing anti-coronavirus medicaments ) 是由 曾慧慧 尹汉维 于 2020-05-06 设计创作，主要内容包括：本发明提供了式(I)的苯并异硒唑衍生物用于制备抗冠状病毒药物或者治疗由冠状病毒引起的疾病的药物的用途。本发明的苯并异硒唑衍生物能够有效抑制2019-nCoV 3CLpro蛋白水解酶的活性,进而抑制2019-nCoV RNA聚合酶的活化,抑制病毒复制,因此,可有效对抗冠状病毒并治疗由冠状病毒引起的疾病。(The invention provides the use of benzisoselenazole derivatives of formula (I) for the preparation of an anti-coronavirus drug or a drug for the treatment of a disease caused by a coronavirus. The benzisoselenazole derivative can effectively inhibit the activity of 2019-nCoV3CLpro proteolytic enzyme, further inhibit the activation of 2019-nCoV RNA polymerase and inhibit virus replication, so that the benzisoselenazole derivative can effectively resist coronavirus and treat diseases caused by the coronavirus.)
1. Use of a benzisoselenazole derivative for the preparation of a medicament against a coronavirus, or for the treatment of a disease caused by a coronavirus, wherein the benzisoselenazole derivative is a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a prodrug or an active metabolite thereof,
wherein R is selected from hydrogen, cyano, hydroxyl, sulfydryl, halogen, nitro, amino, COOH and SO3H、C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylthio radical, C2-12Alkenyl radical, C1-12Alkylamido radical, C1-12Alkanoyloxy group, 3-to 14-membered heterocyclic group, C6-14Aryl and 5-14 membered heteroaryl; wherein said C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylthio radical, C1-12Alkylamido radical, C1-12Alkanoyloxy group, 3-to 14-membered heterocyclic group, C6-14Aryl and 5-14 membered heteroaryl optionally substituted with one or moreSubstituted with one substituent selected from: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, COOH, SO3H、C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C2-12Alkenyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
p is an integer of 0 to 4;
l is selected from — (CH)2)n-#、*-(CH2)n-NH-(CH2)n-#、*-(CH2)n-NRN-(CH2)n-#、*-(CH2)n-CH(OH)-(CH2)n-#、*-(CH2)n-NH-C(O)-(CH2)n-#、*-(CH2)n-C(O)-NH-(CH2)n-#、*-(CH2)n-O-(CH2)n-#、*-(CH2)n-O-C(O)-(CH2)n-#、*-(CH2)n-C(O)-O-(CH2)n-#、*-(CH2)n-C(O)-(CH2)n-#、*-(CH2)n-C(O)-C(O)-(CH2)n-#、*-(CH2)n-S(O)-(CH2)n-#、*-(CH2)n-S(O)2-(CH2)n-#、*-(CH2)n-C3-8Cycloalkylene- (CH)2)m-#、*-(CH2)n-S-S-(CH2)m-#、*-(CHRL)(CH2)n-S-S-(CH2)m(CHRL)-#、*-(CH2)n-(CHRL)-S-S-(CHRL)-(CH2)m- #, phenylene, biphenylene, triphenylene, phenyl- (CH)2)n-#、*-(CH2)n-phenyl- #, — phenyl- (CH)2)n-phenyl- #, — phenyl- (CH)2)n-S(O)2- # and- (CH)2)n-S(O)2-phenyl- #; wherein denotes the attachment site to the N atom of the benzisoselenazole moiety and # denotes the attachment site to the Q moietyPoint; n is an integer of 0 to 12, m is an integer of 0 to 12, RNIs represented by C1-12Alkyl of RLRepresents halogen, hydroxyl, amino, carboxyl or mercapto;
q is selected from H, C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylthio radical, C1-12Alkylamido radical, C1-12Alkyl acyloxy, C2-12Alkenyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; wherein said C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylamido radical, C1-12Alkanoyloxy group, 3-to 14-membered heterocyclic group, C6-14Aryl, 5-14 membered heteroaryl optionally substituted with one or more substituents selected from: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, COOH, SO3H、C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C2-12Alkenyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
2. The use according to claim 1, wherein in the compound of formula (I),
l is selected from — (CH)2)2-#、*-(CH2)3-#、*-(CH2)4-#、*-(CH2)5-#、*-(CH2)6-#、*-(CH2)7-#、*-(CH2)8-#、*-(CH2)9-#、*-(CH2)10-#、*-(CH2)11-#、*-(CH2)12- #, cyclopentylene, cyclohexylene, phenylene, biphenylene, triphenylene, phenyl- (CH)2)n-#、*-(CH2)n-phenyl- #, — phenyl- (CH)2)n-phenyl- # '(' phenyl-S (O))2-#、*-(CH2)n-S(O)2-phenyl- #, - (CH)2)n-NH-(CH2)n-#、*-(CH2)n-NRN-(CH2)n-#、*-(CH2)n-CH(OH)-(CH2)n-#、*-(CH2)n-NH-C(O)-(CH2)n-#、*-(CH2)n-C(O)-NH-(CH2)n-#、*-(CH2)n-O-(CH2)n-#、*-(CH2)n-O-C(O)-(CH2)n-#、*-(CH2)n-C(O)-O-(CH2)n-#、*-(CH2)n-C(O)-(CH2)n-#、*-(CH2)n-C(O)-C(O)-(CH2)n-#、*-(CH2)n-S(O)-(CH2)n-#、*-(CH2)n-S(O)2-(CH2)n-#、*-(CH2)n-cyclopropylene- (CH)2)m-#、*-(CH2)n-cyclobutylidene- (CH)2)m-#、*-(CH2)n-cyclopentylene- (CH)2)m-#、*-(CH2)n-cyclohexylidene- (CH)2)m-#、*-(CH2)n-S-S-(CH2)m-#、*-(CHRL)(CH2)n-S-S-(CH2)m(CHRL)-#、*-(CH2)n-(CHRL)-S-S-(CHRL)-(CH2)m- #; wherein denotes the attachment site to the N atom of the benzisoselenazole moiety, # denotes the attachment site to the Q moiety; n is 0, 1,2, 3,4, 5 or 6, m is 0, 1,2, 3,4, 5 or 6, RNIs represented by C1-6Alkyl of RLRepresents halogen, hydroxyl, amino, carboxyl or mercapto;
