Substituted naphtho[2,3-b]furans as water-soluble prodrugs for preventing and/or treating cancer

1. A compound represented by formula (1A), or a pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein

A 1 and A 2 are identical or different, and each independently is —C(═O)B, —C(═O)CR 3A R 3B B, —CO 2 B, —C(═S)OB, —CONR 3C B, —C(═S)NR 3C B, —SO 2 B, —SO 2 CR 3A R 3B B, —SO 2 (OB), —SO 2 NR 3C B, —P(═O)(B) 2 , —P(═O)(CR 3A R 3B B) 2 , —P(═O)(OB) 2 , —P(═O)(NR 3C B) 2 , or a hydrogen atom, wherein A 1 and A 2 are not both hydrogen atoms,

wherein

B is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, an optionally substituted 3- to 12-membered cyclic amino group, or a group represented by the following formula (B):

wherein

* denotes a bonding position;

X is a single bond, an optionally substituted C 1-10 alkylene, an optionally substituted C 3-10 cycloalkylene, an optionally substituted 3- to 12-membered monocyclic or a polycyclic heterocycle, a 3- to 12-membered cyclic aminyl linker group, a C 2-10 alkenylene, a C 2-10 alkynylene, a C 6-10 arylene, or a C 5-10 heteroarylene;

Y is a single bond, —O—, —OCO—, —OCO 2 —, —OCONR 4A —, —OSO 2 —, —OSO 2 NR 4A —, —CO—, —CO 2 —, —CONR 4A —, —NR 4A —, —NR 4A CO—, —NR 4A CO 2 —, —R 4A CONR 4B —, —NR 4A SO 2 —, —NR 4A SO 2 O—, —NR 4A SO 2 NR 4B —, —S—, —SO—, —SO 2 —, —SO 2 O—, —SO 2 NR 4A —, or a 3- to 12-membered cyclic aminyl linker group;

R 4A and R 4B are identical or different, and each independently is a hydrogen atom, a C 1-10 alkyl group, a C 3-10 cycloalkyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclic group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 6-10 aryl group, or a C 5-10 heteroaryl group;

Z is a single bond, an optionally substituted C 1-10 alkylene, an optionally substituted C 3-10 cycloalkylene, an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle, a 3- to 12-membered cyclic aminyl linker group, a C 2-10 alkenylene, a C 2-10 alkynylene, a C 6-10 arylene, or a C 5-10 heteroarylene;

n is 0, 1, or 2;

V is —NHR 5 , an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, or an optionally substituted 3- to 12-membered cyclic amino group, wherein the 3- to 12-membered monocyclic or polycyclic heterocyclic group and the 3- to 12-membered cyclic amino group have at least one or more secondary nitrogen atoms in the ring; and

R 5 is a hydrogen atom, an optionally substituted C 1-10 alkyl group, a C 3-10 cycloalkyl group, an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 6-10 aryl group, or a C 5-10 heteroaryl group, and

wherein

the 3- to 12-membered monocyclic or polycyclic heterocyclic group and the 3- to 12-membered cyclic amino group have at least one or more secondary nitrogen atoms in the ring; and

R 3A , R 3B , and R 3C are identical or different, and each independently is a hydrogen atom, an optionally substituted C 1-10 alkyl group, a C 3-10 cycloalkyl group, an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 6-10 aryl group, or a C 5-10 heteroaryl group;

R 1 is a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an amino group, a 3- to 12-membered cyclic amino group, a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a C 6-10 aryl group, a 3- to 12-membered monocyclic or polycyclic heterocyclic group, a C 1-6 alkylcarbonyl group, a C 3-10 cycloalkylcarbonyl group, a C 6-10 arylcarbonyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclylcarbonyl group, a carboxy group, C 1-6 alkoxycarbonyl group, a C 3-10 cycloalkoxycarbonyl group, a C 6-10 aryloxycarbonyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclyloxycarbonyl group, a aminocarbonyl group, a 3- to 12-membered cyclic aminocarbonyl group, a C 1-6 alkylthio group, a C 3-10 cycloalkylthio group, a C 6-10 arylthio group, a 3- to 12-membered monocyclic or polycyclic heterocyclylthio group, a sulfinate group, a C 1-6 alkylsulfinyl group, a C 3-10 cycloalkylsulfinyl group, a C 6-10 arylsulfinyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclylsulfinyl group, a aminosulfinyl group, a 3- to 12-membered cyclic aminosulfinyl group, a sulfonate group, a C 1-6 alkylsulfonyl group, a C 3-10 cycloalkylsulfonyl group, a C 6-10 arylsulfonyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclylsulfonyl group, a aminosulfonyl group, or a 3- to 12-membered cyclic aminosulfonyl group;

