Use of heterocyclic derivatives with cardiomyocyte proliferation activity for treatment of heart diseases

A method for promoting cardiomyocyte proliferation and/or regeneration of cardiomyocyte in vitro, which comprises a step of:

• contacting cardiomyocyte with a compound, or a pharmaceutically acceptable salt, a solvate, a stereoisomer or a prodrug, thereby promoting cardiomyocyte proliferation and/or regeneration;
• wherein
• the compound has a structure of Formula I:
• wherein
• Lb, ring B1 and La together form
• ring A1 is selected from the group consisting of C3-C10 heterocyclic group, C4-C10 heteroaryl, and C6-C10 aryl, wherein the heterocycle and heteroaryl each have 1-4 heteroatoms selected from N, O, and S;
• ring A2 is
• Rc is selected from the group consisting of halogen, —OH, nitro, cyano, sulfonyl, R″, —N(R″)2—, R″—O—, R″—S—, R″—S(O)2—, R″—S(O)—, R″—C(O), R″—C(O)O—, and R″—OC(O)—;
• wherein each R″ is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, —C1-C4 alkylene-C3-C6 cycloalkyl, —C1-C4 alkylene-C6-C10 aryl, —C1-C4 alkylene-4 to 7-membered heterocycloalkyl, and —C1-C4 alkylene-5 to 7-membered heteroaryl;
• and
• Rd is selected from the group consisting of halogen, R″, and R″—O—;
• wherein each R″ is independently selected from the group consisting of H and C1-C6 alkyl;
• n1 is 1, 2, 3, 4 or 5;
• n2 is 0, 1, or 2;
• or, the compound is selected from the group consisting of:
• or, the compound is selected from the following table:
• Compound ID
• Name
• TJU-B004
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-{[2-(morpholin-4-yl)
• ethyl]amino}-4,5-dihydro-1H-imidazol-5-one
• TJU-B005
• 4-[(2H-1,3-benzodioxol-5-yl)methyl]-2-(phenylamino)-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B006
• (4Z)-4-[(2,3-dihydro-1,4-benzodioxin-6-yl)methylidene]-2-[(4-
• methoxyphenyl)amino]-4,5-dihydro-1H-imidazol-5-one
• TJU-B007
• (4Z)-4-[(2,3-dihydro-1,4-benzodioxin-6-yl)methylidene]-2-(phenylamino)-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B009
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(4-methoxyphenyl)
• amino]-4,5-dihydro-1H-imidazol-5-one
• TJU-B011
• (4Z)-4-[(6-chloro-2H-1,3-benzodioxol-5-yl)methylidene]-2-(phenylamino)-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B013
• (4Z)-4-[1-(2H-1,3-benzodioxol-5-yl)ethylidene]-2-(phenylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B014
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-1-methyl-2-(phenylamino)-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B016
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-1-methyl-2-[(propan-2-yl)
• amino]-4,5-dihydro-1H-imidazol-5-one
• TJU-B019
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(benzylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B021
• (4Z)-2-[(4-aminophenyl)amino]-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B026
• (4Z)-4-[(2,3-dihydro-1,4-benzodioxin-6-yl)methylidene]-2-{[2-(morpholin-4-
• yl)ethyl]amino}-4,5-dihydro-1H-imidazol-5-one
• TJU-B027
• (4Z)-2-[(2H-1,3-benzodioxol-5-yl)amino]-4-[(2H-1,3-benzodioxol-5-yl)
• methylidene]-4,5-dihydro-1H-imidazol-5-one
• TJU-B028
• (4Z)-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-2-
• (phenylamino)-4,5-dihydro-1H-imidazol-5-one
• TJU-B029
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(cyclopropylmethyl)
• amino]-4,5-dihydro-1H-imidazol-5-one
• TJU-B031
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(pyridin-3-yl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B033
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(methylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B034
• (4Z)-2-amino-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B036
• (4Z)-2-amino-4-[(3-methoxyphenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B038
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(propan-2-yl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B039
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-phenyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B040
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(ethylamino)-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B043
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(phenylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B045
• (4Z)-2-amino-1-methyl-4-(phenylmethylidene)-4,5-dihydro-1H-imidazol-5-
• one
• TJU-B049
• (4Z)-2-amino-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B050
• (4Z)-2-amino-4-[(4-fluorophenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B051