q is selected from H, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl, benzisoselenazolyl, sugar residue, amino acid residue, Re-NH-Rf、 WhereinRepresents a linking group to the L group,
R5and R6Independently of one another, from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COORbAnd SO3Rb；
RbSelected from hydrogen, C1-6Alkyl and C1-6An alkoxy group;
Rcand RdIndependently of one another, from hydrogen, C1-6Alkyl and phenyl; or RcAnd RdTogether with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic or heteroaromatic ring;
Reand RfIndependently of one another, from C1-6Alkyl and C3-7A cycloalkyl group;
said C is1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl radical, C3-7The cycloalkyl, benzisoselenazole, sugar residue, and amino acid residue may be optionally substituted with one or more substituents selected from the group consisting of: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, C1-6Alkyl radical, C3-7Cycloalkyl and C1-6An alkoxy group.
3. The compound according to claim 1 or 2, wherein the benzisoselenazole derivative of formula (I) is a compound of the following formula (I-1):
wherein R, L and p have the definitions given in claim 1 or 2, respectively, for compounds of formula (I);
preferably, the benzisoselenazole derivative of formula (I-1) is selected from the compounds in Table 1 below:
TABLE 1
4. The compound of claim 1 or 2, wherein the benzisoselenazole derivative of formula (I) is a compound of formula (I-2a), formula (I-2b), or formula (I-2 c):
wherein R, L and p have the definitions given in claim 1 or 2, respectively, for compounds of formula (I);
preferably, the benzisoselenazole derivative of formula (I-2a), formula (I-2b), or formula (I-2c) is selected from the compounds in Table 2 below:
TABLE 2
5. The compound according to claim 1 or 2, wherein the benzisoselenazole derivative of formula (I) is a compound of formula (I-3):
wherein R and p have the definitions given in claim 1 or 2, respectively, for compounds of formula (I); and r is an integer from 0 to 12, preferably an integer from 2 to 4.
Preferably, the benzisoselenazole derivative of formula (I-3) is selected from the compounds in Table 3 below:
TABLE 3
6. The compound according to claim 1 or 2, wherein the benzisoselenazole derivative of formula (I) is a compound of formula (I-4):
wherein R is1、R2、R3、R4、R5、R6、R7、R8Separately stand in H, C1-6Alkyl radical, C1-6Alkoxy or halogen; and t is an integer from 1 to 4, preferably 2 or 3;
preferably, the benzisoselenazole derivative of formula (I-4) is selected from the compounds in Table 4 below:
TABLE 4
7. The use according to claim 1 or 2, wherein the benzisoselenazole derivative of formula (I) is a compound of formula (I-5a) or formula (I-5 b):
in the formula (I-5a), R1Selected from hydrogen, halogen, nitrile group, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COOH, -CORb、CONHRb、CONRcRd、SO3R, aryl, heteroaryl, cycloalkyl, heterocyclyl, which groups may optionally be substituted by C1-6Alkyl radical, C1-6Alkoxy, halogen, nitrile, aryl, heteroaryl, preferably by-H, -CH3Halogen, -OAc, -OH, more preferably by-H, -CH3-Cl, -F, -OAc, -OH;
R2is selected from C1-12Alkylene, phenylene, biphenylene, triphenylene, cyclohexylene, cyclopentane, -RaSSRa-、-(RaO)uRa-、-(CH2)(RaO)3Ra-、-RaN(CH3)2Ra-or-RaNHRa-；
RaIs C1-6An alkylene group; rbIs H, C1-6Alkyl radical, C1-6An alkoxy group; rc、RdIndependently selected from H, C1-6Alkyl or phenyl, or Rc、RdForm a nitrogen-containing heterocycle or nitrogen-containing heteroaryl ring with the attached N;
R3selected from-H, phenylcarbonyl, C1-6An alkyloxycarbonyl group;
u is an integer of 0 to 4;
or
In the formula (I-5b), R1' is selected from hydrogen, halogen, nitrile group, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COOH, -CORb、CONHRb、CONRcRd、SO3R, aryl, heteroaryl, cycloalkyl, heterocyclyl, which groups may optionally be substituted by C1-6Alkyl radical, C1-6Alkoxy, halogen, nitrile, aryl, heteroaryl, preferably by-H, -CH3Halogen, -OAc, -OH, more preferably by-H、-CH3-Cl, -F, -OAc, -OH;
