Epiminocycloalkyl[b] indole derivatives as serotonin sub-type 6 (5-HT6) modulators and uses thereof

A process for preparation of a product compound of formula (I):

• wherein
• n is an integer from 1 to 2;
• and
• R1 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of R1 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR8, —C(O)R8, —C(O)OR8, —C(O)NR8R9, —NHR8, —NR8R9, —SR8, —S(O)R8, —S(O)2R8, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R2 is independently —C(O)R8, —C(O)OR8, —C(O)NR8R9, —S(O)R8, —S(O)2R8, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl;
• R3 and R6 are independently H, halogen, CF3, CHF2, CH2F, OH, OR8, —C(O)R8, —C(O)OR8, —C(O)NR8R9, —O—(CH2)p—C(O)NR8R9, —NHR8, —NR8R9, —SR8, —S(O)R8, —S(O)2R8, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, wherein p is an integer from 0 to 6;
• R4 and R5 are independently H, C1-C6 alkyl, halogen, or R7SO2—;
• R7 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each one of R7 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR8, —C(O)R8, —C(O)OR8, —C(O)NR8R9, —NHR8, —NR8R9, —SR8, —S(O)R8, —S(O)2R8, NH2, CN, NO2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and a mono or polycyclic heteroaryl, each one of substituents optionally substituted from 1 to 3 times with substitutents selected from the group consisting of halogen, H, OH, OR8, —C(O)R8, —C(O)OR8, —C(O)NR8R9, —NHR8, —NR8R9, —SR8, —S(O)R8, —S(O)2R8, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and mono or polycyclic aryl;
• R8 and R9 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur each one of R8 and R9 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl, and a monocyclic heteroaryl;
• or R8 and R9 can combine to form a 4- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and a monocyclic aryl, with the proviso that at least one of R4 and R5, but not both, is R7SO2—;
• or an oxide thereof, or a pharmaceutically acceptable salt thereof said process comprising:
• providing a first intermediate having the structure:
• and
• reacting a first intermediate with an electrophile R1Z under conditions effective to form the compound of formula (I), wherein Z is a leaving group.

A process for resolution of diastereomers comprising:

• providing a mixture of the diastereomers of the compound of formula (II)
• wherein:
• R3 and R6 are independently H, halogen, CF3, CHF2, CH2F, OH, OR8, —C(O)R8, —C(O)OR8, —C(O)NR8R9, —NR8R9, —SR8, —S(O)R8, —S(O)2R8, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl;
• and
• X is independently chloro, bromo, iodo, or triflyl;
• and
• subjecting the mixture to a resolution procedure under conditions effective to separate the diastereomers of the compound of formula (II) from one another.