• (4Z)-4-[(7-methoxy-2H-1,3-benzodioxol-5-yl)methylidene]-2-(phenylamino)-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B052
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(cyclopropylmethyl)
• amino]-1-methyl-4,5-dihydro-1H-imidazol-5-one
• TJU-B056
• (4Z)-2-amino-4-[(3-chlorophenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B057
• (4Z)-2-amino-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-1-methyl-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B058
• 4-{[(4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-5-oxo-4,5-dihydro-1H-
• imidazol-2-yl]amino} benzonitrile
• TJU-B059
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-cyclopropyl-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B060
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(4-chlorophenyl)amino]-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B063
• (4Z)-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-2-phenyl-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B064
• (4Z)-2-amino-4-[(6-chloro-2H-1,3-benzodioxol-5-yl)methylidene]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B065
• (4Z)-2-amino-4-[(7-methoxy-2H-1,3-benzodioxol-5-yl)methylidene]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B066
• (4Z)-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-2-{[2-
• (morpholin-4-yl)ethyl]amino}-4,5-dihydro-1H-imidazol-5-one
• TJU-B067
• (4Z)-2-amino-4-[(2-fluorophenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B070
• (4Z)-2-amino-4-[(3,4-dimethoxyphenyl)methylidene]-1-methyl-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B085
• (4Z)-4-[(3,4-dimethoxyphenyl)methylidene]-2-(phenylamino)-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B088
• (4Z)-2-[(2H-1,3-benzodioxol-5-yl)amino]-4-[(2H-1,3-benzodioxol-5-yl)
• methylidene]-1-methyl-4,5-dihydro-1H-imidazol-5-one
• TJU-B097
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(pyridin-2-yl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B110
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(4-methylphenyl)
• amino]-4,5-dihydro-1H-imidazol-5-one
• TJU-B253
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(cyclohexylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B254
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(2-methoxyphenyl)
• amino]-4,5-dihydro-1H-imidazol-5-one

A method for treating a cardiovascular disease, which comprises a step of:

• administering a compound or a pharmaceutically acceptable salt, a solvate, a stereoisomer or a prodrug to a subject in need;
• wherein
• the compound has a structure of Formula I:
• wherein
• Lb, ring B1 and La together form
• ring A1 is selected from the group consisting of C3-C10 heterocyclic group, C4-C10 heteroaryl, and C6-C10 aryl, wherein the heterocycle and heteroaryl each have 1-4 heteroatoms selected from N, O, and S;
• ring A2 is
• Rc is selected from the group consisting of halogen, —OH, nitro, cyano, sulfonyl, R″, —N(R″)2—, R″—O—, R″—S—, R″—S(O)2—, R″—S(O)—, R″—C(O), R″—C(O)O—, and R″—OC(O)—;
• wherein each R″ is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, —C1-C4 alkylene-C3-C6 cycloalkyl, —C1-C4 alkylene-C6-C10 aryl, —C1-C4 alkylene-4 to 7-membered heterocycloalkyl, and —C1-C4 alkylene-5 to 7-membered heteroaryl;
• and
• Rd is selected from the group consisting of halogen, R″, and R″—O—;
• wherein R″ is each independently selected from the group consisting of H, C1-C6 alkyl;
• n1 is 1, 2, 3, 4 or 5;
• n2 is 0, 1, or 2;
• or, the compound is selected from the group consisting of:
• or, the compound is selected from the following table:
• Compound ID
• Name
• TJU-B004
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-{[2-(morpholin-4-yl)ethyl]
• amino}-4,5-dihydro-1H-imidazol-5-one
• TJU-B005
• 4-[(2H-1,3-benzodioxol-5-yl)methyl]-2-(phenylamino)-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B006
• (4Z)-4-[(2,3-dihydro-1,4-benzodioxin-6-yl)methylidene]-2-[(4-methoxyphenyl)
• amino]-4,5-dihydro-1H-imidazol-5-one
• TJU-B007
• (4Z)-4-[(2,3-dihydro-1,4-benzodioxin-6-yl)methylidene]-2-(phenylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B009
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(4-methoxyphenyl)amino]-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B011
• (4Z)-4-[(6-chloro-2H-1,3-benzodioxol-5-yl)methylidene]-2-(phenylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B013
• (4Z)-4-[1-(2H-1,3-benzodioxol-5-yl)ethylidene]-2-(phenylamino)-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B014