R2' selected from C1-12Alkylene, phenylene, biphenylene, triphenylene, cyclohexylene, cyclopentane, -RaSSRa-、-(RaO)uRa-、-(CH2)(RaO)3Ra-、-RaN(CH3)2Ra-or-RaNHRa-；
RaIs C1-6An alkylene group; rbIs H, C1-6Alkyl radical, C1-6An alkoxy group; rc、RdIndependently selected from H, C1-6Alkyl or phenyl, or Rc、RdForm a nitrogen-containing heterocycle or nitrogen-containing heteroaryl ring with the attached N;
R3' is selected from-H, phenylcarbonyl, C1-6An alkyloxycarbonyl group;
u is an integer of 0 to 4;
preferably, the benzisoselenazole derivative of formula (I-5a) or formula (I-5b) is selected from the compounds in Table 5 below:
TABLE 5
8. The use according to claim 1 or 2, wherein the benzisoselenazole derivative of formula (I) is a compound of the following formula (I-6):
wherein R and p have the definitions given in claim 1 or 2, respectively, for compounds of formula (I);
r' is selected from hydrogen and C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6alkyl-OH, Re-NH-Rf、 And a sugar residue;
R5and R6Independently of one another, from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COORbAnd SO3Rb；
RbSelected from hydrogen, C1-6Alkyl and C1-6An alkoxy group;
Rcand RdIndependently of one another, from hydrogen, C1-6Alkyl and phenyl; or RcAnd RdTogether with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic or heteroaromatic ring;
Reand RfIndependently of one another, from C1-6Alkyl and C3-7A cycloalkyl group;
preferably, the sugar residue may be a D-glucopyranosyl group, such as 1,3,4, 6-tetra-O-acetyl-2-deoxy-D-glucopyranosyl group;
more preferably, the benzisoselenazole derivative of formula (I-6) is selected from the compounds in Table 6 below:
TABLE 6
9. Use of a benzisoselenazole derivative of formula (II) for the preparation of a medicament against coronavirus or for the treatment of a disease caused by coronavirus:
wherein R, p and L have the definitions given in claim 1 or 2, respectively, for compounds of formula (I);
R1、R2independently of one another, from C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio orWherein the S atom is singly bonded to the Se atom;
preferably, R1And R2Are all made ofWherein the S atom is singly bonded to the Se atom;
more preferably, the benzisoselenazole derivative of formula (II) is selected from the compounds in table 7 below:
TABLE 7
10. Use of a benzisoselenazole derivative of formula (III) for the preparation of a medicament against a coronavirus or for the treatment of a disease caused by a coronavirus:
wherein R, p and L have the definitions given in claim 1 or 2, respectively, for compounds of formula (I);
R2is selected from C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio orWherein the S atom is singly bonded to the Se atom;
preferably, the benzisoselenazole derivative of formula (III) is a compound in table 8 below:
TABLE 8
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of benzisoselenazole derivatives in preparation of anti-coronavirus medicines.
Background
Coronaviruses belong phylogenetically to the order of the nested viruses (Nidovirales) the family of Coronaviridae (Coronaviridae) the genus coronaviruses (Coronavirus). Viruses of the genus coronavirus are enveloped, single-stranded, positive-stranded, linear-genome RNA viruses, and are a large group of viruses widely found in nature.
The coronavirus is firstly separated from the chicken in 1937, and the virus particles have the diameter of 60-200 nm, the average diameter of 100nm, are spherical or elliptical and have polymorphism. The virus has an envelope, spinous processes exist on the envelope, the whole virus is like coronas, and the spinous processes of different coronaviruses have obvious difference.
2019 novel coronaviruses (2019-nCoV or SARS-CoV-2, causing novel coronavirus pneumonia COVID-19) are the 7 th known coronavirus that can infect humans, and the remaining 6 are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (causing severe acute respiratory syndrome) and MERS-CoV (causing middle east respiratory syndrome), respectively. 2019-nCoV belongs to beta coronavirus, has an envelope, is round or elliptical in particle shape, is usually polymorphic, and has a diameter of 60-140 nm. The gene characteristics are obviously different from SARS-CoV and MERS-CoV. The present research shows that the homology of the strain and the bat SARS-like coronavirus (bat-SL-CoVZC45) reaches more than 85 percent.
2019-nCoV is an RNA virus, the proliferation of which depends on the regeneration of maternal RNA by RNA-dependent RNA polymerase (RdRp), while the 2019-nCoV3CLpro protein is a key protein of the 2019-nCoV key protein RdRp in an active form, and the 2019-nCoV3CLpro protein is assembled into the active RdRp by hydrolyzing viruses pp1a and pp1ab proteins to form a mature product nsp1-16, and the 2019-nCoV3CLpro is considered to be one of the drug targets for treating coronavirus at present.
There is currently a great need for active agents that are effective against coronaviruses, in particular 2019-nCoV.
Disclosure of Invention
The invention provides an application of benzisoselenazole derivatives in preparing anti-coronavirus medicines, wherein the benzisoselenazole derivatives are compounds shown as a formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs or active metabolites thereof,
wherein R is selected from hydrogen, cyano, hydroxyl, sulfydryl, halogen, nitro, amino, COOH and SO3H、C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylthio radical, C2-12Alkenyl radical, C1-12Alkylamido radical, C1-12Alkanoyloxy group, 3-to 14-membered heterocyclic group, C6-14Aryl and 5-14 membered heteroaryl(ii) a Wherein said C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylthio radical, C1-12Alkylamido radical, C1-12Alkanoyloxy group, 3-to 14-membered heterocyclic group, C6-14Aryl and 5-14 membered heteroaryl are optionally substituted with one or more substituents selected from: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, COOH, SO3H、C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C2-12Alkenyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
p is an integer of 0 to 4;
l is selected from — (CH)2)n-#、*-(CH2)n-NH-(CH2)n-#、*-(CH2)n-NRN-(CH2)n-#、*-(CH2)n-CH(OH)-(CH2)n-#、*-(CH2)n-NH-C(O)-(CH2)n-#、*-(CH2)n-C(O)-NH-(CH2)n-#、*-(CH2)n-O-(CH2)n-#、*-(CH2)n-O-C(O)-(CH2)n-#、*-(CH2)n-C(O)-O-(CH2)n-#、*-(CH2)n-C(O)-(CH2)n-#、*-(CH2)n-C(O)-C(O)-(CH2)n-#、*-(CH2)n-S(O)-(CH2)n-#、*-(CH2)n-S(O)2-(CH2)n-#、*-(CH2)n-C3-8Cycloalkylene- (CH)2)m-#、*-(CH2)n-S-S-(CH2)m-#、*-(CHRL)(CH2)n-S-S-(CH2)m(CHRL)-#、*-(CH2)n-(CHRL)-S-S-(CHRL)-(CH2)m- #, phenylene, biphenylene, triphenylene, phenyl- (CH)2)n-#、*-(CH2)n-phenyl- #, — phenyl- (CH)2)n-phenyl- #, — phenyl- (CH)2)n-S(O)2- # and- (CH)2)n-S(O)2-phenyl- #;
wherein denotes the attachment site to the N atom of the benzisoselenazole moiety, # denotes the attachment site to the Q moiety;
n is an integer of 0 to 12, m is an integer of 0 to 12, RNIs represented by C1-12Alkyl of RLRepresents halogen, hydroxyl, amino, carboxyl or mercapto;
q is selected from H, C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylthio radical, C1-12Alkylamido radical, C1-12Alkyl acyloxy, C2-12Alkenyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; wherein said C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C1-12Alkylamido radical, C1-12Alkanoyloxy group, 3-to 14-membered heterocyclic group, C6-14Aryl, 5-14 membered heteroaryl optionally substituted with one or more substituents selected from: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, COOH, SO3H、C1-12Alkyl radical, C3-12Cycloalkyl radical, C1-12Alkoxy radical, C2-12Alkenyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
According to an embodiment of the invention, in the compound of formula (I), R is selected from hydrogen, cyano, hydroxy, mercapto, halogen, nitro, amino, COOH, SO3H、C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl, 3-10 membered heterocyclic group, C6-10Aryl and 5-10 membered heteroaryl; wherein said C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl, 3-10 membered heterocyclic group, C6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, COOH, SO3H、C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C2-6Alkenyl, 3-10 membered heterocyclic group, C6-10Aryl and 5-10 membered heteroaryl;