R 2A , R 2B , R 2C , and R 2D are identical or different, and each independently is a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a amino group, a 3- to 12-membered cyclic amino group, a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 6-10 aryl group, a 3- to 12-membered monocyclic or polycyclic heterocyclic group, a C 1-6 alkoxy group, a C 3-10 cycloalkoxy group, a C 6-10 aryloxy group, a 3- to 12-membered monocyclic or polycyclic heterocyclyloxy group, a carboxy group, a C 1-6 alkylcarbonyl group, a C 3-10 cycloalkylcarbonyl group, a C 6-10 arylcarbonyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclylcarbonyl group, a C 1-6 alkoxycarbonyl group, a C 3-10 cycloalkoxycarbonyl group, a C 6-10 aryloxycarbonyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclyloxycarbonyl group, an aminocarbonyl group, a 3- to 12-membered cyclic aminocarbonyl group, a C 1-6 alkylthio group, a C 3-10 cycloalkylthio group, a C 6-10 arylthio group, a 3- to 12-membered monocyclic or polycyclic heterocyclylthio group, a sulfinate group, a C 1-6 alkylsulfinyl group, a C 3-10 cycloalkylsulfinyl group, a C 6-10 arylsulfinyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclylsulfinyl group, a aminosulfinyl group, a 3- to 12-membered cyclic aminosulfinyl group, a sulfonate group, a C 1-6 alkylsulfonyl group, a C 3-10 cycloalkylsulfonyl group, a C 6-10 arylsulfonyl group, a 3- to 12-membered monocyclic or polycyclic heterocyclylsulfonyl group, an aminosulfonyl group, or a 3- to 12-membered cyclic aminosulfonyl group; and

R 8 is an optionally substituted C 1-10 alkyl group,

wherein

a substituent of the optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, the optionally substituted 3- to 12-membered cyclic amino group, the optionally substituted C 1-10 alkyl group, the optionally substituted C 1-10 alkylene, and the optionally substituted C 3-10 cycloalkylene, in B, R 3A , R 3B , R 3C , R 5 , R 8 , X, Z, and V is a group optionally substituted with one to five identical or different substituents each independently selected from the group consisting of

(1) a halogen atom,

(9) an optionally substituted C 6-10 aryl group,

(17) —NR 6 R 7 ,

(18) —CO 2 R 6 ,

(20) —CONR 6 R 7 ,

(21) —SO 2 R 6 ,

(22) —SO 2 NR 6 R 7 ,

(24) —OCO 2 R 6 ,

(25) —OCONR 6 R 7 , and

(26) —NR 6 CO 2 R 7

wherein

a substituent in the (9), is a group optionally substituted with one to five identical or different substituents each independently selected from the group consisting of

(a) a halogen atom,

(b) a hydroxy group,

(c) a C 1-6 alkyl group,

(d) a C 1-6 alkoxy group,

(e) a cyano group,

(f) a carboxy group,

(g) a sulfinate group,

(h) a sulfonate group,

(i) a phosphate group,

(i) a C 1-6 alkoxycarbonyl group,

(k) a C 1-6 alkylcarbonyl group,

(l) —NR 6 R 7 ,

(m) —CO 2 R 6

(n) a guanidine group,

(o) —CONR 6 R 7 ,

(p) —SO 2 R 6 ,

(q) —SO 2 NR 6 R 7 ,

(r) a C 6-10 aryl group,

(s) C 5-10 heteroaryl group,

(t) a 3- to 12-membered cyclic amino group optionally substituted with one to three C 1-6 alkyl groups, and

(u) a 3- to 12-membered monocyclic or polycyclic heterocyclic group optionally substituted with one to three C 1-6 alkyl groups, and

R 6 and R 7 are identical or different, and each independently is a hydrogen atom, or a C 1-10 alkyl group optionally substituted with one to two groups selected from the group consisting of a carboxy group, wherein R 6 and R 7 , when both are optionally substituted C 1-10 alkyl groups, may be taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered cyclic amino group.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof,

wherein

A 1 and A 2 are identical or different, and each independently is —C(═O)B, —C(═O)CR 3A R 3B B, —CO 2 B, —CONR 3C B, or a hydrogen atom, wherein A 1 and A 2 are not both hydrogen atoms,

wherein

B is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, an optionally substituted 3- to 12-membered cyclic amino group, or a group represented by the following formula (B):

wherein

* denotes a bonding position;

X is a single bond, an optionally substituted C 1-10 alkylene, or an optionally substituted C 3-10 cycloalkylene;

Y is a single bond, —O—, or —NR 4A —;

R 4A is a hydrogen atom;

Z is a single bond, or an optionally substituted C 1-10 alkylene;

n is 0, or 1;

V is —NHR 5 , an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, or an optionally substituted 3- to 12-membered cyclic amino group, wherein the 3- to 12-membered monocyclic or polycyclic heterocyclic group and the 3- to 12-membered cyclic amino group have at least one or more secondary nitrogen atoms in the ring; and

R 5 is a hydrogen atom, or an optionally substituted C 1-10 alkyl group, and

R 3A , R 3B , and R 3C are identical or different, and each independently a hydrogen atom, or an optionally substituted C 1-10 alkyl group;

R 1 , R 2A , R 2B , R 2C , and R 2D are each independently a hydrogen atom; and

R 8 is an optionally substituted C 1-10 alkyl group.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