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-1-methyl-2-(phenylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B016
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-1-methyl-2-[(propan-2-yl)
• amino]-4,5-dihydro-1H-imidazol-5-one
• TJU-B019
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(benzylamino)-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B021
• (4Z)-2-[(4-aminophenyl)amino]-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B026
• (4Z)-4-[(2,3-dihydro-1,4-benzodioxin-6-yl)methylidene]-2-{[2-(morpholin-4-yl)
• ethyl]amino}-4,5-dihydro-1H-imidazol-5-one
• TJU-B027
• (4Z)-2-[(2H-1,3-benzodioxol-5-yl)amino]-4-[(2H-1,3-benzodioxol-5-yl)
• methylidene]-4,5-dihydro-1H-imidazol-5-one
• TJU-B028
• (4Z)-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-2-(phenylamino)-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B029
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(cyclopropylmethyl)amino]-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B031
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(pyridin-3-yl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B033
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(methylamino)-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B034
• (4Z)-2-amino-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B036
• (4Z)-2-amino-4-[(3-methoxyphenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B038
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(propan-2-yl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B039
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-phenyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B040
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(ethylamino)-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B043
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(phenylamino)-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B045
• (4Z)-2-amino-1-methyl-4-(phenylmethylidene)-4,5-dihydro-1H-imidazol-5-one
• TJU-B049
• (4Z)-2-amino-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B050
• (4Z)-2-amino-4-[(4-fluorophenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B051
• (4Z)-4-[(7-methoxy-2H-1,3-benzodioxol-5-yl)methylidene]-2-(phenylamino)-
• 4,5-dihydro-1H-imidazol-5-one
• TJU-B052
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(cyclopropylmethyl)amino]-
• 1-methyl-4,5-dihydro-1H-imidazol-5-one
• TJU-B056
• (4Z)-2-amino-4-[(3-chlorophenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B057
• (4Z)-2-amino-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-1-methyl-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B058
• 4-{[(4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-5-oxo-4,5-dihydro-1H-imid
• azol-2-yl]amino}benzonitrile
• TJU-B059
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-cyclopropyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B060
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(4-chlorophenyl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B063
• (4Z)-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-2-phenyl-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B064
• (4Z)-2-amino-4-[(6-chloro-2H-1,3-benzodioxol-5-yl)methylidene]-4,5-dihydro-
• 1H-imidazol-5-one
• TJU-B065
• (4Z)-2-amino-4-[(7-methoxy-2H-1,3-benzodioxol-5-yl)methylidene]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B066
• (4Z)-4-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-2-{[2-(morpholin-
• 4-yl)ethyl]amino}-4,5-dihydro-1H-imidazol-5-one
• TJU-B067
• (4Z)-2-amino-4-[(2-fluorophenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B070
• (4Z)-2-amino-4-[(3,4-dimethoxyphenyl)methylidene]-1-methyl-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B085
• (4Z)-4-[(3,4-dimethoxyphenyl)methylidene]-2-(phenylamino)-4,5-dihydro-1H-
• imidazol-5-one
• TJU-B088
• (4Z)-2-[(2H-1,3-benzodioxol-5-yl)amino]-4-[(2H-1,3-benzodioxol-5-yl)
• methylidene]-1-methyl-4,5-dihydro-1H-imidazol-5-one
• TJU-B097
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(pyridin-2-yl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B110
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(4-methylphenyl)amino]-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B253
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-(cyclohexylamino)-4,5-
• dihydro-1H-imidazol-5-one
• TJU-B254
• (4Z)-4-[(2H-1,3-benzodioxol-5-yl)methylidene]-2-[(2-methoxyphenyl)amino]-
• 4,5-dihydro-1H-imidazol-5-one