p is an integer of 0 to 4;
l is selected from — (CH)2)n-#、*-(CH2)n-NH-(CH2)n-#、*-(CH2)n-NRN-(CH2)n-#、*-(CH2)n-CH(OH)-(CH2)n-#、*-(CH2)n-NH-C(O)-(CH2)n-#、*-(CH2)n-C(O)-NH-(CH2)n-#、*-(CH2)n-O-(CH2)n-#、*-(CH2)n-O-C(O)-(CH2)n-#、*-(CH2)n-C(O)-O-(CH2)n-#、*-(CH2)n-C(O)-(CH2)n-#、*-(CH2)n-C(O)-C(O)-(CH2)n-#、*-(CH2)n-S(O)-(CH2)n-#、*-(CH2)n-S(O)2-(CH2)n-#、*-(CH2)n-C3-8Cycloalkylene- (CH)2)m-#、*-(CH2)n-S-S-(CH2)m-#、*-(CHRL)(CH2)n-S-S-(CH2)m(CHRL)-#、*-(CH2)n-(CHRL)-S-S-(CHRL)-(CH2)m- #, phenylene, biphenylene, triphenylene, phenyl- (CH)2)n-#、*-(CH2)n-phenyl- # and [ -phenyl- (CH)2)n-phenyl- #, — phenyl- (CH)2)n-S(O)2- # and- (CH)2)n-S(O)2-phenyl- #; wherein represents a compound represented by formula (I) and benzisoselenazoleThe attachment site of the N atom of the moiety, # denotes the attachment site to the Q moiety; n is an integer of 0 to 12, m is an integer of 0 to 12, RNIs represented by C1-6Alkyl of (A), RLRepresents halogen, hydroxyl, amino, carboxyl or mercapto;
q is selected from H, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl, 3-10 membered heterocyclic group, C6-10Aryl and 5-10 membered heteroaryl; wherein said C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl, 3-10 membered heterocyclic group, C6-10Aryl, 5-10 membered heteroaryl optionally substituted with one or more substituents selected from: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, COOH, SO3H、C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C2-6Alkenyl, 3-10 membered heterocyclic group, C6-10Aryl and 5-10 membered heteroaryl.
According to an embodiment of the invention, in the compound of formula (I), L is selected from — (CH)2)2-#、*-(CH2)3-#、*-(CH2)4-#、*-(CH2)5-#、*-(CH2)6-#、*-(CH2)7-#、*-(CH2)8-#、*-(CH2)9-#、*-(CH2)10-#、*-(CH2)11-#、*-(CH2)12- #, cyclopentylene, cyclohexylene, phenylene, biphenylene, triphenylene, phenyl- (CH)2)n-#、*-(CH2)n-phenyl- #, — phenyl- (CH)2)n-phenyl- # '(' phenyl-S (O))2-#、*-(CH2)n-S(O)2-phenyl- #, - (CH)2)n-NH-(CH2)n-#、*-(CH2)n-NRN-(CH2)n-#、*-(CH2)n-CH(OH)-(CH2)n-#、*-(CH2)n-NH-C(O)-(CH2)n-#、*-(CH2)n-C(O)-NH-(CH2)n-#、*-(CH2)n-O-(CH2)n-#、*-(CH2)n-O-C(O)-(CH2)n-#、*-(CH2)n-C(O)-O-(CH2)n-#、*-(CH2)n-C(O)-(CH2)n-#、*-(CH2)n-C(O)-C(O)-(CH2)n-#、*-(CH2)n-S(O)-(CH2)n-#、*-(CH2)n-S(O)2-(CH2)n-#、*-(CH2)n-cyclopropylene- (CH)2)m-#、*-(CH2)n-cyclobutylidene- (CH)2)m-#、*-(CH2)n-cyclopentylene- (CH)2)m-#、*-(CH2)n-cyclohexylidene- (CH)2)m-#、*-(CH2)n-S-S-(CH2)m-#、*-(CHRL)(CH2)n-S-S-(CH2)m(CHRL)-#、*-(CH2)n-(CHRL)-S-S-(CHRL)-(CH2)m- #; wherein denotes the attachment site to the N atom of the benzisoselenazole moiety, # denotes the attachment site to the Q moiety; n is 0, 1,2, 3,4, 5 or 6, m is 0, 1,2, 3,4, 5 or 6, RNIs represented by C1-6Alkyl of RLRepresents halogen, hydroxyl, amino, carboxyl or mercapto.
According to an embodiment of the invention, in the compound of formula (I), Q is selected from H, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl, benzisoselenazolyl, sugar residue, amino acid residue, Re-NH-Rf、 WhereinRepresents a linking group to the L group,
R5and R6Independently of one another, from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COORbAnd SO3Rb；
RbSelected from hydrogen, C1-6Alkyl and C1-6An alkoxy group;
Rcand RdIndependently of one another, from hydrogen, C1-6Alkyl and phenyl; or RcAnd RdTogether with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic or heteroaromatic ring;
Reand RfIndependently of one another, from C1-6Alkyl and C3-7A cycloalkyl group;
said C is1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamido radical, C1-6Alkyl acyloxy, C2-6Alkenyl radical, C3-7The cycloalkyl, benzisoselenazole, sugar residue, and amino acid residue may be optionally substituted with one or more substituents selected from the group consisting of: cyano, hydroxy, mercapto, halogen, amino, nitro, oxo, thio, C1-6Alkyl radical, C3-7Cycloalkyl and C1-6An alkoxy group.
