BETA-SUBSTITUTED BETA-AMINO ACIDS AND ANALOGS AS CHEMOTHERAPEUTIC AGENTS

摘要

β-Substituted β-amino acids, β-substituted β-amino acid derivatives, and β-substituted β-amino acid analogs and (bio)isosteres and their use as chemotherapeutic agents are disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres are selective LAT1/4F2hc substrates and exhibit rapid uptake and retention in tumors expressing the LAT1/4F2hc transporter. Methods of synthesizing the β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and methods of using the compounds for treating cancer are also disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs exhibit selective uptake in tumor cells expressing the LAT1/4F2hc transporter and accumulate in cancerous cells when administered to a subject in vivo. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres exhibit cytotoxicity toward several tumor types.

主权项

1. A compound of Formula (1): or a pharmaceutically acceptable salt thereof, wherein: at least one of R1 and R5 is independently selected from halogen, —N(R10)2, —N+(—O−)(R10)2, —N(OR10)(R10), —NO2, —NO, —N(R10)(S(═O)R10), —N(R10)(S(═O)2R10), —N(R10)(C(O)R10), —N(R10)(C(O)OR10), —N(R10)(C(O)N(R10)2, —CN, —COOR10, —CON(R10)2, —OH, —SH, C1-4 alkylsulfanyl, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, —S(O)N(R10)2, —S(O)2N(R10)2, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy, substituted C1-6 alkoxy, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C3-6 cycloalkyloxy, substituted C3-6 cycloalkyloxy, C4-12 cycloalkylalkyl, substituted C4-12 cycloalkylalkyl, C6-10 aryl, substituted C6-10 aryl, C7-16 arylalkyl, substituted C7-16 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C1-6 heteroalkoxy, substituted C1-6 heteroalkoxy, C3-6 heterocycloalkyl, substituted C3-6 heterocycloalkyl, C4-12 heterocycloalkylalkyl, substituted C4-12 heterocycloalkylalkyl, C5-10 heteroaryl, substituted C5-10 heteroaryl, C6-16 heteroarylalkyl, and substituted C6-16 heteroarylalkyl; one of R1, R2, R3, R4, and R5 comprises a chemotherapeutic moiety; each of the other of R1, R2, R3, R4, and R5 is independently selected from hydrogen, deuterio, halogen, —OH, —N(R10)2, —NO2, —NO, —CN, —COOR10, —CON(R10)2, C1-4 alkylsulfanyl, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C1-6 alkoxy, substituted C1-6 alkoxy, C1-6 heteroalkoxy, substituted C1-6 heteroalkoxy, C4-8 cycloalkylalkyl, and C4-8 cycloalkylheteroalkyl; R6 is selected from a carboxylic acid (—COOH), a carboxylic acid analog, and a carboxylic acid (bio)isostere; each R7 is independently selected from hydrogen, deuterio, halogen, hydroxyl, C1-6 alkyl, C3-6 cycloalkyl, benzyl, and phenyl; or two R7 together with the carbon to which they are bonded form a ring selected from a C3-6 cycloalkyl ring and a C3-6 heterocycloalkyl ring; R8 is selected from hydrogen, deuterio, halogen, C1-6 alkyl, substituted C1-6 alkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C1-6 alkoxy, substituted C1-6 alkoxy, C1-6 heteroalkoxy, substituted C1-6 heteroalkoxy, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C3-6 cycloalkyloxy, substituted C3-6 cycloalkyloxy, —OH, —COOR10, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, C3-6 cycloalkyl, and phenyl; each R10 is independently selected from hydrogen, deuterio, C1-4 alkyl and C1-4 alkoxy, or two geminal R10 together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; and L is —(X)a—, wherein,
each X is independently selected from a bond (“—”), —C(R16)2—, wherein each R16 is independently selected from hydrogen, deuterio, halogen, hydroxyl, C1-4 alkyl and C1-4 alkoxy, or two R16 together with the carbon to which they are bonded form a C3-6 cycloalkyl ring or a C3-6 heterocycloalkyl ring, —O—, —S—, —SO—, —SO2—, —CO—, and —N(R17)—, wherein R17 is selected from hydrogen and C1-4 alkyl; anda is selected from 0, 1, 2, 3, and 4.