Heterocyclic compounds and methods of preparation thereof

A chemical compound of Formula I:

• wherein:
• R1:
• (i) is selected from the group consisting of H and C1-C6 alkyl;
• or (ii) together with R2 form a chain of 2 to 4 carbon atoms to which are attached substituents independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof;
• R2:
• (i) is selected from the group consisting of C1-C6 alkyl, aryl, heteroaryl, CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(═NOH)(C1-C6 alkyl), and C(═NOH)(C1-C6 substituted alkyl);
• or (ii) together with R1 form a chain of 2 to 4 carbon atoms to which are attached substituents independently selected from the group consisting of H, C1-C6 alkyl, aryl, and heteroaryl;
• or (iii) together with b form a chain of 3 or 4 atoms, one atom of which is selected from the group consisting of C, N, and O, while the remainder are carbon, which chain contains 0, 1, or 2 double bonds, and to which chain are attached substituents independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 substituted alkyl, CF3, and cyano;
• or (iv) is selected from the group consisting of H and C1-C6 alkyl, if b is halogen, CHF2, CF3, OCH3, or OCHF2;
• a:
• (i) is selected from the group consisting of H and halogen;
• or (ii) together with Z form one of (A) a saturated chain of one oxygen and one carbon atom with oxygen connected to the 5-position of the indole ring of Formula I, and (B) a chain of 2 or 3 carbon atoms, to which chain are attached substituents independently selected from the group consisting of H and halogen, and (C) a chain of 2 or 3 carbon atoms containing one double bond;
• b:
• (i) is selected from a group consisting of H, halogen, CH3, CHF2, CF3, OCH3, and cyano;
• or (ii) together with R2 form a chain of 3 or 4 atoms, one atom of which is selected from the group consisting of C, N, and O, while the remainder are carbon, which chain contains 0, 1, or 2 double bonds, and to which chain are attached substituents independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, CF3, and cyano;
• R3:
• (i) is selected from the group consisting of H and C1-C6 alkyl;
• or (ii) together with R4 and the N atom to which they are attached form a 4-7 membered heterocyclyl ring;
• or (iii) together with f and the N atom to which R3 is attached form an azetidine or pyrrolidine ring;
• and
• R4:
• (i) is selected from the group consisting of H and C1-C6 alkyl;
• or (ii) together with R3 and the N atom to which they are attached form a 4-7 membered heterocyclyl ring;
• wherein:
• c, d, e, and f are each H;
• or three of c, d, e, and f are H and the remaining substituent is a lower alkyl group;
• or c and f are each H, and d and e together are —CH2— or —CH2CH2—, thereby giving rise to a cyclopropane or cyclobutane ring;
• or c, d, and e are each H, and f, R3, and the N atom to which R3 is attached form together an azetidine or pyrrolidine ring, such ring carrying substituents independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl;
• or d, e, and f are each H, and c, R3, and the N atom to which R3 is attached form together an azetidine or pyrrolidine ring, such ring carrying substituents independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
• or d, e, and f are each H, and c and Z together comprise 1 or 2 carbon atoms so as to give rise to a pyran or oxepan ring, such ring carrying substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
• and
• wherein:
• Z:
• (i) is selected from the group consisting of H, R5, (R6)(R7)N—C(O)—, C1-C6 alkyl-C(O), C3-C6 cycloalkyl-C(O), aryl-C(O), and heteroaryl-C(O), wherein R5 is selected from the group consisting of C1-C6 alkyl, and wherein R6 and R7 are each independently selected from the group consisting of H and C1-C4 alkyl;
• or (ii) is (R8O)(R9O)P(O)—, wherein R8 and R9 are each independently H or a cationic counterion of a phosphate salt form;
• or (iii) together with c form a linkage that gives rise to a pyran or oxepan ring;
• or (iv) together with a form one of (A) a saturated chain of one oxygen and one carbon atom (with oxygen connected to the 5-position of the indole ring of Formula I), and (B) a chain of 2 or 3 carbon atoms, and (C) a chain of 2 or 3 carbon atoms containing one double bond;
• and
• any isotopologue and any pharmaceutically acceptable salt thereof.

A chemical compound of Formula II:

• wherein:
• R1:
• (i) is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 substituted alkyl;
• or (ii) together with R2 form a chain of 2 to 4 carbon atoms;
• R2:
• (i) is selected from the group consisting of C1-C6 alkyl;
• or (ii) together with R1 form a chain of 2 to 4 carbon atoms;
• or (iv) is selected from the group consisting of H and C1-C6 alkyl, if b is halogen, CHF2 or CF3;
• a:
• (i) is selected from the group consisting of H and halogen;
• or (ii) together with Z form one of (A) a saturated chain of one oxygen and one carbon atom, and (B) a chain of 2 or 3 carbon atoms, to which chain are attached substituents independently selected from the group consisting of H and halogen, and (C) a chain of 2 or 3 carbon atoms containing one double bond;
• b is selected from a group consisting of H, halogen, CHF2, and CF3;
• R3:
• (i) is selected from the group consisting of H and C1-C6 alkyl;
• or (ii) together with R4 and the N atom to which they are attached form a 4-7 membered heterocyclyl ring;
• or (iii) together with f and the N atom to which R3 is attached form an azetidine or pyrrolidine ring;
• or (iv) together with d form a —CH2CH2— linkage, or —CH2— linkage;
• R4:
• (i) is selected from the group consisting of H, C1-C6 alkyl, cyclopropyl, phenyl, and substituted phenyl;
• or (ii) together with R3 and the N atom to which they are attached form a 4-7 membered heterocyclyl ring;
• or (iii) together with f form a —CH2CH2— linkage;
• c, d, e, and f are each H;
• or three of c, d, e, and f are H and the remaining substituent is a lower alkyl group;
• or c and f are each H, and d and e together are —CH2— or —CH2CH2—, thereby giving rise to a cyclopropane or cyclobutane ring;
• or c, d, and e are each H, and f, R3, and the N atom to which R3 is attached form together an azetidine or pyrrolidine ring;
• or d, e, and f are each H, and c and a together are —CH2CH2—, —CH2CH2CH2—, or —CH2OCH2—;
• and
• Z:
• (i) is selected from the group consisting of H, phenyl, —OOCC(CH3)3, acetyl, —C(O)N(H)-i-Pr, —C(O)NMe2;
• or (ii) is (R8O)(R9O)P(O)—, wherein R8 and R9 are each independently H or a cationic counterion of a phosphate salt form;
• or (iii) together with a form a —CH2CH2— linkage, —CH(Me)CH2— linkage, —CH2CH2CH2-linkage, or —CH═CH— linkage;
• and
• any isotopologue and any pharmaceutically acceptable salt thereof.

A chemical compound of Formula III:

• wherein:
• R2 and X form a —OCH2CH2— linkage, a —OCH2CH2CH2— linkage, a —SCH2CH2— linkage, or a —SCH2CH2CH2— linkage;
• a, b, c, d, e, and f are each H;
• and
• R3 and R4 are each methyl;
• and
• any isotopologue and any pharmaceutically acceptable salt thereof.