According to an embodiment of the present invention, the above sugar residue may be a D-glucopyranosyl group, such as 1,3,4, 6-tetra-O-acetyl-2-deoxy-D-glucopyranosyl group.
According to an embodiment of the invention, the above amino acid residue is substituted with a thiol group and further linked to the L moiety through the thiol group.
According to an embodiment of the invention, in the compound of formula (I), R is selected from hydrogen, hydroxy, halogen, COOH, SO3H、C1-6Alkyl and C1-6An alkoxy group.
According to an embodiment of the invention, in the compound of formula (I), R is selected from hydrogen, hydroxy, fluoro, chloro, bromo, iodo, COOH, SO3H. Methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 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.
According to an embodiment of the present invention, the benzisoselenazole derivative of formula (I) is a compound of formula (I-1) below:
wherein R, L and p each independently have the definitions given above for the compounds of formula (I).
According to the present invention, the benzisoselenazole derivative of formula (I-1) is selected from the compounds in Table 1 below:
TABLE 1
In an embodiment of the present invention, the benzisoselenazole derivative of formula (I) is a compound of formula (I-2a), formula (I-2b), or formula (I-2 c):
in the compounds of the above formula (I-2a), formula (I-2b) and formula (I-2c), R, L and p each have the definitions given above for the compounds of formula (I).
According to the present invention, the benzisoselenazole derivative of formula (I-2a), formula (I-2b), or formula (I-2c) is selected from the compounds in Table 2 below:
TABLE 2
In an embodiment of the present invention, the benzisoselenazole derivative of formula (I) is a compound of formula (I-3) below:
wherein R and p each have the definitions given above for the compounds of formula (I);
r is an integer of 0 to 12, preferably an integer of 2 to 4.
According to the present invention, the benzisoselenazole derivative of formula (I-3) is selected from the compounds in Table 3 below:
TABLE 3
In an embodiment of the present invention, the benzisoselenazole derivative of formula (I) is a compound of formula (I-4) below:
wherein R is1、R2、R3、R4、R5、R6、R7、R8Separately stand in H, C1-6Alkyl radical, C1-6Alkoxy or halogen; t is an integer from 1 to 4, preferably 2 or 3.
According to the invention, the benzisoselenazole derivative of formula (I-4) is selected from the compounds of Table 4 below:
TABLE 4
In an embodiment of the present invention, the benzisoselenazole derivative of formula (I) is a compound of formula (I-5a) or formula (I-5 b):
in the formula (I-5a), R1Selected from hydrogen, halogen, nitrile group, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COOH, -CORb、CONHRb、CONRcRd、SO3R, aryl, heteroaryl, cycloalkyl, heterocyclyl, which groups may optionally be substituted by C1-6Alkyl radical, C1-6Alkoxy, halogen, nitrile, aryl, heteroaryl, preferably by-H, -CH3Halogen, -OAc, -OH, more preferably by-H, -CH3-Cl, -F, -OAc, -OH;
R2is selected from C1-12Alkylene, phenylene, biphenylene, triphenylene, cyclohexylene, cyclopentane, -RaSSRa-、-(RaO)uRa-、-(CH2)(RaO)3Ra-、-RaN(CH3)2Ra-or-RaNHRa-；
RaIs C1-6An alkylene group; rbIs H, C1-6Alkyl radical, C1-6An alkoxy group; rc、RdIndependently selected from H, C1-6Alkyl or phenyl, or Rc、RdForm a nitrogen-containing heterocycle or nitrogen-containing heteroaryl ring with the attached N;
R3selected from-H, phenylcarbonyl, C1-6An alkyloxycarbonyl group;
u is an integer of 0 to 4;
or
In the formula (I-5b), R1' is selected from hydrogen, halogen, nitrile group, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COOH, -CORb、CONHRb、CONRcRd、SO3R, aryl, heteroaryl, cycloalkyl, heterocyclyl, which groups may optionally be substituted by C1-6Alkyl radical, C1-6Alkoxy, halogen, nitrile, aryl, heteroaryl, preferably by-H, -CH3Halogen, -OAc, -OH, more preferably by-H, -CH3-Cl, -F, -OAc, -OH;
R2' selected from C1-12Alkylene, phenylene, biphenylene, triphenylene, cyclohexylene, cyclopentane, -RaSSRa-、-(RaO)uRa-、-(CH2)(RaO)3Ra-、-RaN(CH3)2Ra-or-RaNHRa-；
RaIs C1-6An alkylene group; rbIs H, C1-6Alkyl radical, C1-6An alkoxy group; rc、RdIndependently selected from H, C1-6Alkyl or phenyl, or Rc、RdForm a nitrogen-containing heterocycle or nitrogen-containing heteroaryl ring with the attached N;
R3' is selected from-H, phenylcarbonyl, C1-6An alkyloxycarbonyl group;
u is an integer of 0 to 4.
