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

1. A method for treating at least one cancer in a patient, wherein the at least one cancer is selected from the group consisting of acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, malignant lymphoma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, hepatoma, pancreatic cancer, colon cancer, cervical cancer, malignant melanoma, osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma, comprising administering to a patient in need thereof a therapeutically and prophylactically effective amount of a compound represented by formula (1A):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof,

wherein:

A 1 is H, —C(O)CR 3A R 3B B, —C(O)NR 3C B, —C(O) 2 B, —C(O)B, —C(S)NR 3C B, —C(S)OB, —P(O)(CR 3A R 3B B) 2 , —P(O)(NR 3C B) 2 , —P(O)(OB) 2 , —P(O)(B) 2 , —S(O) 2 CR 3A R 3B B, —S(O) 2 NR 3C B, —S(O) 2 OB, or —S(O) 2 B;

A 2 is H, —C(O)CR 3A R 3B B, —C(O)NR 3C B, —C(O) 2 B, —C(O)B, —C(S)NR 3C B, —C(S)OB, —P(O)(CR 3A R 3B B) 2 , —P(O)(NR 3C B) 2 , —P(O)(OB) 2 , —P(O)(B) 2 , —S(O) 2 CR 3A R 3B B, —S(O) 2 NR 3C B, —S(O) 2 OB, or —S(O) 2 B;

R 1 is H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OH, S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;

R 2A is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;

R 2B is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;

R 2C is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;

R 2D is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;

R 3A is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;

R 3B is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;

R 3C is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;

B is optionally substituted 3- to 12-membered heterocyclyl; or

B is formula (B):

wherein:

X is a single bond, optionally substituted C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, optionally substituted C 3-10 cycloalkylene, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 arylene, or C 5-10 heteroarylene;

Y is a single bond, —C(O)—, —C(O)NR 4A —, —C(O)O—, —NR 4A —, —NR 4A C(O)—, —NR 4A C(O)NR 4B —, —NR 4A C(O)O—, —NR 4A S(O) 2 —, —NR 4A S(O) 2 NR 4B —, —NR 4A S(O) 2 O—, —O—, —OC(O)—, —OC(O)NR 4A —, —OC(O)O—, —OS(O) 2 —, —OS(O) 2 NR 4A —, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 NR 4A —, —S(O) 2 O—, or 3- to 12-membered cyclic aminylene;

R 4A is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;

R 4B is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;

Z is a single bond, optionally substituted C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, optionally substituted C 3-10 cycloalkylene, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 arylene, or C 5-10 heteroarylene;

V is —NHR 5 or optionally substituted 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl has at least one secondary nitrogen atom in the ring;

R 5 is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl, wherein the 3- to 12-membered heterocyclyl has at least one secondary nitrogen atom in the ring;

n is 0, 1, or 2; and

* denotes a bonding position; and

R 8 is optionally substituted C 1-10 alkyl;

wherein in B, R 3A , R 3B , R 3C , R 5 , R 8 , V, X, and Z, the optionally substituted 3- to 12-membered heterocyclyl, C 1-10 alkyl, C 1-10 alkylene, and C 3-10 cycloalkylene is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of halogen, C(O)NR 6 R 7 , C(O)OR 6 , NR 6 R 7 , NR 6 C(O)OR 7 , OC(O)NR 6 R 7 , OC(O)OR 6 , S(O) 2 R 6 , S(O) 2 NR 6 R 7 , and optionally substituted C 6-10 aryl;

wherein in B, R 3A , R 3B , R 3C , R 5 , R 8 , V, X, and Z, the optionally substituted C 6-10 aryl substituent is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NR 6 R 7 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OR 6 , NR 6 R 7 , NH(CNH)NH 2 , OH, OC 1-6 alkyl, OP(O)(OH) 2 , S(O)OH, S(O) 2 R 6 , S(O) 2 NR 6 R 7 , S(O) 2 OH, S(O) 2 OC 1-6 alkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl;

wherein in B, R 3A , R 3B , R 3C , R 5 , R 8 , V, X, and Z, the optionally substituted 3- to 12-membered heterocyclyl is optionally substituted with one, two, or three independently selected C 1-6 alkyl substituents;

R 6 is H or C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or two C(O)OH substituents; and

R 7 is H or C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or two C(O)OH substituents; or

R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 3- to 12-membered cyclic aminyl;

with the proviso that A 1 and A 2 are not both hydrogen atoms.

2. The method according to claim 1 , wherein V is —NHR 5 .

3. The method according to claim 1 , wherein R 8 is CH 3 .

4. The method according to claim 1 , wherein:

A 1 is —C(O)NR 3C B; and

A 2 is —C(O)NR 3C B.

5. The method according to claim 1 , wherein:

A 1 is H or —C(O)NR 3C B; and

A 2 is H or —C(O)NR 3C B.

6. The method according to claim 1 , wherein:

A 1 is H, —C(O)NR 3C B, or —C(O) 2 B; and

A 2 is H, —C(O)NR 3C B, or —C(O) 2 B.

7. The method according to claim 1 , wherein:

A 1 is —C(O)NHB;

A 2 is —C(O)NHB;

B is a monocyclic 3- to 6-membered heterocyclyl; or

B is formula (B):

wherein:

X is C 1-6 alkylene, optionally substituted with one or two independently selected C(O)OR 6 substituents;

V is —NHR 5 or a monocyclic 3- to 6-membered heterocyclyl, wherein the monocyclic 3- to 6-membered heterocyclyl has at least one secondary nitrogen atom in the ring;

R 5 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or two C(O)OH substituents;

n is 0; and

* denotes a bonding position; and

R 6 is C 1-6 alkyl.

8. The method according to claim 1 , wherein:

A 1 is H, —C(O)CR 3A R 3B B, —C(O)NR 3C B, —C(O) 2 B, or —C(O)B;

A 2 is H, —C(O)CR 3A R 3B B, —C(O)NR 3C B, —C(O) 2 B, or —C(O)B;

R 1 is H;

R 2A is H;

R 2B is H;

R 2C is H;

R 2D is H;

R 3A is H or optionally substituted C 1-10 alkyl;

R 3B is H or optionally substituted C 1-10 alkyl;

R 3C is H or optionally substituted C 1-10 alkyl; and

B is optionally substituted 3- to 12-membered heterocyclyl; or

B is formula (B):

wherein:

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

Y is a single bond, —NR′—, or —O—;

R 4A is H;

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

V is —NHR 5 or optionally substituted 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl has at least one secondary nitrogen atom in the ring;

R 5 is H or optionally substituted C 1-10 alkyl;

n is 0 or 1; and

* denotes a bonding position.

9. The method according to claim 1 , wherein the compound, or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, is selected from the group consisting of:

10. The method according to claim 1 , wherein the compound, or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, is selected from the group consisting of:

11. The method according to claim 1 , wherein the compound, or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, is selected from the group consisting of:

12. The method according to claim 1 , wherein the compound, or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, is: