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

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, substituted C6-16 heteroarylalkyl, and a chemotherapeutic moiety; at least 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, a carboxylic acid (bio)isostere, hydroxamic acids (—CONR12OH), boronic acids (—B(OH)(OR12), phosphinic acids or derivatives thereof (—PO(OH)R12), and phosphonic acid or derivatives thereof (—PO(OH)(OR12)), sulfinic acid (—SOOH), sulfonic acid (—SO2OH), sulfonamide (—SO2NHR12 or —NHSO2R12), sulfonimide or acyl sulfonimide (—SO2NHCOR12 or —CONHSO2R12), sulfonylureas (—SO2NHCONHR12 or —NHCONHSO2R12), amide (—CONHR12 or —NHCOR12), acylcyanamide (—CONHCN), 2,2,2-trifluoroethan-1-ols (—CH(CF3)OH), 2,2,2-trifluoromethyl ketones and hydrates thereof (—COCF3 and —C(OH)2CF3), acidic heterocycles and annular tautomers of any of the foregoing, and acidic oxocarbocycles or cyclic polyones and resonance forms of any of the foregoing; wherein R12 is selected from hydrogen, C1-6 alkyl, C1-4 fluoroalkyl, C3-6 cycloalkyl, and C6-10 aryl; 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, 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, —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.