According to the present invention, the benzisoselenazole derivative of formula (I-5a) or formula (I-5b) is selected from the compounds in the following Table 5:
TABLE 5
In an embodiment of the present invention, the benzisoselenazole derivative of formula (I) is a compound of formula (I-6) below:
wherein R and p each have the definitions given above for the compounds of formula (I);
r' is selected from hydrogen and C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6alkyl-OH, Re-NH-Rf、 And a sugar residue;
R5and R6Independently of one another, from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, N (C)1-6Alkyl radical)2、NH(C1-6Alkyl), COORbAnd SO3Rb；
RbSelected from hydrogen, C1-6Alkyl and C1-6An alkoxy group;
Rcand RdIndependently of one another, from hydrogen, C1-6Alkyl and phenyl; or RcAnd RdTogether with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic or heteroaromatic ring;
Reand RfIndependently of one another, from C1-6Alkyl and C3-7A cycloalkyl group.
According to an embodiment of the invention, the sugar residue may be a D-glucopyranosyl group, such as 1,3,4, 6-tetra-O-acetyl-2-deoxy-D-glucopyranosyl group.
According to the present invention, the benzisoselenazole derivative of formula (I-6) is selected from the compounds in Table 6 below:
TABLE 6
The invention also provides the use of a benzisoselenazole derivative of formula (II) below for the preparation of a medicament against coronaviruses:
wherein R, p and L each have the definitions given above for the compounds of formula (I)
R1、R2Independently of one another, from C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio orWherein the S atom is singly bound to the Se atom.
According to an embodiment of the invention, R1And R2Are all made ofWherein the S atom is singly bound to the Se atom.
According to the invention, the benzisoselenazole derivative of formula (II) is selected from the compounds in table 7 below:
TABLE 7
The invention also provides the use of a benzisoselenazole derivative of formula (III) below for the preparation of a medicament against coronaviruses:
wherein R, p and L each have the definitions given above for the compounds of formula (I);
R2is selected from C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio orWherein the S atom is singly bound to the Se atom.
According to the present invention, the benzisoselenazole derivative of formula (III) is a compound in the following table 8:
TABLE 8
According to the invention, the coronaviruses include HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV and 2019-nCoV, in particular 2019-nCoV.
The invention also provides application of the benzisoselenazole derivative shown in the formula (I) in preparing a medicament for treating diseases caused by coronavirus.
According to the invention, the coronaviruses include HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV and 2019-nCoV, in particular 2019-nCoV.
According to the invention, the disease caused by coronavirus includes respiratory diseases, such as upper respiratory diseases and/or lower respiratory diseases, such as acute and chronic infections of the upper and lower respiratory tract.
According to the present invention, the diseases caused by coronavirus include severe acute respiratory syndrome, middle east respiratory syndrome and novel coronavirus pneumonia CODVID-19.
In addition, the present invention provides a method for treating coronavirus infection in a mammal, which comprises administering a therapeutically effective amount of the benzisoselenazole derivative represented by the above formula (I) to the mammal in need thereof.
Advantageous effects
The benzisoselenazole derivative can effectively inhibit the activity of 2019-nCoV3CLpro proteolytic enzyme, further inhibit the activation of 2019-nCoVRNA polymerase, inhibit the replication of viruses and finally eliminate the viruses. Thus, it is effective against coronavirus and diseases caused by coronavirus.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
The term "alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having the indicated number of carbon atoms. For example, "C1-12Alkyl "denotes straight-chain and branched alkyl groups having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a 2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group, or the like, or isomers thereof.
The term "alkoxy" is to be understood as meaning-O-alkyl, wherein alkyl has the above-mentioned definition.
The term "alkylthio" is to be understood as meaning-S-alkyl, wherein alkyl has the above-mentioned definition.
The term "cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having the indicated number of carbon atoms. The term "C3-12Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9, 10, 11 or 12 carbon atoms. Said C is3-12Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.
The term "alkylene" denotes a divalent alkyl group having the indicated number of carbon atoms, e.g. C1-12Alkylene represents divalent C1-12An alkyl group.
The term "alkenyl" is understood to mean a straight-chain or branched monovalent hydrocarbon radical having the indicated number of carbon atoms and one or more olefinic bonds, for example, C2-12Alkenyl, preferably C2-6Alkenyl radicals, e.g. "C2-6Alkenyl "means having 2,3,4, 5, or 6 carbon atoms (i.e., C)2-6Alkenyl) having 2 or 3 carbon atoms (i.e., C)2-3Alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-enyl, m-n-enyl, m-E-4-enyl, m-2-enyl, m-pent-1-enyl, m-2-methyl-enyl, m-2-methylvinyl, m-2-methyl-2-methylvinyl, m-but-2-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z)) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
The term "heterocyclyl" refers to a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring containing the indicated number of ring atoms, e.g. 3 to 14 ring atoms, which contains 1 to 5 heteroatoms independently selected from N, O and S, preferably a "3-to 10-membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.
