Phenethylamines and methods of preparation thereof

A chemical compound of Formula 1, or isotopologue or pharmaceutically acceptable salt thereof:

• wherein:
• R1:
• (i) is selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio, and halogen, if each of R2 and R3 is independently selected from H, CH3, or halogen;
• or (ii) together with R2 form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety;
• or (iii) together with b form an alkanediyl, alkenediyl, or heteroalkanediyl moiety;
• R2:
• (i) is selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio, and halogen, if each of R1 and R3 is independently selected from H, CH3, or halogen;
• or (ii) together with R1 form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety;
• R3:
• (i) is selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio, and halogen, if each of R1 and R2 is independently selected from H, CH3, or halogen;
• or (ii) together with Z form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety;
• wherein:
• one of R4, R5, R6, R7, and R8 is selected from the group consisting of R9, OR9, SR9, S(O)R9, S(O)2R9, N(R9)C(O)R9, N(R9)C(O)OR9, N(R9)C(O)N(H)R9, N(R9)C(O)N(C1-C6 alkyl)R9, N(R9)S(O)2R9, CH2OR9, CH2SR9, CH2S(O)R9, CH2S(O)2R9, CH2N(R9)C(O)R9, CH2N(R9)C(O)OR9, CH2N(R9)C(O)N(H)R9, CH2N(R9)C(O)N(C1-C6 alkyl)R9, CH2N(R9)S(O)2R9, CH═NOR9, C(C1-C6 alkyl)═NOR9, C(O)OR9, C(O)N(H)R9, C(O)N(C1-C6 alkyl)R9, CH2C(O)OR9, CH2C(O)N(H)R9, CH2C(O)N(C1-C6 alkyl)R9, CN, and halogen, a second one of R4, R5, R6, R7 or R8 is selected from the group consisting of H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3, and halogen, and the remainder of R4, R5, R6, R7, and R8 are each independently H, CH3, or halogen;
• or if R4 and R5 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, then each of R6, R7, and R8 is independently selected from the group consisting of H, CH3, and halogen;
• or if R4 and b together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, then one of R5, R6, R7, and R8 is selected from the group consisting of H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3, and halogen, and the remainder of R5, R6, R7, and R8 are each independently selected from the group consisting of H, CH3, and halogen;
• or if R4 and together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, then one of R5, R6, R7, and R8 is selected from the group consisting of H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3, CN, and halogen, and the remainder of R5, R6, R7, and R8 are each independently selected from the group consisting of H, CH3, and halogen;
• wherein:
• X is selected from the group consisting of CN, C(O)NH2, C(O)N(H)R9, C(O)N(C1-C6 alkyl)R9, C(O)(C4-C6 heterocyclyl), CHF2, CF3, OH, O(C1-C6 alkyl), OCHF2, OCF3, S(C1-C6 alkyl), SCF3, SCHF2, F, C, aryl, and heteroaryl generally;
• Y is selected from the group consisting of H, CH3, C(O)R9, CH2OC(O)R9, and C(O)OR9;
• Z:
• (i) is selected from the group consisting of H, C1-C10 alkyl, substituted C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, C2-C10 heteroalkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C3 alkyl), (C3-C6 cycloalkyl)(C1-C3 heteroalkyl), C4-C6 heterocyclyl, (C4-C6 heterocyclyl)(C1-C3 alkyl), (C4-C6 heterocyclyl)(C1-C3 heteroalkyl), aryl(C1-C3 alkyl), aryl(C1-C3 heteroalkyl), heteroaryl(C1-C3 alkyl), heteroaryl(C1-C3 heteroalkyl), C(O)R9, C(O)OR9, CH2OC(O)R9, C(O)NH2, C(O)N(H)R9, C(O)N(C1-C6 alkyl)R9, and C(O)(C4-C6 heterocyclyl);
• or (ii) together with R3 form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety;
• wherein two of a, b, and c are each independently selected from the group consisting of H, CH3, and C2H5, while the third of a, b, and c is H, but if c and R4 together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety then a and b are each independently selected from H or CH3;
• and
• wherein R9 is, independently for each occurrence, selected from the group consisting of H, C1-C6 alkyl, C1-C6 heteroalkyl, substituted C1-C6 alkyl, substituted C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), (C3-C6 cycloalkyl)(C1-C6 heteroalkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), (C3-C6 heterocyclyl)(C1-C6 heteroalkyl), aryl, aryl(C1-C6 alkyl), aryl(C1-C6 heteroalkyl), heteroaryl, heteroaryl(C1-C6 alkyl), and heteroaryl(C1-C6 heteroalkyl).