A 1 and A 2 are —CONHB,

wherein

B is a 3- to 6-membered monocyclic heterocyclic group or a group represented by the formula (B),

wherein

X is C 1-6 alkylene optionally substituted with one to two substituents selected from the group consisting of a carboxy group and —CO 2 R 6 ,

n is 0,

V is —NHR 5 or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group has at least one or more secondary nitrogen atoms in the ring,

R 5 is a hydrogen atom, or a C 1-6 alkyl group optionally substituted with one to two carboxy groups, and

R 6 is a C 1-6 alkyl group,

wherein

the 3- to 6-membered monocyclic heterocyclic group has at least one or more secondary nitrogen atoms in the ring.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

A 1 and A 2 are identical or different, and each independently is —CO 2 B, —CONR 3C B, or a hydrogen atom, wherein A 1 and A 2 are not both hydrogen atoms.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

A 1 and A 2 are identical or different, and each independently is —CONR 3C B, or a hydrogen atom, wherein A 1 and A 2 are not both hydrogen atoms.

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

wherein

A 1 and A 2 are each independently —CONR 3C B.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof,

wherein

R 8 is a methyl group.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein V is —NHR 5 .

9. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

10. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((3-aminopropyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-aminoethyl)carbamate),

(2S,2′S)-4,4′-((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(2-(methylamino)butanoic acid),

2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid,

3,3′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))dipropionic acid,

(2S,2′S)-3,3′-((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(2-aminopropionic acid),

dimethyl 4,4′-((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))(2 S,2′S)-bis(2-aminobutanoate),

dimethyl 3,3′-((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))(2 S,2′S)-bis(2-aminopropanoate),

2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(propane-3,1-diyl))bis(azanediyl))diacetic acid,

2,2′-((2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))bis(acetyl))bis(azanediyl))diacetic acid,

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(piperidin-1-ylsulfonyl)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(N,N-dimethyl sulfamoyl)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(isopropylsulfonyl)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((3-((2-(N,N-dimethylsulfamoyl)ethyl)amino)propyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((3-((2-(methylsulfonyl)ethyl)amino)propyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(methylsulfonyl)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(azetidin-1-yl)-2-oxoethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((3-((2-(azetidin-1-yl)-2-oxoethyl)amino)propyl)carbamate),

2,2′-((2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(propane-3,1-diyl))bis(azanediyl))bis(acetyl))bis(azanediyl))diacetic acid,

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(carbamoyloxy)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((3-((2-(carbamoyloxy)ethyl)amino)propyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-((methoxycarbonyl)amino)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((3-((2-((methoxycarbonyl)amino)ethyl)amino)propyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-((methoxycarbonyl)oxy)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((3-((2-((methoxycarbonyl)oxy)ethyl)amino)propyl)carbamate),

2-acetyl-4-hydroxynaphtho[2,3-b]furan-9-yl (3-((2-(N,N-dimethylsulfamoyl)ethyl)amino)propyl)carbamate,

2-acetyl-4-hydroxynaphtho[2,3-b]furan-9-yl (3-((2-(methylsulfonyl)ethyl)amino)propyl)carbamate,

(3-((((2-acetyl-4-hydroxynaphtho[2,3-b]furan-9-yl)oxy)carbonyl)amino)propyl)glycylglycine,

2-acetyl-4-hydroxynaphtho[2,3-b]furan-9-yl (3-((2-(azetidin-1-yl)-2-oxoethyl)amino)propyl)carbamate,

2-acetyl-4-hydroxynaphtho[2,3-b]furan-9-yl (3-((2-(carbamoyloxy)ethyl)amino)propyl)carbamate,

2-acetyl-4-hydroxynaphtho[2,3-b]furan-9-yl (3-((2-((methoxycarbonyl)amino)ethyl)amino)propyl)carbamate, and

2-acetyl-4-hydroxynaphtho[2,3-b]furan-9-yl (3-((2-((methoxycarbonyl)oxy)ethyl)amino)propyl)carbamate.

11. A compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:

2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid,

3,3′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))dipropionic acid,

dimethyl 4,4′-((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))(2 S,2′S)-bis(2-aminobutanoate),

2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(propane-3,1-diyl))bis(azanediyl))diacetic acid,

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(N,N-dimethyl sulfamoyl)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(isopropylsulfonyl)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(methylsulfonyl)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(azetidin-1-yl)-2-oxoethyl)amino)ethyl)carbamate)),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-(carbamoyloxy)ethyl)amino)ethyl)carbamate),

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-((methoxycarbonyl)amino)ethyl)amino)ethyl)carbamate), and

2-acetylnaphtho[2,3-b]furan-4,9-diyl bis((2-((2-((methoxycarbonyl)oxy)ethyl)amino)ethyl)carbamate).

12. A compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:

2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid,

3,3′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))dipropionic acid, and

dimethyl 4,4′-((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))(2 S,2′S)-bis(2-aminobutanoate).

13. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid.

14. A compound which is 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid monohydrochloride dihydrate.