The term "aryl" is to be understood as a mono-, bi-or tricyclic hydrocarbon ring of a monovalent aromatic or partially aromatic character having the indicated number of carbon atoms, for example 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms, preferably "C6-14Aryl ". The term "C6-10Aryl "is understood to mean preferably having 6, 7, 8, 9Monocyclic, bicyclic or tricyclic hydrocarbon ring of monovalent or partially aromatic character of 10, 11, 12, 13 or 14 carbon atoms ("C)6-14Aryl group "), in particular a ring having 6 carbon atoms (" C6Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C9Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl. When said C is6-14When the aryl group is substituted, it may be mono-or polysubstituted. And, the substitution site thereof is not limited, and may be, for example, ortho-, para-or meta-substitution.
The term "heteroaryl" is to be understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having the indicated number of ring atoms, e.g., 3 to 20 ring atoms, and comprising 1 to 5 heteroatoms independently selected from N, O, S, Se, Te and the like, e.g., "5-14 membered heteroaryl". The term "5-to 14-membered heteroaryl" is to be understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contains 1 to 5, preferably 1 to 3, heteroatoms selected independently from N, O and S, and which, in addition, in each case may be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, benzisoselenazolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The term "oxo" refers to an oxy substitution (═ O) formed by oxidation of a carbon atom, a nitrogen atom or a sulfur atom in a substituent.
The term "thio" refers to a group C ═ S formed by replacement of the oxygen atom in the carbonyl group by a sulfur atom.
Pharmaceutically acceptable salts of the benzisoselenazole derivatives of the present invention include: acid addition salts of said compounds with inorganic or organic acids; the inorganic acid is at least one selected from hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; the organic acid is selected from 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, succinic acid, lauric acid, and mixtures thereof, At least one of D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid;
alternatively, the pharmaceutically acceptable salts of the benzisoselenazole derivatives of the present invention are alkali metal salts, alkaline earth metal salts, ammonium salts thereof, or salts with organic bases that provide physiologically acceptable cations, such as salts with at least one of the following: sodium ions, potassium ions, calcium ions, magnesium ions, 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, 1-amino-2, 3, 4-butanetriol.
The compounds of the invention may be present in the form of solvates, such as hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Depending on their molecular structure, the compounds of the invention may be chiral and may therefore exist in various enantiomeric forms. These compounds may thus be present in racemic or optically active form. The compounds of the invention or intermediates thereof may be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.
Detailed Description
Hereinafter, the use of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
The benzisoselenazole derivatives of the present invention may be prepared by methods known in the art or by methods in the literature. For example, reference may be made to the following preparation methods: the preparation process described in CN106977472A, in particular the preparation processes described in examples 1 to 34; the preparation method described in CN106146371A, in particular the preparation methods described in examples 1 to 5; the preparation process described in CN104119329A, in particular the preparation processes described in examples 1 to 68; the preparation process described in CN102898402A, in particular the preparation processes described in examples 1 to 96; the preparation process described in CN102234254A, in particular the preparation processes described in examples 1 to 13; the preparation method described in CN101921303A, in particular the preparation methods described in examples 1 to 6; the preparation method described in CN101786976A, in particular the preparation method described in example 1; the preparation method described in CN100497324C, in particular the preparation methods described in examples 1 to 9; the preparation method described in CN1990475A, in particular the preparation methods described in examples 1 to 17; the preparation method described in CN1704409A, in particular the preparation methods described in examples 1 to 9; the preparation method described in CN1280279C, in particular the preparation methods described in examples 1 to 12; the preparation method described in CN1242999C, in particular the preparation methods described in examples 1 to 4; the production method described in CN202010287745.6, particularly the production methods of examples 1 to 8. Said documents are incorporated in their entirety into the present application by reference.
2019-nCoV is an RNA virus, the proliferation of which depends on the regeneration of maternal RNA by RNA-dependent RNA polymerase (RdRp), while the 2019-nCoV3CLpro protein is a key protein of the 2019-nCoV key protein RdRp in an active form, and the 2019-nCoV3CLpro protein is assembled into the active RdRp by hydrolyzing viruses pp1a and pp1ab proteins to form a mature product nsp1-16, and the 2019-nCoV3CLpro is considered to be one of the drug targets for treating coronavirus at present. Based on the basic characteristic that the 2019-nCoV3CLpro protein is a proteolytic enzyme, a screening system for detecting the activity of the 2019-nCoV3CLpro protein by a fluorescence method is established. The 2019-nCoV3CLpro protein can specifically cut a substrate with Gln (Q) at the position P1, the activity of the protein can be detected by using a fluorescent polypeptide as the substrate, and the activity of the proteolytic enzyme can be reflected by detecting the generation of a fluorescent signal.
Table 9:
from the above results, it can be seen that the benzisoselenazole derivative of the present invention can effectively inhibit the activity of 2019-nCoV3CLpro protease, and further inhibit the activity of RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication. Thus, it is effective against coronavirus and diseases caused by coronavirus.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
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